Extensive differential gene expression and regulation by sex in human skeletal muscle

Abstract: The identification of sex-differential gene regulatory elements is essential for understanding sex-differential patterns of health and disease. We leveraged bulk and single-nucleus RNA sequencing (RNA-seq) and single-nucleus ATAC-seq data from 281 skeletal muscle biopsies to characterize sex differences in gene expression and regulation at the cell-type and whole-tissue levels. We found highly concordant sex-biased expression of over 2,100 genes across the three muscle fiber types and bulk tissue. Gene pathways related to mitochondrial activity and energy metabolism were enriched for male-biased expression, whereas those related to signal transduction and cell differentiation were enriched for female-biased expression. We found widespread sex-biased chromatin accessibility enriched in proximal and distal gene regulatory states; in gene promoters, sex-biased chromatin accessibility was positively associated with sex-biased expression. Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) also showed extensive sex-biased expression in the fiber-type and bulk data, respectively. Together, these results highlight nuclear and cytoplasmic mechanisms for sex-differential gene regulation in skeletal muscle.

Hanks SC
Mauger AS
Varshney A
Ciotlos DL
Manickam N
Narisu N
Shumway AJ
Orchard P
Erdos MR
Sweeney MD
Okamoto J
Jackson AU
Stringham HM
Bonnycastle LL
Zhou X
Lakka TA
Mohlke KL
Tuomilehto J
Laakso M
Boehnke M
Sethupathy P
Collins FS
Koistinen HA
Parker SCJ
Scott LJ

Humans
Male
Female
Muscle, Skeletal
RNA, Long Noncoding
Gene Expression Regulation
MicroRNAs
Sex Characteristics
Chromatin
Sex Factors


Hutchinson-Gilford Progeria Syndrome

Adam MP
Bick S
Mirzaa GM
Pagon RA
Wallace SE
Amemiya A
Gordon LB
Brown WT
Collins FS


Adipose tissue eQTL meta-analysis highlights the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits

Abstract: Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. In the present study, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34,774 conditionally distinct expression quantitative trait locus (eQTL) signals at 18,476 genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared with primary eQTL signals, nonprimary eQTL signals had lower effect sizes, lower minor allele frequencies and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTLs with genome-wide association study (GWAS) signals for 28 cardiometabolic traits identified 1,835 genes. Inclusion of nonprimary eQTL signals increased discovery of colocalized GWAS-eQTL signals by 46%. Furthermore, 21 genes with ≥2 colocalized GWAS-eQTL signals showed a mediating gene dosage effect on the GWAS trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.

Brotman SM
El-Sayed Moustafa JS
Guan L
Broadaway KA
Wang D
Jackson AU
Welch R
Currin KW
Tomlinson M
Vadlamudi S
Stringham HM
Roberts AL
Lakka TA
Oravilahti A
Fernandes Silva L
Narisu N
Erdos MR
Yan T
Bonnycastle LL
Raulerson CK
Raza Y
Yan X
Parker SCJ
Kuusisto J
Pajukanta P
Tuomilehto J
Collins FS
Boehnke M
Love MI
Koistinen HA
Laakso M
Mohlke KL
Small KS
Scott LJ

Quantitative Trait Loci
Humans
Genome-Wide Association Study
Gene Expression Regulation
Polymorphism, Single Nucleotide
Alleles
Adipose Tissue
Genetic Heterogeneity
Gene Frequency
Male
Cardiovascular Diseases

Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural


Normal Bone Matrix Mineralization but Altered Growth Plate Morphology in the Lmna(G609G/G609G) Mouse Model of Progeria

Abstract: Hutchison-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by a mutation in LMNA, the gene encoding A-type lamins, leading to premature aging with severely reduced life span. HGPS is characterized by growth deficiency, subcutaneous fat and muscle issues, wrinkled skin, alopecia, and atherosclerosis. Patients also develop a bone phenotype with reduced bone mineral density, osteolysis and striking demineralization of long bones. To further clarify the tissue modifications in HGPS, we characterized bone mineralization in the LmnaG609G/G609G progeria mouse model. Femurs from 8-week-old mice and humeri from 15-week-old mice were analyzed using quantitative backscattered electron imaging to assess bone mineralization density distribution, osteocyte lacunae sections and structural bone histomorphometry. Tissue sections were stained with Giemsa and Goldner trichrome for histologic evaluation. Bone tissue from Lmna+/+ and LmnaG609G/G609G mice had similar mineral content at 3 different bone sites with specific tissue ages. The osteocyte lacunae features were not statistically different, but more empty lacunae were found in LmnaG609G/G609G at both animal ages. Bone histomorphometry and histology demonstrated decreased bone volume per tissue volume in primary (8W: -23%, p=0.001; 15W: -38%, p=0.002) and secondary spongiosa (8W: -36%, p=0.001; 15W: -49 %, ns), as well as growth plate dysplasia with thinner unmineralized resting and proliferative zones in the LmnaG609G/G609G mice versus controls (8W: -18%, p=0.006; 15W: -25%, p=0.001). Overall, the LmnaG609G/G609G mouse develops chondrodysplasia with reduced trabecular bone volume. Mineral content findings at several tissue sites and ages suggest that bone dysplasia results from impaired bone formation with normal bone turnover.

Blouin S
Hartmann MA
Fratzl-Zelman N
Messmer P
Whisenant D
Erdos MR
Collins FS
Eriksson M
Strandgren C
Cabral WA
Dechat T

Animals
Progeria
Disease Models, Animal
Mice
Lamin Type A
Growth Plate
Calcification, Physiologic
Bone Matrix
Bone Density
Male

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural


Characterization of the craniofacial abnormalities of the homozygous G608G progeria mouse model

Abstract: Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by premature aging, impacting multiple organ systems, including cardiovascular, musculoskeletal, and integumentary. Significant abnormalities in a transgenic mouse model (homozygous G608G mutation), specifically targeting the development of skull and facial bone indices through high-resolution CT scanning and cephalometric analysis. Key measurements include bone thickness, skull volume, and cranial suture integrity. Bone volume increased significantly in HGPS mice by 8 months of age compared to wildtype mice. Cortical thickness showed a trend toward increased values in HGPS mice. Cranial metrics revealed distinct differences. HGPS mice exhibited smaller internasal width, interzygomatic distance, and palatine length compared to WT mice over time.

Beeram I
Cubria MB
Kamalapathy P
Yeritsyan D
Dubose AJ
Razavi AH
Nafisi N
Erdos MR
Snyder BD
Cabral WA
Collins FS
Nazarian A


Global Elimination of Hepatitis C Virus

Abstract: Hepatitis C virus (HCV) is predominantly transmitted through parenteral exposures to infectious blood or body fluids. In 2019, approximately 58 million people worldwide were infected with HCV, and 290,000 deaths occurred due to hepatitis C-related conditions, despite hepatitis C being curable. There are substantial barriers to elimination, including the lack of widespread point-of-care diagnostics, cost of treatment, stigma associated with hepatitis C, and challenges in reaching marginalized populations, such as people who inject drugs. The World Health Organization (WHO) has set goals to eliminate hepatitis C by 2030. Several countries, including Australia, Egypt, Georgia, and Rwanda, have made remarkable progress toward hepatitis C elimination. In the United States, the Biden-Harris administration recently issued a plan for the national elimination of hepatitis C. Global progress has been uneven, however, and will need to accelerate considerably to reach the WHO's 2030 goals. Nevertheless, the global elimination of hepatitis C is within reach and should remain a high public health priority.

Fleurence RL
Alter HJ
Collins FS
Ward JW

Humans
Global Health
Hepatitis C
Disease Eradication
World Health Organization
Hepacivirus
Antiviral Agents

Journal Article
Review
Research Support, Non-U.S. Gov't


Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature

Abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder in children caused by a point mutation in the lamin A gene, resulting in a toxic form of lamin A called progerin. Accelerated atherosclerosis leading to heart attack and stroke are the major causes of death in these patients. Endothelial cell (EC) dysfunction contributes to the pathogenesis of HGPS related cardiovascular diseases (CVD). Endothelial cell-cell communications are important in the development of the vasculature, and their disruptions contribute to cardiovascular pathology. However, it is unclear how progerin interferes with such communications that lead to vascular dysfunction. An antibody array screening of healthy and HGPS patient EC secretomes identified Angiopoietin-2 (Ang2) as a down-regulated signaling molecule in HGPS ECs. A similar down-regulation of Ang2 mRNA and protein was detected in the aortas from an HGPS mouse model. Addition of Ang2 to HGPS ECs rescues vasculogenesis, normalizes endothelial cell migration and gene expression, and restores nitric oxide bioavailability through eNOS activation. Furthermore, Ang2 addition reverses unfavorable paracrine effects of HGPS ECs on vascular smooth muscle cells. Lastly, by utilizing adenine base editor (ABE)-corrected HGPS ECs and progerin-expressing HUVECs, we demonstrated a negative correlation between progerin and Ang2 expression. Lastly, our results indicated that Ang2 exerts its beneficial effect in ECs through Tie2 receptor binding, activating an Akt-mediated pathway. Together, these results provide molecular insights into EC dysfunction in HGPS and suggest that Ang2 treatment has potential therapeutic effects in HGPS-related CVD.

