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Cited by 6Evolution and Genetic DynamicsGenetic Associations and EpidemiologyEvolutionary Psychology and Human Behavior

The DOI matches its Crossref record; 93 of the 93 references it cites were found in a registry or an index; 3 of the 64 sources its claims cite were checked for support.

Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans

Open access
Brigos-Barril, Eva, Vasallo, Claudia, Farré, Xavier, Morcillo-Suárez, Carlos, Polo-Alonso, Sara, Rodríguez-Fernández, Blanca, Valenzuela, Alejandro, Sarabia, Carlos, Bosch, Elena, Laayouni, Hafid, Vilor-Tejedor, Natàlia, Navarro, Arcadi, Muntané, Gerard·2026·Nature Ecology & Evolution
DOI 10.1038/s41559-026-03140-zPMC PMC13541616
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Abstract

Abstract The persistence of genetic variants that increase susceptibility to complex diseases poses an evolutionary paradox: despite their detrimental health effects, these variants are not eliminated by natural selection. Life-history theory proposes that trade-offs and pleiotropic effects across fitness components may explain the evolutionary maintenance of disease-associated alleles. We hypothesize that certain disease-risk alleles might segregate in the population because they confer reproductive advantages, even at the expense of late-life costs on health and longevity. Leveraging genome-wide association studies, we investigated genetic correlations and pleiotropic relationships between 62 complex diseases, longevity, and fertility. In our study, we estimated fertility by meta-analyzing complementary measures of offspring number and used parental lifespan as a proxy for longevity. We found that 85% of diseases showed negative genetic correlations with longevity, whereas 87% of diseases with significant correlations showed positive associations with fertility. Moreover, most disease-risk variants were associated with reduced longevity, even after accounting for socioeconomic confounders. Fertility-increasing alleles exhibited evolutionary signals consistent with adaptive selection despite having pleiotropic effects on disease-risk. Finally, we compared the number of offspring among individuals with high genetic risk of disease and found that, for most diseases, affected individuals had more offspring than disease-free individuals. However, for early-onset conditions, non-affected individuals exhibited higher fertility, highlighting the reproductive cost of early-onset diseases. These findings support the Antagonistic Pleiotropy theory, showing that alleles that enhance early-life reproductive success can persist despite late-life health costs. By uncovering these evolutionary trade-offs between reproduction, longevity, and disease risk, our study shows how Darwinian selection continues to shape contemporary patterns of human disease susceptibility. Understanding these evolutionary trade-offs can inform public health approaches and help anticipate unintended consequences of targeting disease-related genetic pathways.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Disease-risk alleles in humans are often genetically correlated with shorter lifespan but higher fertility, and fertility-increasing disease-risk alleles show signatures of recent positive selection. Mendelian randomization supports a causal direction from disease liability to reduced longevity, while demographic data show fertility effects depend on age at disease onset.

Key findings

  • Across 62 complex diseases, 41 had significant genetic correlations with longevity, and 35 of these (85%) were negative; the strongest negative correlations were for circulatory diseases such as heart failure (rg = −0.74, P = 5.32 × 10−67) and hypertension (rg = −0.69, P = 1.39 × 10−145). For fertility, 30 diseases had significant correlations, and 26 (87%) were positive, including ADHD (rg = 0.41, P = 1.1 × 10−27).
  • Pleiotropy analyses identified 1,142 independent shared SNPs for disease and longevity, with 82% (n = 942) showing negative pleiotropy; 460 independent SNPs were shared for disease and fertility, with 49.8% positive and 50.2% negative pleiotropy. Fertility and longevity themselves had a modest negative genetic correlation (rg = −0.10, P = 2.4 × 10−3), and 7 of 8 identified pleiotropic variants were concordant with antagonistic pleiotropy.
  • Fertility-increasing disease-risk alleles showed stronger recent positive selection signals than fertility-decreasing alleles: SDS Mann–Whitney P = 2.7 × 10−4, nSL P = 7.6 × 10−3, with permutation Pemp = 3 × 10−4 and 6.7 × 10−3; integrated haplotype score did not reach significance (P = 7.5 × 10−2). Fertility-increasing alleles also had antagonistic longevity effects (one-sample, one-tailed t-test, P = 3 × 10−10).
  • In two-sample MR, 22 of 62 diseases showed significant inverse associations with longevity, including hypertension (OR = 0.62, 95% CI: 0.59–0.65) and coronary artery disease (OR = 0.63, 95% CI: 0.55–0.71); 16 of 22 remained significant after socioeconomic adjustment. Fertility MR associations were modest and not robust, and reverse MR estimates did not survive multiple-testing correction.
  • In UK Biobank, 52 of 62 diseases showed significant fertility differences by diagnosis status; for 41 diseases (79%), diagnosed individuals had higher fertility, while for 11 diseases diagnosed individuals had lower fertility, 8 of which had onset under 20 years. After age 45, all diseases were linked to higher fertility among diagnosed individuals.

