vo2max 2.0.0: 2026 evidence rebuild of the Generation I expert module (O. Borysova). Adds every independent genome-wide-significant lead of the largest 2021-2026 GWAS for the trait plus functional variants, with evidence tiers (S-D); errors in the original rows corrected with recorded reasons (provenance in logs/authoring.log); gnomAD v4.1 frequencies; closed. Built with just-dna-compiler main a05cd54.

data/vo2max/README.md

@@ -0,0 +1,112 @@
+# VO2 Max — aerobic fitness and training response (version 2.0.0)
+
+This module looks at spots in your DNA linked to **cardiorespiratory fitness** — how much oxygen your
+body can use during hard exercise (VO2max) — and, in the original rows, to how much VO2max improves with
+training. Every effect here is small. Fitness depends far more on training, age, sex and body
+composition than on any DNA spot, and nothing in this module is a diagnosis.
+
+## What is in it
+
+| Group (`category`) | Rows | What it means |
+|---|---|---|
+| *VO2max GWAS lead (direct fitness test)* | 14 variants × 3 genotypes | Genome-wide significant (p < 5×10⁻⁸) in the UK Biobank fitness GWAS (N = 69,416 with a submaximal cycle-ergometer test) — Cai et al. 2023, *Nat Commun*, PMID 37400433, Supplementary Table 3 / Supplementary Data 1 |
+| *Heart-rate-informed fitness locus* | 123 variants × 3 genotypes | Genome-wide significant for **resting heart rate** in the same paper (UK Biobank, >450,000), kept in the 160-variant fitness instrument because their effect on measured fitness was directionally consistent (nominal p < 0.05 for fitness). Their fitness effects are weak individually and partly reflect resting heart rate |
+| *Candidate gene (tested, small or no effect)* | 2 variants × 3 genotypes | ACTN3 R577X (rs1815739, weight 0 — no endurance effect in 2025 meta-analysis) and PPARGC1A Gly482Ser (rs8192678) |
+| *(blank — original rows)* | 13 variants, 39 rows | Olga Borysova's expert-curated rows on **VO2max training response** (HERITAGE and related studies), kept unchanged |
+
+Totals: 152 variants, 456 genotype rows, 161 study rows citing 12 papers.
+
+## How the rows were chosen (selection rule, 2026 rebuild)
+
+* **Tier A (GWAS).** Anchor: Cai L, et al. *Causal associations between cardiorespiratory fitness and type 2
+  diabetes.* Nat Commun 2023;14:3904 (PMID 37400433) — the largest genome-wide study of measured
+  cardiorespiratory fitness available 2021–2026. Every variant of its 160-variant fitness instrument
+  (Supplementary Data 1: 14 direct fitness-GWAS leads + 146 resting-heart-rate variants retained after
+  radial filtering) was taken, with the effect allele, effect-allele frequency, β (ml O₂·min⁻¹·kg⁻¹
+  fat-free mass per allele), s.e. and p transcribed from that table. 22 were dropped because they cannot be
+  represented honestly (see below). rs7412 (APOE) is in the instrument and already in the legacy rows, so
+  only a `studies.csv` row was added for it.
+* **Tier B (candidate/functional).** Only candidate variants with a 2019–2026 meta-analysis were added:
+  ACTN3 rs1815739 (Chelly 2025, PMID 40845214; El Ouali 2024, PMID 38609671) and PPARGC1A rs8192678
+  (Su 2025, PMID 41574190; Chen 2019, PMID 31938000). **Candidate-gene evidence for athletic performance is
+  weak and inconsistent**: a 2026 systematic review of 204 studies (PMID 42931598) concluded that individual
+  variants have modest, context-dependent effects and that the evidence does not support talent
+  identification or training prescription. ACE I/D, EPAS1 and EPOR were considered and not added (below).
+* **Tier C (legacy).** Olga Borysova's 39 rows are unchanged.
+
+Considered and not used as row sources: HUNT direct VO2peak GWAS (Klevjer 2022, PMID 35482759; N = 4,525,
+loci largely unreplicated), HUNT and FinnGen polygenic-score papers (PMIDs 41402372, 40672480 preprint,
+42087449 — genome-wide scores, no per-variant lead table), Predict-HIIT training-response GWAS (PMID
+33985508; no genome-wide-significant variant), small athlete GWAS (PMID 41345885) and a 228-person HIIT
+GWAS (PMID 37170954). No cardiorespiratory-fitness score is in the PGS Catalog as of this rebuild.