Vakili S
Izydore EK
Losert L
Cabral WA
Tavarez UL
Shores K
Xue H
Erdos MR
Truskey GA
Collins FS
Cao K

Angiopoietin-2
Animals
Humans
Progeria
Mice
Endothelial Cells
Cell Movement
Signal Transduction
Disease Models, Animal


Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization

Abstract: Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

Willems SM
Ng NHJ
Fernandez J
Fine RS
Wheeler E
Wessel J
Kitajima H
Marenne G
Sim X
Yaghootkar H
Wang S
Chen S
Chen Y
Chen YI
Grarup N
Li-Gao R
Varga TV
Asimit JL
Feng S
Strawbridge RJ
Kleinbrink EL
Ahluwalia TS
An P
Appel EV
Arking DE
Auvinen J
Bielak LF
Bihlmeyer NA
Bork-Jensen J
Brody JA
Campbell A
Chu AY
Davies G
Demirkan A
Floyd JS
Giulianini F
Guo X
Gustafsson S
Jackson AU
Jakobsdottir J
Järvelin MR
Jensen RA
Kanoni S
Keinanen-Kiukaanniemi S
Li M
Lu Y
Luan J
Manning AK
Marten J
Meidtner K
Mook-Kanamori DO
Muka T
Pistis G
Prins B
Rice KM
Sanna S
Smith AV
Smith JA
Southam L
Stringham HM
Tragante V
van der Laan SW
Warren HR
Yao J
Yiorkas AM
Zhang W
Zhao W
Graff M
Highland HM
Justice AE
Marouli E
Medina-Gomez C
Afaq S
Alhejily WA
Amin N
Asselbergs FW
Bonnycastle LL
Bots ML
Brandslund I
Chen J
Danesh J
de Mutsert R
Dehghan A
Ebeling T
Elliott P
EPIC-Interact Consortium
Farmaki AE
Faul JD
Franks PW
Franks S
Fritsche A
Gjesing AP
Goodarzi MO
Gudnason V
Hallmans G
Harris TB
Herzig KH
Hivert MF
Jørgensen T
Jørgensen ME
Jousilahti P
Kajantie E
Karaleftheri M
Kardia SLR
Kinnunen L
Koistinen HA
Komulainen P
Kovacs P
Kuusisto J
Laakso M
Lange LA
Launer LJ
Leong A
Lindström J
Manning Fox JE
Männistö S
Maruthur NM
Moilanen L
Mulas A
Nalls MA
Neville M
Pankow JS
Pattie A
Petersen ERB
Puolijoki H
Rasheed A
Redmond P
Renström F
Roden M
Saleheen D
Saltevo J
Savonen K
Sebert S
Skaaby T
Small KS
Stančáková A
Stokholm J
Strauch K
Tai ES
Taylor KD
Thuesen BH
Tönjes A
Tsafantakis E
Tuomi T
Tuomilehto J
Understanding Society Scientific Group
Uusitupa M
Vääräsmäki M
Vaartjes I
Zoledziewska M
Abecasis G
Balkau B
Bisgaard H
Blakemore AI
Blüher M
Boeing H
Boerwinkle E
Bønnelykke K
Bottinger EP
Caulfield MJ
Chambers JC
Chasman DI
Cheng CY
Collins FS
Coresh J
Cucca F
de Borst GJ
Deary IJ
Dedoussis G
Deloukas P
den Ruijter HM
Dupuis J
Evans MK
Ferrannini E
Franco OH
Grallert H
Hansen T
Hattersley AT
Hayward C
Hirschhorn JN
Ikram A
Ingelsson E
Karpe F
Kaw KT
Kiess W
Kooner JS
Körner A
Lakka T
Langenberg C
Lind L
Lindgren CM
Linneberg A
Lipovich L
Liu CT
Liu J
Liu Y
Loos RJF
MacDonald PE
Mohlke KL
Morris AD
Munroe PB
Murray A
Padmanabhan S
Palmer CNA
Pasterkamp G
Pedersen O
Peyser PA
Polasek O
Porteous D
Province MA
Psaty BM
Rauramaa R
Ridker PM
Rolandsson O
Rorsman P
Rosendaal FR
Rudan I
Salomaa V
Schulze MB
Sladek R
Smith BH
Spector TD
Starr JM
Stumvoll M
van Duijn CM
Walker M
Wareham NJ
Weir DR
Wilson JG
Wong TY
Zeggini E
Zonderman AB
Rotter JI
Morris AP
Boehnke M
Florez JC
McCarthy MI
Meigs JB
Mahajan A
Scott RA
Gloyn AL
Barroso I


Integrated clinical risk prediction of type 2 diabetes with a multifactorial polygenic risk score

Abstract: Combining information from multiple GWASs for a disease and its risk factors has proven a powerful approach for development of polygenic risk scores (PRSs). This may be particularly useful for type 2 diabetes (T2D), a highly polygenic and heterogeneous disease where the additional predictive value of a PRS is unclear. Here, we use a meta-scoring approach to develop a metaPRS for T2D that incorporated genome-wide associations from both European and non-European genetic ancestries and T2D risk factors. We evaluated the performance of this metaPRS and benchmarked it against existing genome-wide PRS in 620,059 participants and 50,572 T2D cases amongst six diverse genetic ancestries from UK Biobank, INTERVAL, the All of Us Research Program, and the Singapore Multi-Ethnic Cohort. We show that our metaPRS was the most powerful PRS for predicting T2D in European population-based cohorts and had comparable performance to the top ancestry-specific PRS, highlighting its transferability. In UK Biobank, we show the metaPRS had stronger predictive power for 10-year risk than all individual risk factors apart from BMI and biomarkers of dysglycemia. The metaPRS modestly improved T2D risk stratification of QDiabetes risk scores for 10-year risk prediction, particularly when prioritising individuals for blood tests of dysglycemia. Overall, we present a highly predictive and transferrable PRS for T2D and demonstrate that the potential for PRS to incrementally improve T2D risk prediction when incorporated into UK guideline-recommended screening and risk prediction with a clinical risk score.

medRxiv : the preprint server for health sciences

Ritchie SC
Taylor HJ
Liang Y
Manikpurage HD
Pennells L
Foguet C
Abraham G
Gibson JT
Jiang X
Liu Y
Xu Y
Kim LG
Mahajan A
McCarthy MI
Kaptoge S
Lambert SA
Wood A
Sim X
Collins FS
Denny JC
Danesh J
Butterworth AS
Di Angelantonio E
Inouye M


Progerin mRNA expression in non-HGPS patients is correlated with widespread shifts in transcript isoforms

Abstract: Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease caused primarily by a C1824T mutation in LMNA. This mutation activates a cryptic splice donor site, producing a lamin variant called progerin. Interestingly, progerin has also been detected in cells and tissues of non-HGPS patients. Here, we investigated progerin expression using publicly available RNA-seq data from non-HGPS patients in the GTEx project. We found that progerin expression is present across all tissue types in non-HGPS patients and correlated with telomere shortening in the skin. Transcriptome-wide correlation analyses suggest that the level of progerin expression is correlated with switches in gene isoform expression patterns. Differential expression analyses show that progerin expression is correlated with significant changes in genes involved in splicing regulation and mitochondrial function. Interestingly, 5' splice sites whose use is correlated with progerin expression have significantly altered frequencies of consensus trinucleotides within the core 5' splice site. Furthermore, introns whose alternative splicing correlates with progerin have reduced GC content. Our study suggests that progerin expression in non-HGPS patients is part of a global shift in splicing patterns.

Yu R
Xue H
Lin W
Collins FS
Mount SM
Cao K


Scalable Hypothalamic Arcuate Neuron Differentiation from Human Pluripotent Stem Cells Suitable for Modeling Metabolic and Reproductive Disorders

Abstract: The hypothalamus, composed of several nuclei, is essential for maintaining our body's homeostasis. The arcuate nucleus (ARC), located in the mediobasal hypothalamus, contains neuronal populations with eminent roles in energy and glucose homeostasis as well as reproduction. These neuronal populations are of great interest for translational research. To fulfill this promise, we used a robotic cell culture platform to provide a scalable and chemically defined approach for differentiating human pluripotent stem cells (hPSCs) into pro-opiomelanocortin (POMC), somatostatin (SST), tyrosine hydroxylase (TH) and gonadotropin-releasing hormone (GnRH) neuronal subpopulations with an ARC-like signature. This robust approach is reproducible across several distinct hPSC lines and exhibits a stepwise induction of key ventral diencephalon and ARC markers in transcriptomic profiling experiments. This is further corroborated by direct comparison to human fetal hypothalamus, and the enriched expression of genes implicated in obesity and type 2 diabetes (T2D). Genome-wide chromatin accessibility profiling by ATAC-seq identified accessible regulatory regions that can be utilized to predict candidate enhancers related to metabolic disorders and hypothalamic development. In depth molecular, cellular, and functional experiments unveiled the responsiveness of the hPSC-derived hypothalamic neurons to hormonal stimuli, such as insulin, neuropeptides including kisspeptin, and incretin mimetic drugs such as Exendin-4, highlighting their potential utility as physiologically relevant cellular models for disease studies. In addition, differential glucose and insulin treatments uncovered adaptability within the generated ARC neurons in the dynamic regulation of POMC and insulin receptors. In summary, the establishment of this model represents a novel, chemically defined, and scalable platform for manufacturing large numbers of hypothalamic arcuate neurons and serves as a valuable resource for modeling metabolic and reproductive disorders.

bioRxiv : the preprint server for biology

Jovanovic VM
Narisu N
Bonnycastle LL
Tharakan R
Mesch KT
Glover HJ
Yan T
Sinha N
Sen C
Castellano D
Yang S
Blivis D
Ryu S
Bennett DF
Rosales-Soto G
Inman J
Ormanoglu P
LeClair CA
Xia M
Schneider M
Hernandez-Ochoa EO
Erdos MR
Simeonov A
Chen S
Collins FS
Doege CA
Tristan CA


Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 h

Abstract: Disruption of pancreatic islet function and glucose homeostasis can lead to the development of sustained hyperglycaemia, beta cell glucotoxicity and subsequently type 2 diabetes. In this study, we explored the effects of in vitro hyperglycaemic conditions on human pancreatic islet gene expression across 24 h in six pancreatic cell types: alpha; beta; gamma; delta; ductal; and acinar. We hypothesised that genes associated with hyperglycaemic conditions may be relevant to the onset and progression of diabetes. We exposed human pancreatic islets from two donors to low (2.8 mmol/l) and high (15.0 mmol/l) glucose concentrations over 24 h in vitro. To assess the transcriptome, we performed single-cell RNA-seq (scRNA-seq) at seven time points. We modelled time as both a discrete and continuous variable to determine momentary and longitudinal changes in transcription associated with islet time in culture or glucose exposure. Additionally, we integrated genomic features and genetic summary statistics to nominate candidate effector genes. For three of these genes, we functionally characterised the effect on insulin production and secretion using CRISPR interference to knock down gene expression in EndoC-βH1 cells, followed by a glucose-stimulated insulin secretion assay. In the discrete time models, we identified 1344 genes associated with time and 668 genes associated with glucose exposure across all cell types and time points. In the continuous time models, we identified 1311 genes associated with time, 345 genes associated with glucose exposure and 418 genes associated with interaction effects between time and glucose across all cell types. By integrating these expression profiles with summary statistics from genetic association studies, we identified 2449 candidate effector genes for type 2 diabetes, HbA1c, random blood glucose and fasting blood glucose. Of these candidate effector genes, we showed that three (ERO1B, HNRNPA2B1 and RHOBTB3) exhibited an effect on glucose-stimulated insulin production and secretion in EndoC-βH1 cells. The findings of our study provide an in-depth characterisation of the 24 h transcriptomic response of human pancreatic islets to glucose exposure at a single-cell resolution. By integrating differentially expressed genes with genetic signals for type 2 diabetes and glucose-related traits, we provide insights into the molecular mechanisms underlying glucose homeostasis. Finally, we provide functional evidence to support the role of three candidate effector genes in insulin secretion and production. The scRNA-seq data from the 24 h glucose exposure experiment performed in this study are available in the database of Genotypes and Phenotypes (dbGap; https://www.ncbi.nlm.nih.gov/gap/ ) with accession no. phs001188.v3.p1. Study metadata and summary statistics for the differential expression, gene set enrichment and candidate effector gene prediction analyses are available in the Zenodo data repository ( https://zenodo.org/ ) under accession number 11123248. The code used in this study is publicly available at https://github.com/CollinsLabBioComp/publication-islet_glucose_timecourse .

Grenko CM
Taylor HJ
Bonnycastle LL
Xue D
Lee BN
Weiss Z
Yan T
Swift AJ
Mansell EC
Lee A
Robertson CC
Narisu N
Erdos MR
Chen S
Collins FS
Taylor DL

Humans
Islets of Langerhans
Glucose
Single-Cell Analysis
Gene Expression Profiling
Transcriptome
Diabetes Mellitus, Type 2
Insulin
Insulin-Secreting Cells
Hyperglycemia


Oral Health-Related Quality of Life in Rare Disorders of Congenital Facial Weakness

Abstract: Congenital facial weakness (CFW) encompasses a heterogenous set of rare disorders presenting with decreased facial movement from birth, secondary to impaired function of the facial musculature. The aim of the present study is to provide an analysis of subject-reported oral health-related quality of life (OHRQoL) in congenital facial weakness (CFW) disorders. Forty-four subjects with CFW and age- and sex- matched controls were enrolled in an Institutional Review Board (IRB)-approved study. Demographic data, medical and surgical history, comprehensive oral examination, and the Oral Health Impact Profile (OHIP-14) were obtained. Compared to unaffected controls, subjects with CFW had higher OHIP-14 scores overall (mean ± SD: 13.11 ± 8.11 vs. 4.46 ± 4.98, p < 0.0001) and within five of seven oral health domains, indicating decreased OHRQoL. Although subjects with Moebius syndrome (MBS) were noted to have higher OHIP-14 scores than those with Hereditary Congenital Facial Paresis (HCFP), there was no significant correlation in OHIP-14 score to age, sex, or specific diagnosis. An increase in OHIP-14 scores in subjects was detected in those who had undergone reanimation surgery. In conclusion, subjects with CFW had poorer OHRQoL compared to controls, and subjects with MBS had poorer OHRQoL than subjects with HCFP. This study provides better understanding of oral health care needs and quality of life in a CFW cohort and suggests that guidelines for dental treatment are required.

International journal of environmental research and public health

On Behalf Of The Moebius Syndrome Research Consortium

Humans
Quality of Life
Male
Female
Oral Health
Adult
Young Adult
Adolescent
Child
Middle Aged
Facial Paralysis
Case-Control Studies
Rare Diseases

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural


Music and medicine: quickening the tempo of progress

Chen WG
Edwards E
Iyengar S
Finkelstein R
Rutter DF
Fleming R
Collins FS

Humans
Music
Heart Rate
Fetal Movement
Medicine


Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Abstract: Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

Suzuki K
Hatzikotoulas K
Southam L
Taylor HJ
Yin X
Lorenz KM
Mandla R
Huerta-Chagoya A
Melloni GEM
Kanoni S
Rayner NW
Bocher O
Arruda AL
Sonehara K
Namba S
Lee SSK
Preuss MH
Petty LE
Schroeder P
Vanderwerff B
Kals M
Bragg F
Lin K
Guo X
Zhang W
Yao J
Kim YJ
Graff M
Takeuchi F
Nano J
Lamri A
Nakatochi M
Moon S
Scott RA
Cook JP
Lee JJ
Pan I
Taliun D
Parra EJ
Chai JF
Bielak LF
Tabara Y
Hai Y
Thorleifsson G
Grarup N
Sofer T
Wuttke M
Sarnowski C
Gieger C
Nousome D
Trompet S
Kwak SH
Long J
Sun M
Tong L
Chen WM
Nongmaithem SS
Noordam R
Lim VJY
Tam CHT
Joo YY
Chen CH
Raffield LM
Prins BP
Nicolas A
Yanek LR
Chen G
Brody JA
Kabagambe E
An P
Xiang AH
Choi HS
Cade BE
Tan J
Broadaway KA
Williamson A
Kamali Z
Cui J
Thangam M
Adair LS
Adeyemo A
Aguilar-Salinas CA
Ahluwalia TS
Anand SS
Bertoni A
Bork-Jensen J
Brandslund I
Buchanan TA
Burant CF
Butterworth AS
Canouil M
Chan JCN
Chang LC
Chee ML
Chen J
Chen SH
Chen YT
Chen Z
Chuang LM
Cushman M
Danesh J
Das SK
de Silva HJ
Dedoussis G
Dimitrov L
Doumatey AP
Du S
Duan Q
Eckardt KU
Emery LS
Evans DS
Evans MK
Fischer K
Floyd JS
Ford I
Franco OH
Frayling TM
Freedman BI
Genter P
Gerstein HC
Giedraitis V
González-Villalpando C
González-Villalpando ME
Gordon-Larsen P
Gross M
Guare LA
Hackinger S
Hakaste L
Han S
Hattersley AT
Herder C
Horikoshi M
Howard AG
Hsueh W
Huang M
Huang W
Hung YJ
Hwang MY
Hwu CM
Ichihara S
Ikram MA
Ingelsson M
Islam MT
Isono M
Jang HM
Jasmine F
Jiang G
Jonas JB
Jørgensen T
Kamanu FK
Kandeel FR
Kasturiratne A
Katsuya T
Kaur V
Kawaguchi T
Keaton JM
Kho AN
Khor CC
Kibriya MG
Kim DH
Kronenberg F
Kuusisto J
Läll K
Lange LA
Lee KM
Lee MS
Lee NR
Leong A
Li L
Li Y
Li-Gao R
Ligthart S
Lindgren CM
Linneberg A
Liu CT
Liu J
Locke AE
Louie T
Luan J
Luk AO
Luo X
Lv J
Lynch JA
Lyssenko V
Maeda S
Mamakou V
Mansuri SR
Matsuda K
Meitinger T
Melander O
Metspalu A
Mo H
Morris AD
Moura FA
Nadler JL
Nalls MA
Nayak U
Ntalla I
Okada Y
Orozco L
Patel SR
Patil S
Pei P
Pereira MA
Peters A
Pirie FJ
Polikowsky HG
Porneala B
Prasad G
Rasmussen-Torvik LJ
Reiner AP
Roden M
Rohde R
Roll K
Sabanayagam C
Sandow K
Sankareswaran A
Sattar N
Schönherr S
Shahriar M
Shen B
Shi J
Shin DM
Shojima N
Smith JA
So WY
Stančáková A
Steinthorsdottir V
Stilp AM
Strauch K
Taylor KD
Thorand B
Thorsteinsdottir U
Tomlinson B
Tran TC
Tsai FJ
Tuomilehto J
Tusie-Luna T
Udler MS
Valladares-Salgado A
van Dam RM
van Klinken JB
Varma R
Wacher-Rodarte N
Wheeler E
Wickremasinghe AR
van Dijk KW
Witte DR
Yajnik CS
Yamamoto K
Yamamoto K
Yoon K
Yu C
Yuan JM
Yusuf S
Zawistowski M
Zhang L
Zheng W
VA Million Veteran Program
Raffel LJ
Igase M
Ipp E
Redline S
Cho YS
Lind L
Province MA
Fornage M
Hanis CL
Ingelsson E
Zonderman AB
Psaty BM
Wang YX
Rotimi CN
Becker DM
Matsuda F
Liu Y
Yokota M
Kardia SLR
Peyser PA
Pankow JS
Engert JC
Bonnefond A
Froguel P
Wilson JG
Sheu WHH
Wu JY
Hayes MG
Ma RCW
Wong TY
Mook-Kanamori DO
Tuomi T
Chandak GR
Collins FS
Bharadwaj D
Paré G
Sale MM
Ahsan H
Motala AA
Shu XO
Park KS
Jukema JW
Cruz M
Chen YI
Rich SS
McKean-Cowdin R
Grallert H
Cheng CY
Ghanbari M
Tai ES
Dupuis J
Kato N
Laakso M
Köttgen A
Koh WP
Bowden DW
Palmer CNA
Kooner JS
Kooperberg C
Liu S
North KE
Saleheen D
Hansen T
Pedersen O
Wareham NJ
Lee J
Kim BJ
Millwood IY
Walters RG
Stefansson K
Ahlqvist E
Goodarzi MO
Mohlke KL
Langenberg C
Haiman CA
Loos RJF
Florez JC
Rader DJ
Ritchie MD
Zöllner S
Mägi R
Marston NA
Ruff CT
van Heel DA
Finer S
Denny JC
Yamauchi T
Kadowaki T
Chambers JC
Ng MCY
Sim X
Below JE
Tsao PS
Chang KM
McCarthy MI
Meigs JB
Mahajan A
Spracklen CN
Mercader JM
Boehnke M
Rotter JI
Vujkovic M
Voight BF
Morris AP
Zeggini E