Methods

  • Fertility GWAS meta-analysis combined three measures—number of children ever born, live births to females, and children fathered by males—using METAL with sample-size weighting, overlap correction, and genomic control.
  • Disease analyses used 62 GWAS summary statistics from European-ancestry studies (>95%), sample size ≥20,000, ≥2,000 cases, and h2SNP ≥2%; longevity used parental lifespan data from nearly one million lifespans in ~450,000 UK Biobank participants.
  • Main analyses included LD score regression for genetic correlations, conjFDR for pleiotropy, functional annotation, selection indices (SDS, iHS, nSL), univariable and multivariable Mendelian randomization with socioeconomic adjustment, and UK Biobank polygenic-score/demographic analyses stratified by disease status and top-decile genetic liability.

Limitations

  • The paper states that modern disease risk may partly reflect ancient adaptive variation in contemporary environments, and that genetic correlations should be interpreted as population- and environment-specific averages rather than fixed biological constants.
  • The paper states that conjFDR lead SNPs are tag variants, not necessarily causal; that sex-stratified data were lacking; that MR remains vulnerable to weak instruments, especially for fertility, and residual confounding; and that analyses relied on European-ancestry individuals, limiting generalizability.
  • The text also makes evident that fertility had only five genome-wide significant loci, limiting power for reverse MR and fertility causal estimates; the authors note these results should be considered inconclusive rather than evidence of absent effects.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41559-026-03140-z

Cites

93 of 93 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

3 of 64 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured

  • Interpretationcitation

    Disease risk reduces lifespan via shared biological pathways.

    “This is aligned with previous findings and reinforces the hypothesis that disease risk reduces lifespan via shared biological pathways45–47.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [45] Timmers, P. R. et al. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. eLife 8, e39856 (2019). source
    • cites [46] Deelen, J. et al. A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nat. Commun. 10, 3669 (2019). source
    • cites [47] Hu, D. et al. Genetic trade-offs between complex diseases and longevity. Aging Cell 21, e13654 (2022). source
  • Interpretationown data

    The negative genetic correlation between fertility and longevity supports the AP theory of aging.

    “supporting the AP theory of aging7,16,50,51”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [7] Charlesworth, B. Evolution in Age-Structured Populations (Cambridge Univ. Press, 1994). source
    • cites [16] Long, E. & Zhang, J. Evidence for the role of selection for reproductively advantageous alleles in human aging. Sci. Adv. 9, eadh4990 (2023). source
    • cites [50] Pettay, J. E., Kruuk, L. E. B., Jokela, J. & Lummaa, V. Heritability and genetic constraints of life-history trait evolution in preindustrial humans. Proc. Natl Acad. Sci. USA 102, 2838–2843 (2005). source

      The Discussion says the genetic tradeoffs between longevity and reproductive timing provide compelling support for antagonistic pleiotropy. The Results report positive genetic correlations of longevity with age at first reproduction and mean interbirth interval, implying a tradeoff with earlier or more frequent reproduction. They do not report a direct negative genetic correlation between fertility itself and longevity. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [51] Tabatabaie, V. et al. Exceptional longevity is associated with decreased reproduction. Aging 3, 1202–1205 (2011). source
  • Findingown data

    Among the 62 diseases analysed, 41 exhibited significant genetic correlations with longevity.

    “Among the diseases analysed, 41 exhibited significant genetic correlations with longevity (P < 0.05).”
    Quote in the paperSubstantial claim
  • Findingown data

    Diseases with later onset exhibited stronger negative genetic correlations with longevity (r = −0.43).

    “Notably, diseases with later onset exhibited stronger negative genetic correlations with longevity (r = −0.43, P = 5 × 10−3; Extended Data Fig. 3a)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Of the 41 diseases with significant genetic correlations with longevity, 35 (85%) demonstrated negative correlations.