+
+### Dropped Tier A candidates (22 of 160)
+
+* 8 indels published only as GRCh37 markers with no rsID (e.g. `6:122514171_CTTTT_C`) — nothing here lifts
+  coordinates between builds.
+* 12 multi-allelic repeat or homopolymer indels whose biallelic I/D coding in the study cannot be mapped to a
+  single VCF allele (including rs763773724, the HTT CAG repeat): rs753131216, rs781155278, rs373999074,
+  rs72394060, rs781388561, rs564190295, rs763773724, rs138564056, rs375963061, rs35987999, rs796269914,
+  rs5879832.
+* 2 strand-ambiguous (C/G) SNPs with effect-allele frequency between 0.42 and 0.58: rs7136054 (0.484),
+  rs2054266 (0.501). The 16 other A/T or C/G SNPs were kept because the study's EAF is far from 0.5 and
+  agrees with UK reference frequencies (TwinsUK/ALSPAC in dbSNP).
+
+## Weights (two scales — read before summing)
+
+* **New GWAS rows:** weight = +β/SD × number of copies of the fitness-raising allele (0, 1 or 2), with
+  SD = 6.9 ml O₂·min⁻¹·kg⁻¹ FFM (implied by the paper's "3% lower diabetes risk per unit = 19% per SD";
+  sex-specific SDs 6.4 and 7.1). Zero copies = 0.0 (`neutral`). Range 0.010–0.180.
+* **Candidate rows:** ln(OR) of the published genotype odds ratio — PPARGC1A Gly/Gly (C/C) = +0.174
+  (OR 1.19 for elite endurance-athlete status, Caucasians); ACTN3 = 0.0 for all genotypes.
+* **Legacy rows** (blank `curator`/`method`): Olga Borysova's ordinal scale {−1, −0.5, 0, 0.5, 1} for
+  training response.
+* Positive = favourable (higher fitness). The scales are **not comparable**: a single legacy row outweighs
+  the sum of all new GWAS rows at typical genotypes. Do not read a module "net weight" as a fitness score.
+  The whole 160-variant score explained about 1% of fitness variance in the Fenland validation cohort.
+
+## Limits
+
+* All Tier A effects come from people of European ancestry in the UK; transfer to other ancestries is
+  unknown.
+* VO2max in UK Biobank was **estimated** from heart rate during a submaximal cycle test, not measured
+  maximally; heart-rate genetics therefore enter both the trait and the instrument.
+* The 146 heart-rate variants were selected *for* consistency with fitness, so their fitness betas are
+  optimistic (selection on the same data).
+* Fitness level (new rows) and training response (legacy rows) are different traits.
+* Effect alleles were taken from the paper. The GWAS Catalog record GCST90310239 lists rs67622553-G as
+  fitness-raising, which contradicts the paper's own Supplementary Table 3 and Supplementary Data 1 (T
+  raises fitness); the paper was followed. For SLC35F1 the instrument uses rs11153730 where Supplementary
+  Table 3 names rs1572226.
+* No `provenance_quote` was authored for the new rows; their numbers come from a supplementary workbook,
+  which the literature checker does not open.
+
+## Provenance
+
+Original module: Olga Borysova (expert curation, v1.x). 2026 rebuild (v2.0.0): AI-assisted, recorded in
+`authorship:` as `ai, agent`; no human has reviewed the new rows yet. Rows added in 2026 carry
+`curator = ai-agent (2026 rebuild, just-module-creator)`.
+
+## Evidence tiers
+
+Every variant carries an evidence tier in `flags` (`tier:S` … `tier:D`) and in `priority`
+(S = high, A = medium, B/C/D = low). The tier never changes `weight`. Most variants in this module are
+weak signals, so the top tier is **S**, kept for the few variants that matter on their own. New (2026) rows
+also start their conclusion with the tier's label.