Humans
Adipocytes
Chromatin
Coronary Artery Disease
Diabetes Mellitus, Type 2
Diabetic Nephropathies
Disease Progression
Endothelial Cells
Enteroendocrine Cells
Epigenomics
Genetic Predisposition to Disease
Genome-Wide Association Study
Islets of Langerhans
Multifactorial Inheritance
Peripheral Arterial Disease
Single-Cell Analysis

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't


Generation of Human Isogenic Induced Pluripotent Stem Cell Lines with CRISPR Prime Editing

Abstract: We developed an efficient CRISPR prime editing protocol and generated isogenic-induced pluripotent stem cell (iPSC) lines carrying heterozygous or homozygous alleles for putatively causal single nucleotide variants at six type 2 diabetes loci (ABCC8, MTNR1B, TCF7L2, HNF4A, CAMK1D, and GCK). Our two-step sequence-based approach to first identify transfected cell pools with the highest fraction of edited cells significantly reduced the downstream efforts to isolate single clones of edited cells. We found that prime editing can make targeted genetic changes in iPSC and optimization of system components and guide RNA designs that were critical to achieve acceptable efficiency. Systems utilizing PEmax, epegRNA modifications, and MLH1dn provided significant benefit, producing editing efficiencies of 36-73%. Editing success and pegRNA design optimization required for each variant differed depending on the sequence at the target site. With attention to design, prime editing is a promising approach to generate isogenic iPSC lines, enabling the study of specific genetic changes in a common genetic background.

Bonnycastle LL
Swift AJ
Mansell EC
Lee A
Winnicki E
Li ES
Robertson CC
Parsons VA
Huynh T
Krilow C
Mohlke KL
Erdos MR
Narisu N
Collins FS

Clustered Regularly Interspaced Short Palindromic Repeats


Population-scale skeletal muscle single-nucleus multi-omic profiling reveals extensive context specific genetic regulation

Abstract: Skeletal muscle, the largest human organ by weight, is relevant in several polygenic metabolic traits and diseases including type 2 diabetes (T2D). Identifying genetic mechanisms underlying these traits requires pinpointing cell types, regulatory elements, target genes, and causal variants. Here, we use genetic multiplexing to generate population-scale single nucleus (sn) chromatin accessibility (snATAC-seq) and transcriptome (snRNA-seq) maps across 287 frozen human skeletal muscle biopsies representing nearly half a million nuclei. We identify 13 cell types and integrate genetic variation to discover >7,000 expression quantitative trait loci (eQTL) and >100,000 chromatin accessibility QTLs (caQTL) across cell types. Learning patterns of e/caQTL sharing across cell types increased precision of effect estimates. We identify high-resolution cell-states and context-specific e/caQTL with significant genotype by context interaction. We identify nearly 2,000 eGenes colocalized with caQTL and construct causal directional maps for chromatin accessibility and gene expression. Almost 3,500 genome-wide association study (GWAS) signals across 38 relevant traits colocalize with sn-e/caQTL, most in a cell-specific manner. These signals typically colocalize with caQTL and not eQTL, highlighting the importance of population-scale chromatin profiling for GWAS functional studies. Finally, our GWAS-caQTL colocalization data reveal distinct cell-specific regulatory paradigms. Our results illuminate the genetic regulatory architecture of human skeletal muscle at high resolution epigenomic, transcriptomic, and cell-state scales and serve as a template for population-scale multi-omic mapping in complex tissues and traits.

Varshney A
Manickam N
Orchard P
Tovar A
Ventresca C
Zhang Z
Feng F
Mears J
Erdos MR
Narisu N
Nishino K
Rai V
Stringham HM
Jackson AU
Tamsen T
Gao C
Yang M
Koues OI
Welch JD
Burant CF
Williams LK
Jenkinson C
DeFronzo RA
Norton L
Saramies J
Lakka TA
Laakso M
Tuomilehto J
Mohlke KL
Kitzman JO
Koistinen HA
Liu J
Boehnke M
Collins FS
Scott LJ
Parker SCJ


Adipose tissue eQTL meta-analysis reveals the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits

Abstract: Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. Here, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34K conditionally distinct expression quantitative trait locus (eQTL) signals in 18K genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared to primary signals, non-primary signals had lower effect sizes, lower minor allele frequencies, and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTL with conditionally distinct genome-wide association study signals for 28 cardiometabolic traits identified 3,605 eQTL signals for 1,861 genes. Inclusion of non-primary eQTL signals increased colocalized signals by 46%. Among 30 genes with ≥2 pairs of colocalized signals, 21 showed a mediating gene dosage effect on the trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.

Brotman SM
El-Sayed Moustafa JS
Guan L
Broadaway KA
Wang D
Jackson AU
Welch R
Currin KW
Tomlinson M
Vadlamudi S
Stringham HM
Roberts AL
Lakka TA
Oravilahti A
Silva LF
Narisu N
Erdos MR
Yan T
Bonnycastle LL
Raulerson CK
Raza Y
Yan X
Parker SCJ
Kuusisto J
Pajukanta P
Tuomilehto J
Collins FS
Boehnke M
Love MI
Koistinen HA
Laakso M
Mohlke KL
Small KS
Scott LJ


Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells

Abstract: Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental line and identified a single likely functional variant at each of 23 T2D-association signals.

Xue D
Narisu N
Taylor DL
Zhang M
Grenko C
Taylor HJ
Yan T
Tang X
Sinha N
Zhu J
Vandana JJ
Nok Chong AC
Lee A
Mansell EC
Swift AJ
Erdos MR
Zhong A
Bonnycastle LL
Zhou T
Chen S
Collins FS

Humans
Diabetes Mellitus, Type 2
Human Embryonic Stem Cells
Genetic Predisposition to Disease
Genome-Wide Association Study
Insulin-Secreting Cells
Polymorphism, Single Nucleotide
Carbonyl Reductase (NADPH)

Journal Article
Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't


US Hepatitis C Elimination Plan-Reply

Humans
Disease Eradication
Hepacivirus
Hepatitis C
United States


Modeling islet enhancers using deep learning identifies candidate causal variants at loci associated with T2D and glycemic traits

Abstract: Genetic association studies have identified hundreds of independent signals associated with type 2 diabetes (T2D) and related traits. Despite these successes, the identification of specific causal variants underlying a genetic association signal remains challenging. In this study, we describe a deep learning (DL) method to analyze the impact of sequence variants on enhancers. Focusing on pancreatic islets, a T2D relevant tissue, we show that our model learns islet-specific transcription factor (TF) regulatory patterns and can be used to prioritize candidate causal variants. At 101 genetic signals associated with T2D and related glycemic traits where multiple variants occur in linkage disequilibrium, our method nominates a single causal variant for each association signal, including three variants previously shown to alter reporter activity in islet-relevant cell types. For another signal associated with blood glucose levels, we biochemically test all candidate causal variants from statistical fine-mapping using a pancreatic islet beta cell line and show biochemical evidence of allelic effects on TF binding for the model-prioritized variant. To aid in future research, we publicly distribute our model and islet enhancer perturbation scores across ~67 million genetic variants. We anticipate that DL methods like the one presented in this study will enhance the prioritization of candidate causal variants for functional studies.

Proceedings of the National Academy of Sciences of the United States of America

Hudaiberdiev S
Taylor DL
Song W
Narisu N
Bhuiyan RM
Taylor HJ
Tang X
Yan T
Swift AJ
Bonnycastle LL
Consortium D
Chen S
Stitzel ML
Erdos MR
Ovcharenko I
Collins FS

Diabetes Mellitus, Type 2
Deep Learning
Enhancer Elements, Genetic
Islets of Langerhans
Genetic Variation
Humans
Computer Simulation

Research Support, U.S. Gov't, Non-P.H.S.


Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis

Abstract: Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

Tenney AP
Di Gioia SA
Webb BD
Chan WM
de Boer E
Garnai SJ
Barry BJ
Ray T
Kosicki M
Robson CD
Zhang Z
Collins TE
Gelber A
Pratt BM
Fujiwara Y
Varshney A
Lek M
Warburton PE
Van Ryzin C
Lehky TJ
Zalewski C
King KA
Brewer CC
Thurm A
Snow J
Facio FM
Narisu N
Bonnycastle LL
Swift A
Chines PS
Bell JL
Mohan S
Whitman MC
Staffieri SE
Elder JE
Demer JL
Torres A
Rachid E
Al-Haddad C
Boustany RM
Mackey DA
Brady AF
Fenollar-Cortés M
Fradin M
Kleefstra T
Padberg GW
Raskin S
Sato MT
Orkin SH
Parker SCJ
Hadlock TA
Vissers LELM
van Bokhoven H
Jabs EW
Collins FS
Pennacchio LA
Manoli I
Engle EC

Animals
Mice
Facial Paralysis
GATA2 Transcription Factor
Motor Neurons
Neurogenesis
Neurons, Efferent


Bone dysplasia in Hutchinson-Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations

Abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of the toxic "progerin" protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the LmnaG609G knock-in (KI) mouse model of HGPS to further define mechanisms of bone loss associated with normal and premature aging disorders. Newborn skeletal staining of KI mice revealed altered rib cage shape and spinal curvature, and delayed calvarial mineralization with increased craniofacial and mandibular cartilage content. MicroCT analysis and mechanical testing of adult femurs indicated increased fragility associated with reduced bone mass, recapitulating the progressive bone deterioration that occurs in HGPS patients. We investigated mechanisms of bone loss in KI mice at the cellular level in bone cell populations. Formation of wild-type and KI osteoclasts from marrow-derived precursors was inhibited by KI osteoblast-conditioned media in vitro, suggesting a secreted factor(s) responsible for decreased osteoclasts on KI trabecular surfaces in vivo. Cultured KI osteoblasts exhibited abnormal differentiation characterized by reduced deposition and mineralization of extracellular matrix with increased lipid accumulation compared to wild-type, providing a mechanism for altered bone formation. Furthermore, quantitative analyses of KI transcripts confirmed upregulation of adipogenic genes both in vitro and in vivo. Thus, osteoblast phenotypic plasticity, inflammation and altered cellular cross-talk contribute to abnormal bone formation in HGPS mice.