    “Notably, 85% of these (35 out of 41) demonstrated negative correlations”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 20
  • It may state two separate claims as one. 21

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    To ensure robustness of MR findings, we employed sensitivity analyses using Cochran's Q statistic, MR-Egger intercept and MR-PRESSO.

    “To ensure the robustness of our findings, we employed sensitivity analyses using Cochran’s Q statistic to assess heterogeneity among instrumental variables and the MR–Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO) to evaluate potential pleiotropy90.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [90] Verbanck, M., Chen, C.-Y., Neale, B. & Do, R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet. 50, 693–698 (2018). source

  • It may state two separate claims as one.

    Findingown data

    The fertility PGS significantly predicted live births and completed pregnancies, explaining approximately 0.43% and 0.42% of variance, respectively.

    “the PGS significantly predicted both the number of live births (P = 0.04) and the number of completed pregnancies (P = 0.04), explaining 0.43% and 0.42% of its variance, respectively”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Increased disease risk is often genetically correlated with a shorter lifespan and higher fertility.

    “Indeed, increased disease risk is often genetically correlated with a shorter lifespan and, contrary to intuition, higher fertility.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Of these 460 loci, 229 (49.8%) exhibited positive pleiotropy and 231 (50.2%) exhibited negative pleiotropy.

    “Of these, 229 loci (49.8%) exhibited positive pleiotropy, where disease-risk alleles were associated with higher fertility, whereas 231 loci (50.2%) exhibited negative pleiotropy, with disease-risk alleles associated with reduced fertility.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingcitation

    Functional annotation of these variants revealed tissue-specific expression patterns, particularly in the testes and brain, and significant enrichment in regulatory elements.

    “Functional annotation of these variants revealed tissue-specific expression patterns, particularly in the testes and brain, and significant enrichment in regulatory elements, as previously shown16.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Long, E. & Zhang, J. Evidence for the role of selection for reproductively advantageous alleles in human aging. Sci. Adv. 9, eadh4990 (2023). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The small number of genome-wide significant variants available for fertility (n = 5) may affect these estimates.

    “may be affected by the small number of genome-wide significant variants available for fertility (n = 5)”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    nSL showed the same divergence between fertility-increasing and fertility-decreasing variants and was significant in permutation-based resampling.

    “Moreover, nSL showed the same divergence (Fig. 2b) and was likewise significant in permutation-based resampling (Pemp = 6.7 × 10−3)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Fertility is a polygenic trait with modest, yet significant, heritability.

    “First, our meta-analysis of offspring counts confirmed that fertility is a polygenic trait with modest, yet significant, heritability”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingcitation

    Individuals with high genetic predisposition to late-onset diseases tend to have more children, reduced childlessness and younger ages at first birth.

    “Individuals with high genetic predisposition to late-onset diseases tend to have more children, reduced childlessness and younger ages at first birth, suggesting early reproductive advantages of these alleles19,22,75.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Williams, G. Pleiotropy, natural selection, and the evolution of senescence. Evol. NY 11, 398–411 (1957). source
    • cites [22] Rodríguez, J. A. et al. Antagonistic pleiotropy and mutation accumulation influence human senescence and disease. Nat. Ecol. Evol. 1, 55 (2017). source
    • cites [75] Rodríguez, J. A. et al. Reply to: Retesting the influences of mutation accumulation and antagonistic pleiotropy on human senescence and disease. Nat. Ecol. Evol. 3, 994–995 (2019). source

  • It may state two separate claims as one.

    Findingown data

    This pattern extends across multiple disease domains, with stronger correlations observed for early-onset conditions.

    “Such a pattern has been previously described for coronary artery disease, whose risk loci are enriched for lifetime reproductive success38, and here we show that it extends across multiple disease domains, with stronger correlations observed for early-onset conditions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Byars, S. G. et al. Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy. PLOS Genet. 13, e1006328 (2017). source

  • It may state two separate claims as one.

    Findingown data

    This pattern persisted across both early- and late-onset diseases and was robust to permutation-based resampling.

    “Stratification by age at disease onset showed that this pattern persisted across both early- and late-onset diseases (Fig. 2a) and was robust to permutation-based resampling (Pemp = 3 × 10−4).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In 70% of the diseases examined, diagnosed individuals had their first child earlier than undiagnosed individuals, with a mean difference of 1.1 years.