+
+| Tier | Meaning | Variants (of which legacy) |
+|---|---|---|
+| S | Strong evidence: an effect large enough to matter on its own (OR/HR ≥ 1.5 or ≤ 0.67, or ≥ 0.5 SD), robustly supported | 0 (0) |
+| A | Well established, small effect (research grade): genome-wide significant in the anchor GWAS and in ≥ 1 further publication, same direction | 3 (0) |
+| B | Single-study signal, small effect (research grade): genome-wide significant in the anchor GWAS only | 11 (0) |
+| C | Early evidence (research only): not genome-wide significant for this trait | 137 (13) |
+| D | Not supported: contradicted, or null in large GWAS / meta-analysis | 1 (0) |
+
+No variant reaches S. Most rows are C, because the heart-rate-informed loci are only nominally associated with measured fitness and the training-response rows come from candidate-gene studies. Replication was read from the GWAS Catalog (REST v2, retrieved 2026-11-03; cohorts of different
+publications may overlap). `also_in:<module>` marks the 6 variants that also appear in another just-dna
+module. Summing weights across modules counts those twice. The rules are adapted from the Longevity Map v2
+requirements (`docs/longevitymap_v2/`).
+
+## Corrections to the original expert-curated rows
+
+The 2026 audit of the Generation I content (Supplementary Table S14 of the Just-DNA-Lite paper) found no errors in this module's original rows that were still present in v1.1.0; the one Generation I error (a mistyped PMID) was already fixed when the module was converted to the current format.

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data/vo2max/manifest.json

@@ -2,11 +2,11 @@
   "manifest_version": "1.0",
   "schema_version": "1.0",
   "identity": {
-    "namespace": "just-dna-seq",
+    "namespace": null,
     "name": "vo2max",
-    "version": "1.1.0",
+    "version": "2.0.0",
     "version_coerced_from": null,
-    "canonical_id": "just-dna-seq/vo2max@1.1.0"
+    "canonical_id": null
   },
   "display": {
     "title": "VO2 Max",
@@ -21,100 +21,280 @@
   "method": "expert-curated",
   "license": null,
   "authority_precedence": [],
-  "weighting": null,
-  "owner": "just-dna-seq",
+  "weighting": {
+    "scale": "Mixed, two scales. (1) Rows with method 'gwas-derived' or 'literature-curated' (added 2026, curator 'ai-agent (2026 rebuild, just-module-creator)'): GWAS rows use +beta_SD per copy of the fitness-raising allele x number of copies (het = beta/SD, hom = 2*beta/SD, zero copies = 0.0, neutral), where beta is the per-allele effect on estimated VO2max (ml O2/min/kg fat-free mass) from Cai et al. 2023 (PMID 37400433, Supplementary Data 1) and SD = 6.9 ml O2/min/kg FFM; range 0.010 to 0.180. Candidate-gene rows use ln(OR) of the published genotype odds ratio (PPARGC1A Gly/Gly = +0.174; ACTN3 = 0.0 for every genotype because the 2025 meta-analysis found no endurance effect). (2) Legacy rows (blank curator/method, i.e. defaults just-dna-seq / expert-curated, by Olga Borysova): curator-set ordinal scale in {-1.0, -0.5, 0, 0.5, 1.0} for VO2max training response; not on the beta scale.",
+    "method": "Tier A: every variant of the 160-variant cardiorespiratory-fitness instrument of Cai et al. 2023 (14 genome-wide-significant leads of the direct UK Biobank fitness GWAS, N=69,416, plus 146 resting-heart-rate GWAS variants retained by radial filtering), minus 22 that could not be represented (8 without rsID on GRCh37 only, 12 multi-allelic repeat indels, 2 strand-ambiguous SNPs with EAF 0.42-0.58). Effect alleles and betas transcribed from the paper's Supplementary Data 1; all betas positive (fitness-raising allele). Tier B: replicated candidate variants with a 2024-2026 meta-analysis. Tier C: legacy rows kept unchanged.",
+    "note": "Positive = favourable (higher fitness), negative = unfavourable. The two scales are NOT comparable: one legacy row (|weight| 0.5-1.0) outweighs the entire sum of the new GWAS rows at typical genotypes, so a module 'net weight' is dominated by the legacy training-response rows. Not comparable with other modules. Per-variant effects are very small; the 160-variant score explained about 1% of fitness variance in Fenland. Not a diagnosis."