Cabral WA
Stephan C
Terajima M
Thaivalappil AA
Blanchard O
Tavarez UL
Narisu N
Yan T
Wincovitch SM
Taga Y
Yamauchi M
Kozloff KM
Erdos MR
Collins FS

Mice
Animals
Progeria
Aging, Premature
Mutation
Lamin Type A
Cell Differentiation
Bone Diseases, Developmental

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural


Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 hours

Abstract: Disruption of pancreatic islet function and glucose homeostasis can lead to the development of sustained hyperglycemia, beta cell glucotoxicity, and ultimately type 2 diabetes (T2D). In this study, we sought to explore the effects of hyperglycemia on human pancreatic islet (HPI) gene expression by exposing HPIs from two donors to low (2.8mM) and high (15.0mM) glucose concentrations over 24 hours, assaying the transcriptome at seven time points using single-cell RNA sequencing (scRNA-seq). We modeled time as both a discrete and continuous variable to determine momentary and longitudinal changes in transcription associated with islet time in culture or glucose exposure. Across all cell types, we identified 1,528 genes associated with time, 1,185 genes associated with glucose exposure, and 845 genes associated with interaction effects between time and glucose. We clustered differentially expressed genes across cell types and found 347 modules of genes with similar expression patterns across time and glucose conditions, including two beta cell modules enriched in genes associated with T2D. Finally, by integrating genomic features from this study and genetic summary statistics for T2D and related traits, we nominate 363 candidate effector genes that may underlie genetic associations for T2D and related traits.

Grenko CM
Bonnycastle LL
Taylor HJ
Yan T
Swift AJ
Robertson CC
Narisu N
Erdos MR
Collins FS
Taylor DL


Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Abstract: Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC)

Humans
Insulin
Genome-Wide Association Study
Insulin Resistance
Diabetes Mellitus, Type 2
Glucose
Blood Glucose


Functional interrogation of twenty type 2 diabetes-associated genes using isogenic hESC-derived β-like cells

Abstract: Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival. We performed RNA-seq and ATAC-seq on hESC-β cells from each knockout line. Analyses of T2D GWAS signals overlapping with HNF4A-dependent ATAC peaks identified a specific SNP as a likely causal variant. In addition, we performed integrative association analyses and identified four genes ( CP, RNASE1, PCSK1N and GSTA2 ) associated with insulin production, and two genes ( TAGLN3 and DHRS2 ) associated with sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental hESC line, to identify a single likely functional variant at each of 23 T2D GWAS signals.

Xue D
Narisu N
Taylor DL
Zhang M
Grenko C
Taylor HJ
Yan T
Tang X
Sinha N
Zhu J
Vandana JJ
Chong ACN
Lee A
Mansell EC
Swift AJ
Erdos MR
Zhou T
Bonnycastle LL
Zhong A
Chen S
Collins FS


Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications

Abstract: Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10-8) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

International Consortium for Blood Pressure (ICBP)

Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC)


A National Hepatitis C Elimination Program in the United States: A Historic Opportunity

Humans
Antiviral Agents
Hepacivirus
Hepatitis C
Hepatitis C, Chronic
United States
Disease Eradication


Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Abstract: Genetic studies have identified ≥240 loci associated with the risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date. We characterized the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans-acting genetic components and mapping cis-acting loci associated with miRNA expression [miRNA-expression quantitative trait loci (eQTLs)]. We found i) 84 heritable miRNAs, primarily regulated by trans-acting genetic effects, and ii) 5 miRNA-eQTLs. We also used several different strategies to identify T2D-associated miRNAs. First, we colocalized miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersected miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and found 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we performed differential expression analysis and identified 14 miRNAs associated with T2D status-including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p-and 4 miRNAs associated with a polygenic score for HbA1c levels-miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.

Taylor HJ
Hung YH
Narisu N
Erdos MR
Kanke M
Yan T
Grenko CM
Swift AJ
Bonnycastle LL
Sethupathy P
Collins FS
Taylor DL

Humans
MicroRNAs
Diabetes Mellitus, Type 2
Glycated Hemoglobin
Islets of Langerhans
Quantitative Trait Loci


NIH Music-Based Intervention Toolkit: Music-Based Interventions for Brain Disorders of Aging

Abstract: Music-based interventions (MBIs) show promise for managing symptoms of various brain disorders. To fully realize the potential of MBIs and dispel the outdated misconception that MBIs are rooted in soft science, the NIH is promoting rigorously designed, well-powered MBI clinical trials. The pressing need of guidelines for scientifically rigorous studies with enhanced data collection brought together the Renée Fleming Foundation, the Foundation for the NIH, the Trans-NIH Music and Health Working Group, and an interdisciplinary scientific expert panel to create the NIH MBI Toolkit for research on music and health across the lifespan. The Toolkit defines the building blocks of MBIs, including a consolidated set of common data elements for MBI protocols, and core datasets of outcome measures and biomarkers for brain disorders of aging that researchers may select for their studies. Utilization of the guiding principles in this Toolkit will be strongly recommended for NIH-funded studies of MBIs.

Edwards E
St Hillaire-Clarke C
Frankowski DW
Finkelstein R
Cheever T
Chen WG
Onken L
Poremba A
Riddle R
Schloesser D
Burgdorf CE
Wells N
Fleming R
Collins FS

Humans
Music
Mindfulness
Brain Diseases
Data Collection
Aging


A saturated map of common genetic variants associated with human height

Abstract: Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

DiscovEHR (DiscovEHR and MyCode Community Health Initiative)

eMERGE (Electronic Medical Records and Genomics Network)

Humans
Body Height
Gene Frequency
Genome, Human
Genome-Wide Association Study
Haplotypes
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Europe
Sample Size
Phenotype
Chromosome Mapping


Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Abstract: Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Wang Z
Emmerich A
Pillon NJ
Moore T
Hemerich D
Cornelis MC
Mazzaferro E
Broos S
Ahluwalia TS
Bartz TM
Bentley AR
Bielak LF
Chong M
Chu AY
Berry D
Dorajoo R
Dueker ND
Kasbohm E
Feenstra B
Feitosa MF
Gieger C
Graff M
Hall LM
Haller T
Hartwig FP
Hillis DA
Huikari V
Heard-Costa N
Holzapfel C
Jackson AU
Johansson Å
Jørgensen AM
Kaakinen MA
Karlsson R
Kerr KF
Kim B
Koolhaas CM
Kutalik Z
Lagou V
Lind PA
Lorentzon M
Lyytikäinen LP
Mangino M
Metzendorf C
Monroe KR
Pacolet A
Pérusse L
Pool R
Richmond RC
Rivera NV
Robiou-du-Pont S
Schraut KE
Schulz CA
Stringham HM
Tanaka T
Teumer A
Turman C
van der Most PJ
Vanmunster M
van Rooij FJA
van Vliet-Ostaptchouk JV
Zhang X
Zhao JH
Zhao W
Balkhiyarova Z
Balslev-Harder MN
Baumeister SE
Beilby J
Blangero J
Boomsma DI
Brage S
Braund PS
Brody JA
Bruinenberg M
Ekelund U
Liu CT
Cole JW
Collins FS
Cupples LA
Esko T
Enroth S
Faul JD
Fernandez-Rhodes L
Fohner AE
Franco OH
Galesloot TE
Gordon SD
Grarup N
Hartman CA
Heiss G
Hui J
Illig T
Jago R
James A
Joshi PK
Jung T
Kähönen M
Kilpeläinen TO
Koh WP
Kolcic I
Kraft PP
Kuusisto J
Launer LJ
Li A
Linneberg A
Luan J
Vidal PM
Medland SE
Milaneschi Y
Moscati A
Musk B
Nelson CP
Nolte IM
Pedersen NL
Peters A
Peyser PA
Power C
Raitakari OT
Reedik M
Reiner AP
Ridker PM
Rudan I
Ryan K
Sarzynski MA
Scott LJ
Scott RA
Sidney S
Siggeirsdottir K
Smith AV
Smith JA
Sonestedt E
Strøm M
Tai ES
Teo KK
Thorand B
Tönjes A
Tremblay A
Uitterlinden AG
Vangipurapu J
van Schoor N
Völker U
Willemsen G
Williams K
Wong Q
Xu H
Young KL
Yuan JM
Zillikens MC
Zonderman AB
Ameur A
Bandinelli S
Bis JC
Boehnke M
Bouchard C
Chasman DI
Smith GD
de Geus EJC
Deldicque L
Dörr M
Evans MK
Ferrucci L
Fornage M
Fox C
Garland T Jr
Gudnason V
Gyllensten U
Hansen T
Hayward C
Horta BL
Hyppönen E
Jarvelin MR
Johnson WC
Kardia SLR
Kiemeney LA
Laakso M
Langenberg C
Lehtimäki T
Marchand LL
Lifelines Cohort Study
Magnusson PKE
Martin NG
Melbye M
Metspalu A
Meyre D
North KE
Ohlsson C
Oldehinkel AJ
Orho-Melander M
Pare G
Park T
Pedersen O
Penninx BWJH
Pers TH
Polasek O
Prokopenko I
Rotimi CN
Samani NJ
Sim X
Snieder H
Sørensen TIA
Spector TD
Timpson NJ
van Dam RM
van der Velde N
van Duijn CM
Vollenweider P
Völzke H
Voortman T
Waeber G
Wareham NJ
Weir DR
Wichmann HE
Wilson JF
Hevener AL
Krook A
Zierath JR
Thomis MAI
Loos RJF
Hoed MD

Actinin
Cross-Sectional Studies
Exercise
Genome-Wide Association Study
Humans
Leisure Activities
Sedentary Behavior


Integrating transcriptomics, metabolomics, and GWAS helps reveal molecular mechanisms for metabolite levels and disease risk

Abstract: Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite levels were more likely to influence gene expression and disease risk compared to the ones that do not. Integrating transcriptomics with metabolomics results prioritized 397 genes for 521 metabolites, including 496 previously identified gene-metabolite pairs with strong functional connections and suggested 33.3% of such gene-metabolite pairs shared the same causal variants with genetic associations of gene expression. Integrating transcriptomics and metabolomics individually with FinnGen GWAS results identified 1,597 genes for 790 disease traits. Integrating transcriptomics and metabolomics jointly with FinnGen GWAS results helped pinpoint metabolic pathways from genes to diseases. We identified putative causal effects of UGT1A1/UGT1A4 expression on gallbladder disorders through regulating plasma (E,E)-bilirubin levels, of SLC22A5 expression on nasal polyps and plasma carnitine levels through distinct pathways, and of LIPC expression on age-related macular degeneration through glycerophospholipid metabolic pathways. Our study highlights the power of integrating multiple sets of molecular traits and GWAS results to deepen understanding of disease pathophysiology.