    “In 70% of the diseases examined (n = 43; FDR < 0.05), diagnosed individuals had their first child earlier than undiagnosed individuals, with a mean difference of 1.1 years (s.d. = 0.52).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Pleiotropy counts correlated with the number of disease cases (r = 0.36, P = 0.005), the total number of genome-wide significant SNPs (r = 0.69, P = 5.9 × 10−10) and the h2SNP (r = 0.5, P = 3.5 × 10−5).

    “Pleiotropy counts correlated with the number of disease cases (r = 0.36, P = 0.005; Supplementary Fig. 7), the total number of genome-wide significant SNPs (r = 0.69, P = 5.9 × 10−10) and the h2SNP (r = 0.5, P = 3.5 × 10−5; Supplementary Fig. 8).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    These results support antagonistic pleiotropy and help explain the persistence of disease-risk alleles in human populations.

    “Together, these results support antagonistic pleiotropy and help explain the persistence of disease-risk alleles in human populations.”
    • Also stated in: § Discussion · boosted
      “Together, these findings shed light on the fundamental trade-offs between disease, longevity and reproduction, providing multi-level support for the antagonistic pleiotropy theory of aging in humans.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The evolutionary logic that health-related costs can be tolerated when coupled to reproductive advantage is consistent with previous work.

    “This evolutionary logic is consistent with previous work, suggesting that health-related costs can be tolerated when coupled to reproductive advantage16,22,56,57.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [16] Long, E. & Zhang, J. Evidence for the role of selection for reproductively advantageous alleles in human aging. Sci. Adv. 9, eadh4990 (2023). source
    • cites [22] Rodríguez, J. A. et al. Antagonistic pleiotropy and mutation accumulation influence human senescence and disease. Nat. Ecol. Evol. 1, 55 (2017). source
    • cites [56] Tropf, F. C. et al. Human fertility, molecular genetics, and natural selection in modern societies. PLoS ONE 10, e0126821 (2015). source
    • cites [57] Gao, Z. Unveiling recent and ongoing adaptive selection in human populations. PLoS Biol. 22, e3002469 (2024). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Hormonal pathways, particularly those involving insulin and insulin-like growth factor 1, have long been associated with the trade-off between reproduction and longevity in model organisms.

    “Hormonal pathways, particularly those involving insulin and insulin-like growth factor 1, have long been associated with the trade-off between reproduction and longevity in model organisms52,53.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [52] Dillin, A., Crawford, D. K. & Kenyon, C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298, 830–834 (2002). source
    • cites [53] Partridge, L., Gems, D. & Withers, D. J. Sex and death: what is the connection? Cell 120, 461–472 (2005). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    This interpretation reflects only two axes of a potentially broader selective landscape that probably also involves other fitness-relevant phenotypes, including immunity.

    “We note, however, that this interpretation reflects only two axes of a potentially broader selective landscape that probably also involves other fitness-relevant phenotypes, including immunity58,59.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Irving-Pease, E. K. et al. The selection landscape and genetic legacy of ancient Eurasians. Nature 625, 312–320 (2024). source
    • cites [59] Pankratov, V. et al. Ancestral genetic components are consistently associated with the complex trait landscape in European biobanks. Eur. J. Hum. Genet. 32, 1492–1499 (2024). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Previous studies have suggested that socioeconomic inequality influences longevity.

    “while previous studies have suggested that socioeconomic inequality influences longevity72”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Ye, C.-J. et al. Mendelian randomization evidence for the causal effects of socio-economic inequality on human longevity among Europeans. Nat. Hum. Behav. 7, 1357–1370 (2023). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    These selection signals should be interpreted as context-dependent and population-specific, because the fertility-related effects captured by contemporary GWASs may vary across socio-ecological settings and may not persist unchanged over time.

    “Of course, these selection signals should be interpreted as context-dependent and population-specific, because the fertility-related effects captured by contemporary GWASs may vary across socio-ecological settings and may not persist unchanged over time.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    Alleles that consistently increase reproductive success are expected to be favoured by natural selection and to rise in frequency.

    “because fertility is a core component of fitness, alleles that consistently increase reproductive success are expected to be favoured by natural selection and, as we show, to rise in frequency and eventually approach or reach fixation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Fertility is a core component of fitness.

  • It may state two separate claims as one.