+  },
+  "owner": null,
   "authors": [],
-  "authorship": [],
+  "authorship": [
+    {
+      "who": "Olga Borysova",
+      "role": "created",
+      "kind": [
+        "human",
+        "human_expert"
+      ],
+      "at": null
+    },
+    {
+      "who": "ai-agent (2026 rebuild, just-module-creator)",
+      "role": "edited",
+      "kind": [
+        "ai",
+        "agent"
+      ],
+      "at": "2026-11-03"
+    }
+  ],
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-    "weights_rows": 39,
-    "study_count": 19,
-    "gene_count": 12,
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+    "weights_rows": 456,
+    "study_count": 161,
+    "gene_count": 132,
     "genes": [
       "ACSL1",
+      "ACTN3",
+      "ACTN4",
+      "ADCK1",
+      "ADGRV1",
+      "AGAP5",
       "AMPD1",
       "APOE",
+      "ARHGAP10",
+      "ARHGAP26",
+      "ARHGEF40",
+      "ATXN1",
+      "B3GAT3",
+      "B3GNT7",
+      "BAHCC1",
+      "BCAR3",
       "BIRC7",
+      "C10orf71",
+      "CACNA1C",
+      "CACNA1D",
+      "CACNB2",
+      "CADM2",
+      "CALCRL",
       "CAMTA1",
+      "CASP7",
+      "CCDC141",
+      "CD40",
+      "CDH2",
+      "CHRM2",
+      "CLIC5",
+      "CLMP",
+      "CMYA5",
+      "CWF19L2",
+      "CXADR",
       "DAAM1",
+      "DGLUCY",
+      "DLC1",
+      "DNAH2",
+      "FARP1",
+      "FBXL17",
+      "FHOD3",
       "FLJ44450",
+      "FNDC3B",
+      "FRMD4B",
+      "GCKR",
+      "GJA1",
+      "GMDS",
+      "GNAS",
+      "GNB4",
+      "GPATCH2",
       "GSTP1",
+      "HEATR5A",
+      "INPP5A",
+      "IP6K1",
+      "JAZF1",
+      "KANSL1",
+      "KCNH2",
+      "KHNYN",
+      "KIAA1755",
+      "KLHL42",
+      "LINC00880",
+      "LINC01122",
+      "LINC01267",
+      "LMCD1",
+      "MAP3K1",
+      "MEF2C-AS2",
+      "MKLN1",
+      "MRPS30",
+      "MSH6",
+      "MXRA7",
+      "MYH11",
+      "MYH6",
       "NDN",
+      "NFAT5",
+      "NFATC1",
       "NLGN1",
+      "NPAS2",
+      "NR3C2",
+      "NUP205",
+      "PDE3A",
+      "PKHD1",
+      "PLEC",
+      "PMP22",
+      "POC5",
+      "PPARGC1A",
+      "RAB40C",
+      "RASSF3",
+      "RBM20",
+      "RBM33",
       "RGS18",
-      "ZIC4"
+      "RNF207",
+      "RNU6-976P",
+      "RPL23AP93",
+      "SCG3",
+      "SCN10A",
+      "SERTAD2",
+      "SLC35F1",
+      "SLC52A1",
+      "SMARCAD1",
+      "SNCAIP",
+      "SPAAR",
+      "SPC24",
+      "SPEG",
+      "SPON1",
+      "SREBF1",
+      "SRL",
+      "SSPN",
+      "STN1",
+      "SVIL",
+      "SYNM-AS1",
+      "TCF7L2",
+      "TCP1P3",
+      "TEKT5",
+      "TET1",
+      "THRB",
+      "TJP2",
+      "TMEM131L",
+      "TMEM161B",
+      "TNR",
+      "TP53I11",
+      "TRPM4",
+      "TVP23C",
+      "VAMP9P",
+      "VSNL1",
+      "WDHD1",
+      "XYLT1",
+      "ZFPM2",
+      "ZHX3",
+      "ZIC4",
+      "ZNF44",
+      "ZNF800",
+      "ZNRD2"
+    ],
+    "categories": [
+      "Candidate gene (tested, small or no effect)",
+      "Heart-rate-informed fitness locus",
+      "VO2max GWAS lead (direct fitness test)"
     ],
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+      "VRS allele identity covers 234/241 allele(s) in resolution.csv (97%) — 7 carry no ga4gh:VA. id. Anything keying on the VA sees only the covered fraction.",
+      "  7 allele(s): an indel or MNV: justification needs the reference sequence, so only the enricher can mint it (re-run it online)"
+    ],
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+      "  7 allele(s): an indel or MNV: justification needs the reference sequence, so only the enricher can mint it (re-run it online)"
     ],
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     "resolution_sources": [
       "cache"
     ],
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+    "vrs_alleles_identified": 234,
     "positional_rows": 0,
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+    "sources": [
+      "gnomad"
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+    "datasets": [
+      "gnomad_v4.1_joint"
+    ],
+    "populations": [
+      "global",
+      "afr",
+      "ami",
+      "amr",
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       "resolution"
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     "licenses": [
-      "Apache-2.0"
+      "Apache-2.0",
+      "CC0-1.0"
     ],
     "attributions": [
-      "Ensembl (https://www.ensembl.org)"
+      "Ensembl (https://www.ensembl.org)",
+      "gnomAD, Broad Institute (https://gnomad.broadinstitute.org)"
+    ],
+    "notices": [
+      "CC0 public-domain dedication for the primary exome/genome data; attribution requested but not required. Users agree not to attempt to reidentify participants. Some layered annotations carry their own terms (SpliceAI is CC BY-NC 4.0, academic/non-commercial)."