Yin X
Bose D
Kwon A
Hanks SC
Jackson AU
Stringham HM
Welch R
Oravilahti A
Fernandes Silva L
FinnGen
Locke AE
Fuchsberger C
Service SK
Erdos MR
Bonnycastle LL
Kuusisto J
Stitziel NO
Hall IM
Morrison J
Ripatti S
Palotie A
Freimer NB
Collins FS
Mohlke KL
Scott LJ
Fauman EB
Burant C
Boehnke M
Laakso M
Wen X

Bilirubin
Carnitine
Genome-Wide Association Study
Glycerophospholipids
Humans
Male
Metabolomics
Quantitative Trait Loci
Solute Carrier Family 22 Member 5
Transcriptome


Response to Comment on: "35 Years of Joyner's Endurance Performance Model: Assessing the Contribution of Physiological Determinants of Performance Proxies in 888 Individuals from Recreational to World Class"

Mougin L
Bailey SJ
Jones AM
Joyner MJ
Mears SA
Pearce R
Zanini M


What is aging?

Zeitschrift fur Gerontologie und Geriatrie


Kommunikation im Alter aus multidisziplinärer Sicht


Reverse Triggering: Seeing More, Knowing Less?


From Black Boxes to Biomarkers: Artificial Intelligence in Surgical Retina


Clinical Outcomes and the Cause of Death in Patients on Dialysis Undergoing Percutaneous Coronary Intervention


From Snapshots to Stories: Cardiovascular Risk Trajectories and the Future of Longitudinal Risk Prediction


Beyond Endpoints: The Role of Prospective Technical Fidelity Quality Assurance in Modern Radiation Therapy Clinical Trials

International journal of radiation oncology, biology, physics

Pham J
Courtney PT
Price AT
Romero T
Qi XS
Lamb J
Steinberg ML
Henke LE
Cao M
Kishan AU


Reimagining Bioethics in the Era of AI Agents

The American journal of bioethics : AJOB


The Ethics of Integration: Why Healthcare AI Must Be Evaluated Within Clinical and Research Workflows


OMB Proposed Rule Change: The New Lysenkoism?


Scholarly Publications in an Era of Artificial Intelligence


The Negative Impact of Travel Budget Cuts on Toxicologic Pathology

Carter J
Frazier K
Werner J
Thuilliez C
Clements P
Ogawa K
Udupa V
Mecklenburg L
Panchal S


Palindromic Rheumatism: Revisiting the Approach to an Enigmatic Condition

International journal of rheumatic diseases


Changing the History of Science-An Editorial Perspective on Critical Developments in Current Citation Practice, "Forgetting" the Pioneers of Scientific Discoveries


Childhood-Onset Movement Disorders at the Forefront: From Genes to Precision Therapy

Movement disorders : official journal of the Movement Disorder Society


Holding the line: Ethics and surgical decision-making in an era of financial pressure in health care systems around the globe

Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA

Seil R
Herbst E
Milano G
Musahl V
Prill R
Enes Kayaalp M
Mengis N
Ayeni OR
Hirschmann MT


Equity requires epistemic justice: A research agenda for palliative care to meet the needs of people living with complex mental health conditions


From the Guest Editors


Integrity: The cornerstone of the veterinary profession

The Canadian veterinary journal = La revue veterinaire canadienne


Professional Autonomy as a Protective Factor Against Burnout: Important but Not Sufficient

Abstract: Burnout among healthcare professionals has become a critical challenge for healthcare systems worldwide. Increasing workload, administrative demands, and workforce shortages have contributed to rising levels of emotional exhaustion and professional disengagement. While burnout is often approached as an individual problem, organisational factors appear to play a central role in its development and prevention. Professional autonomy has emerged as a potentially protective factor, as greater control over clinical decision-making and work organisation is associated with improved well-being and job satisfaction. However, the benefits of autonomy depend on supportive organisational environments, adequate resources, and effective leadership. Furthermore, autonomy alone cannot offset the effects of excessive workload and chronic organisational stress. This editorial discusses the relationship between professional autonomy and burnout and argues that sustainable burnout prevention requires structural organisational changes in addition to promoting professional independence.


Optimising Performance Through Sleep: An Evidence-Based Review

Abstract: Sleep is increasingly being recognised as an important factor influencing athletic performance, recovery and overall health. This narrative review aims to discuss the factors that can affect sleep in athletes and how sleep can affect performance. Traditionally, athlete well-being has focused on training and nutrition; however, new evidence and initiatives now highlight sleep as an important element of performance. This review examines current evidence on sleep duration, sleep quality and sleep disturbances in athletic populations, with a particular focus on the effects related to competition. Athletes often report shorter sleep durations than non-athletes, despite experiencing less sleep fragmentation and quicker sleep onset. One study found that on nights before a competition day, athletes went to bed earlier (22:56 hr ± 49.2 min), woke up later (8:12 hr ± 58.6 min) and slept for longer (7:57 hr ± 60.9 min). A significant number of athletes face poor sleep quality, difficulty falling asleep, and excessive daytime sleepiness. Sleep disruptions are also common around competitions, with post-competition nights showing reductions in total sleep time and sleep quality compared to pre-competition nights. Factors contributing to this include late competition times, heightened physiological and psychological arousal, increased caffeine intake, travel demands and use of technology. Overall, these findings demonstrate that inadequate and disturbed sleep is widespread among athletes, especially during competition periods, which may impact recovery, cognitive function and emotional stability.


Platelet-Rich Plasma: Are We Ahead of the Evidence?


No rule, no accountability: Why intensive care needs a statutory triage framework


Distributed Manufacturing, Foreign Establishments, and Why the FDA's New Proposed Rule Matters to Clinical Pharmacology

Clinical pharmacology in drug development


Unlocking the power and potential of the Cas12 family members and their ancestors for crop genome editing


What Good Is a "Good Death?"

Journal of the American Geriatrics Society


[From clinical cases to daily practice]

Abstract: This issue of the Revue Médicale de Liège highlights the diversity of clinical situations encountered in daily practice, ranging from life-threatening emergencies to rare complications of modern therapies. These reports emphasize the importance of rigorous clinical reasoning, multimodality imaging and multidisciplinary management in optimizing patient care and safety.

Editorial
Journal Article
Introductory Journal Article
English Abstract


Greetings From the New Editor-in-Chief


Immunotherapy Rechallenge in HCC: A Second Chance for Response?

Liver international : official journal of the International Association for the Study of the Liver

Da Fonseca LG
Guerrero A
Muñoz-Martínez SG


Cone-Beam Computed Tomography in the Follow-Up of Endodontic Treatment: The Development of S3-Level Guidelines Including Evidence-Based and Expert-Led Recommendations

Meschi N
Pauwels R
Duncan HF
McGuigan MB
Cotti E
Del Fabbro M
Shemesh H
Jacobs R


Systemic regulation of the private healthcare sector is needed to ensure patient accessibility is not limited by out-of-pocket costs

Abstract: The viability of the Australian private healthcare sector, and hence, private psychiatric care, is determined by a range of complex, inter-related factors. The private health insurance industry and Medicare reimbursement partially underwrite the costs of procedures, private hospital care and some allied healthcare. Psychiatric hospital cover sits almost entirely within the most expensive private health insurance Gold tier cover. Private outpatient fees are set by medical specialists, and patients receive a Medicare reimbursement for these consultations. There has been increasing concern regarding out-of-pocket costs for patients accessing private psychiatric hospital and outpatient care. A substantial 15% of all health expenditure in Australia is paid directly by individuals as out-of-pocket costs - almost double the share contributed by private health insurers. It is estimated that 72% of these out-of-pocket costs is attributable to individual-physician fee variation. Instead of focussing on providers or payors, a systemic private healthcare regulatory approach is needed to address the overall costs issue.

Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists

Looi JC
Allison S
Bastiampillai T
Kisely S
Liu WM


Advancing the gerontological landscape through workforce innovation


Editorial on: 'Lowering the C-Reactive Protein Threshold Improves Risk Stratification in Acute Ulcerative Colitis: A Propensity-Matched Analysis'. Authors' Reply

Etchegaray A
Goetz N
Hanigan K
Phillips J
Kumar R
Tambakis G
Radford-Smith G
Walker G
Croft A


Technology or Context? Interpreting the Association Between IVUS Guidance and Mortality After Peripheral Arterial Intervention

Cardiovascular and interventional radiology

Munive AC
Otálvaro D
Torres Cortes DF
Mejía Núñez JA


Consent: Doctor, can you please do my operation?

Wickramasinghe NRL
Clement ND
Greenbrook JTV


Experience-based medicine: a new paradigm

European archives of psychiatry and clinical neuroscience

Leucht S
Hiller S
Priller J
Böge K
Seidel M
Rodolico A


Treatment for cognitive impairment in schizophrenia: insights from exercise-based integrative interventions


Editorial: Risankizumab in Refractory Crohn's Disease-From Real-World Effectiveness to Strategic Positioning and Early Monitoring. Authors' Reply

Ferreiro-Iglesias R
Zabana Y
Barreiro-de Acosta M


Editorial: Comparative Effectiveness in Chronic Constipation-Interpreting Real-World Evidence. Authors' Reply


Perspectives on the economic costs of disease outbreaks to health systems

Abstract: Disease outbreaks are non-random public health phenomena attributed to known or idiopathic human, animal, and animal-based factors; a realm referred to as the One Health concept; a new global public health order for control and prevention of epidemics, endemics, and pandemics. These are diseases of viral, prion, bacterial, fungal, and parasitic origin, transmitted between vertebrate animals and humans and vice versa. Emergence and re-emergence of zoonotic diseases such as rabies, Ebola, COVID-19, monkeypox, avian influenza, anthrax, brucellosis, leptospirosis, and Lyme disease continue to affect populations across the world, pointing to unexpected budget impacts of the affected countries.