    Interpretationown data

    This pattern is consistent with a directional influence of disease liability on longevity and is also compatible with vertical pleiotropy.

    “This pattern is consistent with a directional influence of disease liability on longevity27,64 and is also compatible with vertical pleiotropy65.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Burgess, S. et al. Dissecting causal pathways using Mendelian randomization with summarized genetic data: application to age at menarche and risk of breast cancer. Genetics 207, 481–487 (2017). source
    • cites [64] Smith, D. G. & Hemani, G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum. Mol. Genet. 23, R89–R98 (2014). source
    • cites [65] Hemani, G., Bowden, J. & Davey Smith, G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum. Mol. Genet. 27, R195–R208 (2018). source

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    The lack of robust significance for fertility should be interpreted as inconclusive rather than as evidence that directional effects are absent.

    “The lack of robust significance for fertility should, therefore, be interpreted as inconclusive rather than as evidence that directional effects are absent.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    The pattern of negative pleiotropic effects among late-onset cardiovascular diseases for longevity could also be explained by mutation accumulation.

    “a pattern that could also be explained by mutation accumulation18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Medawar, P. B. An Unsolved Problem of Biology: An Inaugural Lecture Delivered at University College, London, 6 December, 1951 (H.K. Lewis and Co., 1952).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. It may state two separate claims as one.

    Interpretationreasoning

    This pattern may reflect greater reproductive costs in early-onset diseases, whereas late-onset diseases may leave a longer window of disease-free reproductive years.

    “This pattern may reflect greater reproductive costs in early-onset diseases, whereas late-onset diseases may leave a longer window of disease-free reproductive years.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    These regulatory features may enable small, coordinated changes in gene expression that mediate complex trade-offs across life-history traits.

    “These regulatory features may enable small, coordinated changes in gene expression that mediate complex trade-offs across life-history traits.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    To validate the evolutionary results, we conducted a leave-one-out analysis for each disease and performed bootstrapping through resampling with replacement.

    “To validate the results, we conducted a leave-one-out analysis for each disease and performed bootstrapping through resampling with replacement.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductnone given

    The GWAS datasets were selected to ensure quality and comparability using criteria: European ancestry (>95%), total sample size ≥20,000, at least 2,000 cases, and SNP heritability ≥2%.

    “To ensure quality and comparability, we selected datasets that met the following criteria: studies in individuals of European ancestry (>95%), with a total sample size ≥20,000, at least 2,000 cases and SNP heritability (h2SNP) ≥ 2%.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    Modern disease risk may, in part, reflect ancient adaptive variation expressed in contemporary environments.

    “First, modern disease risk may, in part, reflect ancient adaptive variation expressed in contemporary environments76.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Barrie, W. et al. Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Nature 625, 321–328 (2024). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    The GWAS meta-analysis used genomic control to correct for population stratification.

    “To further reduce potential biases, genomic control was implemented to correct for population stratification.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data

    We evaluated potential GWAS-related confounding by calculating Pearson correlations between rg and key study characteristics and conducted a disease-wise bootstrap analysis to identify influential outliers.

    “We evaluated potential GWAS-related confounding by calculating Pearson correlations between rg and key study characteristics (for example, heritability and sample size). To identify influential outliers, we conducted a disease-wise bootstrap analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Study design and conductnone given

    Pleiotropic lead SNPs identified through conjFDR are tag variants capturing shared association signals.

    “Second, pleiotropic lead SNPs identified through conjFDR are tag variants capturing shared association signals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationnone given

    Genetic correlations should not be interpreted as fixed biological constants, but rather as population- and environment-specific averages that depend on the phenotypic definitions and exposures captured in a given study.

    “In this context, genetic correlations should not be interpreted as fixed biological constants, but rather as population- and environment-specific averages that depend on the phenotypic definitions and exposures captured in a given study.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Our findings suggest age-dependent trade-offs between disease risk, longevity and reproduction, which may explain the persistence of disease-associated variants in human populations.

    “Our findings suggest age-dependent trade-offs between disease risk, longevity and reproduction, which may explain the persistence of disease-associated variants in human populations3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Nesse, R. M. & Williams, G. C. Why We Get Sick: The New Science of Darwinian Medicine (Vintage Books, 1996).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: Selection removes disease-risk alleles that reduce fitness while preferentially retaining those whose harmful effects are offset by gains in fertility.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    Our analyses rely on individuals of European ancestry, which may limit generalizability to other populations.