     ],
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@@ -124,37 +304,19 @@
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-        "detail": "none of 7 citation(s) carries an authored DOI or PMC id, so there was nothing to compare against PubMed's own",
-        "source": "pubmed",
-        "release": null,
-        "checked_at": "2026-09-26T17:35:41Z",
-        "producer": "just-dna-enricher 0.7.2"
-      },
       {
         "check": "clinical_significance",
         "subjects": 0,
@@ -163,8 +325,8 @@
         "detail": null,
         "source": "clinvar",
         "release": "clinvar_2026-06-27",
-        "checked_at": "2026-09-26T23:44:40Z",
-        "producer": "just-dna-enricher 0.7.0"
+        "checked_at": "2026-11-04T09:00:25Z",
+        "producer": "just-dna-enricher 0.7.3"
       },
       {
         "check": "dataset_currency",
@@ -174,8 +336,8 @@
         "detail": "the module records no release, so it makes no claim about where its rows came from",
         "source": null,
         "release": null,
-        "checked_at": "2026-09-26T23:44:40Z",
-        "producer": "just-dna-enricher 0.7.0"
+        "checked_at": "2026-11-04T09:00:25Z",
+        "producer": "just-dna-enricher 0.7.3"
       },
       {
         "check": "evidence_status_currency",
@@ -185,8 +347,8 @@
         "detail": "this module records no citation drafted from CIViC's API, so there is no recorded curation status to re-ask about",
         "source": "civic",
         "release": null,
-        "checked_at": "2026-09-26T23:44:40Z",
-        "producer": "just-dna-enricher 0.7.0"
+        "checked_at": "2026-11-04T09:00:25Z",
+        "producer": "just-dna-enricher 0.7.3"
       },
       {
         "check": "genome_build_agreement",
@@ -196,19 +358,8 @@
         "detail": "the GRCh37 service is the only thing that can tell an old-assembly coordinate from a wrong ref, and there is no local GRCh37 data",
         "source": "ensembl-grch37",
         "release": null,
-        "checked_at": "2026-09-26T23:44:40Z",
-        "producer": "just-dna-enricher 0.7.0"
-      },
-      {
-        "check": "provenance_quote",
-        "subjects": 0,
-        "findings": 0,
-        "skipped": "nothing_to_check",
-        "detail": "no provenance quote or regex on any citation, so none of them asked this question",
-        "source": "europepmc",
-        "release": null,
-        "checked_at": "2026-09-26T17:35:41Z",
-        "producer": "just-dna-enricher 0.7.2"
+        "checked_at": "2026-11-04T09:00:25Z",
+        "producer": "just-dna-enricher 0.7.3"
       },
       {
         "check": "published_refutation",
@@ -218,19 +369,19 @@
         "detail": "no authored direction sits beside a published refutation (basis accepted)",
         "source": "civic",
         "release": "civic_01-Sep-2026",
-        "checked_at": "2026-09-26T23:44:40Z",
-        "producer": "just-dna-enricher 0.7.0"
+        "checked_at": "2026-11-04T09:00:25Z",
+        "producer": "just-dna-enricher 0.7.3"
       },
       {
         "check": "reference_allele",
-        "subjects": 13,
+        "subjects": 0,
         "findings": 0,
-        "skipped": null,
-        "detail": null,
+        "skipped": "offline",
+        "detail": "no sequence access this run, so no authored ref was compared",
         "source": "seqrepo",
         "release": null,
-        "checked_at": "2026-09-26T17:35:39Z",
-        "producer": "just-dna-enricher 0.7.2"
+        "checked_at": "2026-11-04T09:00:25Z",
+        "producer": "just-dna-enricher 0.7.3"
       },
       {
         "check": "rsid_coordinate_agreement",
@@ -240,62 +391,67 @@
         "detail": "no row authors both an rsID and a coordinate, so the module makes no pair claim to compare — this is not a comparison that found nothing",