Humans
Disease Outbreaks
Animals
Zoonoses
Public Health
Global Health
One Health
Delivery of Health Care
Cost of Illness
Communicable Diseases, Emerging


Urology for older adults: a blind spot in international guidelines?

Juliebø-Jones P
Somani BK
Baug S
Madaan S
Palumbo C
Jeong CW
Albersen M
Beisland C


Enhancing Multidisciplinary Collaboration in Healthcare to Achieve SDGs during the COVID-19 Pandemic


Closing Critical Gaps in the 2026 Bundibugyo Ebola Response: Five Actionable Priorities

Abstract: The 2026 Bundibugyo virus disease (BDBV) outbreak in the Democratic Republic of the Congo and adjacent Uganda has revealed major deficiencies in outbreak response. The available diagnostics, vaccines, and therapies were primarily designed against Zaire Ebola virus - leaving us ill-prepared for BDBV detection and control. We call for five immediate actions to strengthen existing efforts. First, rapidly establish a decentralized three-tier molecular diagnostic network to allow timely detection and genomic surveillance. Second, since there are few approved treatments that target BDBV specifically, adaptive platform trials should assess the potential of repurposed host-directed therapies. Third, in conflict-affected settings, routine enabling environment data collection to strengthen surveillance is needed, whilst digital proximity tracing and social support mechanisms, such as community tracing collaborative (CTC) responses to combat community transmission through contact identification and isolation, would also add value. Fourth, ring vaccination strategies with recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) as a post-exposure intervention should be explored, given the potential for cross-protection against BDBV. Fifth, implementation of extensive genomic surveillance should be enhanced to differentiate between continuous human transmission and sporadic zoonotic spillover events while informing ecology-based control strategies. Together, these recommendations highlight actionable, scalable steps that can be implemented quickly through existing systems and out-of-the-box solutions. Filling these key gaps could significantly affect the outcome of this current outbreak and enhance regional and global preparedness for future ebolavirus outbreaks.


Rewiring metabolic-immune circuitry in pancreatic ductal adenocarcinoma (PDAC)


Moving cardio-oncology upstream: Integrating cardiovascular prevention into routine cancer care


The declaration of Adelaide white paper: guidelines for author responsibility in peer review

Marcu LG
Clement C
Friedl A
Harbron R
Rühm W
Stoeva M
Thorne M
Toma-Dasu I
Trapp J
Wojcik A
Woloschak G


The limits of pooled evidence in early-stage NSCLC: are we comparing treatments or patients?


Is conization with lymph node dissection safe for International Federation of Gynecology and Obstetrics 2018 stage IB1 cervical cancer measuring 1 to 2 cm?

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society

El Hajj H
Gouy S
Limkin E
Scherier S
Morice P


Personalized circulating tumor DNA-based minimal residual disease assessment for optimizing interval debulking surgery timing in advanced ovarian cancer: toward precision surgical oncology


Same Pill, Different Impact - Reassessing the Efficacy of Nirmatrelvir-Ritonavir


Treatment and prevention of HIV/AIDS: Unfinished business

Abstract: Since the inception of World AIDS Day in 1988, advances with antiretroviral drugs have revolutionized the landscape of HIV/AIDS treatment and prevention. In 2025, we reflect on progress made, highlight promising therapeutic developments, and look ahead to what is needed to end the AIDS epidemic.

Humans
Acquired Immunodeficiency Syndrome
Anti-HIV Agents
HIV Infections


Reflection on the Legacy of Lawrence Gostin in Global Health

Abstract: The tenth anniversary of the publication of Lawrence Gostin's seminal treatise Global Health Law affords us the opportunity to reflect on his enduring legacy as a preeminent scholar, and one of the field's founding thought leaders.

The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics

Global Health
Humans
History, 20th Century
History, 21st Century


HIV/AIDS and COVID-19: Shared Lessons From 2 Pandemics

Abstract: The global experiences with the human immunodeficiency virus (HIV)/AIDS and coronavirus disease 2019 (COVID-19) pandemics hold important lessons for preparing for, and responding to, future outbreaks of emerging or reemerging infectious diseases. Scores of infectious diseases have emerged or reemerged over the past 4 decades, and future outbreaks are inevitable. The next emerging pathogen likely will again come from unanticipated sources and pose puzzles in terms of microbiology, transmission, natural history, pathogenesis, and epidemiology, and will present challenges to developing countermeasures such as diagnostics, therapeutics, and vaccines. Although dozens of lessons could be addressed, 8 selected lessons common to HIV/AIDS and COVID-19 are addressed here. Consideration of the commonality of lessons learned from HIV/AIDS and COVID-19, the 2 most devastating pandemics over the past half century, will help us-and those who follow us-to minimize the impact of future outbreaks and prevent them from becoming global pandemics.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Humans
Acquired Immunodeficiency Syndrome
COVID-19
Global Health
HIV Infections
Pandemics
SARS-CoV-2


Expanded Access of Unproven Drugs: Not the Final Word

Humans
Health Services Accessibility
Drug Approval
United States


RNA vaccines: A transformational advance

Abstract: Vaccines have stemmed many infectious diseases, but when SARS-CoV-2 emerged, traditional vaccine development would not have been fast enough. This year's Nobel Prize in Physiology or Medicine recognizes work that enabled the rapid development of mRNA vaccines, which halted the COVID-19 pandemic. The feat was a product of basic biological insights coupled with technological innovations, which have transformed vaccine design.

Humans
mRNA Vaccines
Pandemics
COVID-19
COVID-19 Vaccines
Vaccines


What keeps me up at night

Abstract: The lessons of COVID-19 must be heeded if the world is to be prepared for the next emergent pathogen with pandemic potential.


Increased neutralization potency and breadth elicited by a SARS-CoV-2 mRNA vaccine forming virus-like particles

Abstract: Vaccines have played a fundamental role in the control of infectious diseases. We previously developed a messenger RNA (mRNA) vaccine against HIV-1 that forms virus-like particles (VLPs) through coexpression of the viral envelope with Gag. Here, we applied the same principle to the design of a VLP-forming mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To promote cognate interaction with simian immunodeficiency virus (SIV) Gag, we engineered different chimeric proteins encompassing the ectodomain and the transmembrane region of the SARS-CoV-2 Spike protein from the Wuhan-Hu-1 strain fused to the gp41 cytoplasmic tail of either HIV-1 (strain WITO) or SIV (strain mac239) with or without a partial truncation at amino acid 745 to enhance membrane expression. Upon cotransfection with SIV gag mRNA, the Spike-SIVCT.745 (SSt) chimera yielded the highest level of cell-surface expression and extracellular VLP release. Immunization of BALB/c mice with SSt+gag mRNA at 0, 4, and 16 wk induced higher titers of Spike-binding and autologous neutralizing antibodies at all time points compared to SSt mRNA alone. Furthermore, mice immunized with SSt+gag mRNA developed neutralizing antibodies effective against different variants of concern. These data demonstrate that the Gag/VLP mRNA platform can be successfully applied to vaccines against different agents for the prevention of infectious diseases of global relevance.

Proceedings of the National Academy of Sciences of the United States of America

Zhang P
Falcone S
Tsybovsky Y
Singh M
Gopan V
Miao H
Seo Y
Rogers D
Renzi I
Lai YT
Narayanan E
Stewart-Jones G
Himansu S
Carfi A
Fauci AS
Lusso P

Humans
Animals
Mice
COVID-19 Vaccines
Antibodies, Viral
SARS-CoV-2
COVID-19
Antibodies, Neutralizing
Spike Glycoprotein, Coronavirus
Simian Immunodeficiency Virus

Journal Article
Research Support, N.I.H., Intramural


Audio Interview: Dr. Fauci on Infectious Disease Challenges


Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities-workshop report

Abstract: On November 7th and 8th, 2022, The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), The Coalition for Epidemic Preparedness Innovation (CEPI), The Bill & Melinda Gates Foundation (BMGF), The Biomedical Advanced Research and Development Authority (BARDA), and the Wellcome Trust hosted a virtual workshop entitled “Mucosal Vaccines for SARS-CoV-2: Scientific Gaps and Opportunities.” During the workshop, researchers and vaccine developers from around the world discussed the potential of mucosal vaccines to block SARS-CoV-2 transmission and reviewed the status of SARS-CoV-2 mucosal vaccine research. Here, we summarize key challenges and opportunities in basic, translational, and clinical research that were highlighted during the meeting. We also provide recommendations to advance the field and accelerate the development of mucosal vaccines for SARS-CoV-2.

Knisely JM
Buyon LE
Mandt R
Farkas R
Balasingam S
Bok K
Buchholz UJ
D'Souza MP
Gordon JL
King DFL
Le TT
Leitner WW
Seder RA
Togias A
Tollefsen S
Vaughn DW
Wolfe DN
Taylor KL
Fauci AS


Pandemic Preparedness and Response: Lessons From COVID-19

Abstract: The global experience with COVID-19 holds important lessons for preparing for, and responding to, future emergences of pathogens with pandemic potential.

