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.
b13d76a verified | # 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. | |