         "source": "ensembl",
         "release": null,
-        "checked_at": "2026-09-26T23:44:40Z",
-        "producer": "just-dna-enricher 0.7.0"
+        "checked_at": "2026-11-04T09:00:25Z",
+        "producer": "just-dna-enricher 0.7.3"
       },
       {
         "check": "rsid_currency",
-        "subjects": 13,
+        "subjects": 0,
         "findings": 0,
-        "skipped": null,
+        "skipped": "not_requested",
         "detail": null,
         "source": "dbsnp",
         "release": null,
-        "checked_at": "2026-09-26T17:35:39Z",
-        "producer": "just-dna-enricher 0.7.2"
+        "checked_at": "2026-11-04T09:00:25Z",
+        "producer": "just-dna-enricher 0.7.3"
       }
     ]
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   "inputs": [
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+      "sha256": "sha256:3c885418ecc7be3dd6c577e3d90842e3f8bf9e2137f631a3df5644cf14043a27",
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   "artifact": {
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+    "digest": "sha256:777dba2bda769896d8850ba03aa83f9f9e18a3499120601fec0bca8dd6d4c75c",
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@@ -309,33 +465,32 @@
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-        "sha256": "sha256:32dae88bcbd2d90cbe172c1f482e471ba40e1475cade9f5be8034f4addaa7df6",
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+        "sha256": "sha256:4f1d02c0e537d683b94f77ffbfd984077f013e6e7d193941317400a30276c5fd",
+        "size": 6544
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-  "logs": [
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-      "sha256": "sha256:1896ebbd20f34bef6e6623d97e796ace641881fec45486807c4927b4d435da6b",
-      "size": 1069
-    }
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+  "logs": [],
   "derived": [
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       "name": "resolution.csv",
-      "sha256": "sha256:9bc3a0b64839b7080ac104e05477cece2e96178282e0f6bb54d87bd68eb6a4ed",
-      "size": 2042
+      "sha256": "sha256:538d9becf0aeade3e30dcb2a4cb5b6de99ae1382ed4b42ec67214d6e32a3ce9a",
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-      "sha256": "sha256:e6951f77c2fe25a9c932ddac0a812bc0995365c25aaf6bd3fef824cf369a9e7b",
-      "size": 4196
+      "sha256": "sha256:55d30a9af8c444f1caf8dc01153ae9a2a2bebc73e72d4898e38937070079b464",
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+    },
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+      "sha256": "sha256:39e548e6e7357e230a72ed1974c1cc8d91b9d4a51f4ae6657312a140b807472a",
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-      "sha256": "sha256:8451c27e8ee2b00a1ebc628b6cf3e215464b04ae0bed442f53dbbd960821915d",
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+      "sha256": "sha256:83dff938e31ad0ab9b35e36ab1199bb8c201c9e6bc8db40a8a0f2eafa35b6f57",
+      "size": 1950
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@@ -349,8 +504,8 @@
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-      "sha256": "sha256:ed1f4ebac79116cac412d4ea32234ef29a3478bde54cd6f0da408c62f15132d1",
-      "size": 327
+      "sha256": "sha256:e9655be35c497a31ec9a34a8ad183f03c63f8e13ae42244a6e7687a3b8f67b91",
+      "size": 768
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   ],
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@@ -360,6 +515,10 @@
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     "size": 130208
   },
-  "readme": null,
+  "readme": {
+    "name": "README.md",
+    "sha256": "sha256:e492013207f4519be6a4b4272989c22557cbc0b8b74c6bbc8fce6c68d23efd7c",
+    "size": 8708
+  },
   "signature": null
 }

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