Humans
COVID-19
Pandemics
Civil Defense
Global Health
Knowledge


MAdCAM-1 costimulation in the presence of retinoic acid and TGF-β promotes HIV infection and differentiation of CD4+ T cells into CCR5+ TRM-like cells

Abstract: CD4+ tissue resident memory T cells (TRMs) are implicated in the formation of persistent HIV reservoirs that are established during the very early stages of infection. The tissue-specific factors that direct T cells to establish tissue residency are not well defined, nor are the factors that establish viral latency. We report that costimulation via MAdCAM-1 and retinoic acid (RA), two constituents of gut tissues, together with TGF-β, promote the differentiation of CD4+ T cells into a distinct subset α4β7+CD69+CD103+ TRM-like cells. Among the costimulatory ligands we evaluated, MAdCAM-1 was unique in its capacity to upregulate both CCR5 and CCR9. MAdCAM-1 costimulation rendered cells susceptible to HIV infection. Differentiation of TRM-like cells was reduced by MAdCAM-1 antagonists developed to treat inflammatory bowel diseases. These finding provide a framework to better understand the contribution of CD4+ TRMs to persistent viral reservoirs and HIV pathogenesis.

Vimonpatranon S
Goes LR
Chan A
Licavoli I
McMurry J
Wertz SR
Arakelyan A
Huang D
Jiang A
Huang C
Zhou J
Yolitz J
Girard A
Van Ryk D
Wei D
Hwang IY
Martens C
Kanakabandi K
Virtaneva K
Ricklefs S
Darwitz BP
Soares MA
Pattanapanyasat K
Fauci AS
Arthos J
Cicala C

Humans
CD4-Positive T-Lymphocytes
HIV Infections
Transforming Growth Factor beta
Tretinoin
Cell Differentiation
Immunologic Memory
Receptors, CCR5

Journal Article
Research Support, Non-U.S. Gov't


Rethinking next-generation vaccines for coronaviruses, influenzaviruses, and other respiratory viruses

Abstract: Viruses that replicate in the human respiratory mucosa without infecting systemically, including influenza A, SARS-CoV-2, endemic coronaviruses, RSV, and many other "common cold" viruses, cause significant mortality and morbidity and are important public health concerns. Because these viruses generally do not elicit complete and durable protective immunity by themselves, they have not to date been effectively controlled by licensed or experimental vaccines. In this review, we examine challenges that have impeded development of effective mucosal respiratory vaccines, emphasizing that all of these viruses replicate extremely rapidly in the surface epithelium and are quickly transmitted to other hosts, within a narrow window of time before adaptive immune responses are fully marshaled. We discuss possible approaches to developing next-generation vaccines against these viruses, in consideration of several variables such as vaccine antigen configuration, dose and adjuventation, route and timing of vaccination, vaccine boosting, adjunctive therapies, and options for public health vaccination polices.

Humans
COVID-19
SARS-CoV-2
Orthomyxoviridae
Influenza, Human
Influenza Vaccines
Antibodies, Viral


Forty years of investment in HIV research: progress towards ending the HIV pandemic and preparation for future pandemics

Journal of the International AIDS Society

Read SW
Kim P
Marovich M
Dieffenbach CW
Fauci AS


It Ain't Over Till It's Over … but It's Never Over - Emerging and Reemerging Infectious Diseases


Anti-PF4 antibodies associated with disease severity in COVID-19

Abstract: Severe COVID-19 is characterized by a prothrombotic state associated with thrombocytopenia, with microvascular thrombosis being almost invariably present in the lung and other organs at postmortem examination. We evaluated the presence of antibodies to platelet factor 4 (PF4)-polyanion complexes using a clinically validated immunoassay in 100 hospitalized patients with COVID-19 with moderate or severe disease (World Health Organization score, 4 to 10), 25 patients with acute COVID-19 visiting the emergency department, and 65 convalescent individuals. Anti-PF4 antibodies were detected in 95 of 100 hospitalized patients with COVID-19 (95.0%) irrespective of prior heparin treatment, with a mean optical density value of 0.871 ± 0.405 SD (range, 0.177 to 2.706). In contrast, patients hospitalized for severe acute respiratory disease unrelated to COVID-19 had markedly lower levels of the antibodies. In a high proportion of patients with COVID-19, levels of all three immunoglobulin (Ig) isotypes tested (IgG, IgM, and IgA) were simultaneously elevated. Antibody levels were higher in male than in female patients and higher in African Americans and Hispanics than in White patients. Anti-PF4 antibody levels were correlated with the maximum disease severity score and with significant reductions in circulating platelet counts during hospitalization. In individuals convalescent from COVID-19, the antibody levels returned to near-normal values. Sera from patients with COVID-19 induced higher levels of platelet activation than did sera from healthy blood donors, but the results were not correlated with the levels of anti-PF4 antibodies. These results demonstrate that the vast majority of patients with severe COVID-19 develop anti-PF4 antibodies, which may play a role in the clinical complications of COVID-19.

Liu Q
Miao H
Li S
Zhang P
Gerber GF
Follmann D
Ji H
Zeger SL
Chertow DS
Quinn TC
Robinson ML
Kickler TS
Rothman RE
Fenstermacher KZJ
Braunstein EM
Cox AL
Farci P
Fauci AS
Lusso P

Humans
Male
Female
Platelet Factor 4
COVID-19
Heparin
Thrombocytopenia
Antibodies
Immunologic Factors
Severity of Illness Index

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural


Interval between prior SARS-CoV-2 infection and booster vaccination impacts magnitude and quality of antibody and B cell responses

Abstract: SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a 2-month period, we evaluated antibody and B cell responses to a third-dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies and memory B cells. Spike-specific B cell responses from recent infection (<180 days) were elevated at pre-boost but comparatively less so at 60 days post-boost compared with uninfected individuals, and these differences were linked to baseline frequencies of CD27lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B cell responses to booster vaccines are impeded by recent infection.

Buckner CM
Kardava L
El Merhebi O
Narpala SR
Serebryannyy L
Lin BC
Wang W
Zhang X
Lopes de Assis F
Kelly SEM
Teng IT
McCormack GE
Praiss LH
Seamon CA
Rai MA
Kalish H
Kwong PD
Proschan MA
McDermott AB
Fauci AS
Chun TW
Moir S

Humans
Antibodies, Neutralizing
Antibodies, Viral
COVID-19
COVID-19 Vaccines
SARS-CoV-2
Vaccination
Viral Vaccines
B-Lymphocytes
mRNA Vaccines


Legends of allergy and immunology: Lorenzo Moretta-Unfolding the mysteries of NK cells and much more

Humans
Hypersensitivity
Killer Cells, Natural
Allergy and Immunology


Recent SARS-CoV-2 infection abrogates antibody and B-cell responses to booster vaccination

Abstract: SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a two-month period, we evaluated antibody and B-cell responses to a third dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies, and memory B cells. Spike-specific B-cell responses from recent infection were elevated at pre-boost but comparatively less so at 60 days post-boost compared to uninfected individuals, and these differences were linked to baseline frequencies of CD27 lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B-cell responses to booster vaccines are impeded by recent infection.

medRxiv : the preprint server for health sciences

Buckner CM
Kardava L
Merhebi OE
Narpala SR
Serebryannyy L
Lin BC
Wang W
Zhang X
de Assis FL
Kelly SEM
Teng IT
McCormack GE
Praiss LH
Seamon CA
Rai MA
Kalish H
Kwong PD
Proschan MA
McDermott AB
Fauci AS
Chun TW
Moir S


Monkeypox - Past as Prologue

Disease Outbreaks
Humans
Mpox, Monkeypox
Monkeypox virus


Prototype Pathogen Approach for Vaccine and Monoclonal Antibody Development: A Critical Component of the NIAID Plan for Pandemic Preparedness

Abstract: Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) emerged 20 years ago, presaging a series of subsequent infectious disease epidemics of international concern. The recent emergence of SARS-CoV-2 has underscored the importance of targeted preparedness research to enable rapid countermeasure development during a crisis. In December 2021 the National Institute of Allergy and Infectious Diseases (NIAID), building upon the successful strategies developed during the SARS-CoV-2 response and to prepare for future pandemics, published a pandemic preparedness plan that outlined a research strategy focused on priority pathogens, technology platforms, and prototype pathogens. To accelerate the discovery, development, and evaluation of medical countermeasures against new or previously unknown pathogens of pandemic potential, we present here a strategy of research directed at select prototype pathogens. In this manner, leveraging a prototype pathogen approach may serve as a powerful cornerstone in biomedical research preparedness to protect public health from newly emerging and reemerging infectious diseases.

Cassetti MC
Pierson TC
Patterson LJ
Bok K
DeRocco AJ
Deschamps AM
Graham BS
Erbelding EJ
Fauci AS

National Institute of Allergy and Infectious Diseases (U.S.)


Early human B cell signatures of the primary antibody response to mRNA vaccination

Abstract: Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.

Kardava L
Rachmaninoff N
Lau WW
Buckner CM
Trihemasava K
Blazkova J
Lopes de Assis F
Wang W
Zhang X
Wang Y
Chiang CI
Narpala S
McCormack GE
Liu C
Seamon CA
Sneller MC
O'Connell S
Li Y
McDermott AB
Chun TW
Fauci AS
Tsang JS
Moir S

2019-nCoV Vaccine mRNA-1273
Antibody Formation
B-Lymphocytes
COVID-19
Humans
Immunity, Cellular
Immunoglobulin A
Immunoglobulin G
RNA, Messenger
SARS-CoV-2
Vaccination


Combination anti-HIV antibodies provide sustained virological suppression

Abstract: Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.

Sneller MC
Blazkova J
Justement JS
Shi V
Kennedy BD
Gittens K
Tolstenko J
McCormack G
Whitehead EJ
Schneck RF
Proschan MA
Benko E
Kovacs C
Oguz C
Seaman MS
Caskey M
Nussenzweig MC
Fauci AS
Moir S
Chun TW

Anti-HIV Agents
Antibodies, Monoclonal
Antibodies, Neutralizing
Broadly Neutralizing Antibodies
Double-Blind Method
HIV Antibodies
HIV Infections
HIV-1
Humans
Viral Load
Viremia

Journal Article
Randomized Controlled Trial


The Concept of Classical Herd Immunity May Not Apply to COVID-19

Journal Article
Research Support, N.I.H., Extramural


Universal Coronavirus Vaccines - An Urgent Need

Animals
COVID-19
COVID-19 Vaccines
Chiroptera
Communicable Diseases, Emerging
Coronavirus
Endemic Diseases
Humans
Pharmaceutical Research
SARS-CoV-2
Vaccine Efficacy
Viral Vaccines