    “Lastly, our analyses rely on individuals of European ancestry, which may limit generalizability to other populations79,80.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [79] Kaptijn, R. et al. The trade-off between female fertility and longevity during the epidemiological transition in the Netherlands. PLoS ONE 10, e0144353 (2015). source
    • cites [80] Morita, M. Demographic studies enhance the understanding of evolutionarily (mal)adaptive behaviors and phenomena in humans: a review on fertility decline and an integrated model. Popul. Ecol. 60, 143–154 (2018). source

  • It may state two separate claims as one.

    Study design and conductcitation

    Our MR findings remain vulnerable to limitations on instrument strength, especially for fertility, due to modest SNP-based heritability and to residual confounding by cohort-specific factors.

    “Fourth, while MR strengthens causal inference, our findings remain vulnerable to limitations on instrument strength, especially for fertility, due to modest SNP-based heritability and to residual confounding by cohort-specific factors15,79.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Hsu, C.-H., Posegga, O., Fischbach, K. & Engelhardt, H. Examining the trade-offs between human fertility and longevity over three centuries using crowdsourced genealogy data. PLoS ONE 16, e0255528 (2021). source
    • cites [79] Kaptijn, R. et al. The trade-off between female fertility and longevity during the epidemiological transition in the Netherlands. PLoS ONE 10, e0144353 (2015). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Previous studies show that age at disease onset influences childlessness, with particularly strong effects when disease manifests during the reproductive years.

    “This is consistent with previous studies showing that age at disease onset influences childlessness, with particularly strong effects when disease manifests during the reproductive years61.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Liu, A. et al. Evidence from Finland and Sweden on the relationship between early-life diseases and lifetime childlessness in men and women. Nat. Hum. Behav. 8, 276–287 (2024). source
36 of 36

  • The paper relies on this without support.

    A systematic analysis of the shared genetic architecture linking human longevity, fertility and complex disease is lacking.

    “Despite growing evidence for these trade-offs, a systematic analysis of the shared genetic architecture linking human longevity, fertility and complex disease is lacking.”

  • The paper relies on this without support.

    It is unclear whether the observed associations reflect deep evolutionary constraints, recent selective pressures or socioeconomic confounding.

    “Moreover, it remains unclear whether the observed associations reflect deep evolutionary constraints, recent selective pressures or socioeconomic confounding.”

  • The paper relies on this without support.

    Alleles that manifest after the reproductive years face weaker selective pressures.

    “The time of disease onset is a critical factor for understanding this evolutionary dynamic, as alleles that manifest after the reproductive years face weaker selective pressures.”

  • The paper relies on this without support.

    Fertility is a core component of fitness.

    “because fertility is a core component of fitness, alleles that consistently increase reproductive success are expected to be favoured by natural selection”

  • The paper relies on this without support.

    Reverse directionality from longevity to disease risk is biologically implausible.

    “Reverse analyses assessing the effect of longevity on disease risk were not performed, as such directionality is biologically implausible.”

  • The paper relies on this without support.

    The underlying pathways in humans have not been exhaustively identified.

    “However, the underlying pathways in humans have not been exhaustively identified.”

  • The paper relies on this without support.

    Selection removes disease-risk alleles that reduce fitness while preferentially retaining those whose harmful effects are offset by gains in fertility.

    “Against a background of continual mutational input, selection is expected to remove disease-risk alleles that reduce fitness while preferentially retaining those whose harmful effects are offset by gains in fertility.”
7 of 7

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Fertility correlations are described as stronger for early-onset diseases despite no onset association

    Major

    The Results report no association between fertility-correlation strength and age at disease onset, whereas the Discussion says the correlations were stronger for early-onset conditions.

1 of 1

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. World Health Assembly, 43. Report of the International Conference for the Tenth Revision of the International Classification of Diseases (World Health Organization, 1990); https://iris.who.int/handle/10665/173188

Cited by

Sorted by citations

Related

Metadata

Authors
Brigos-Barril, E., Vasallo, C., Farré, X., Morcillo-Suárez, C., Polo-Alonso, S., Rodríguez-Fernández, B., Valenzuela, A., Sarabia, C., Bosch, E., Laayouni, H., Vilor-Tejedor, N., Navarro, A., & Muntané, G.
Affiliations
  • Universitat Pompeu Fabra (ES)
  • Barcelona Institute of Science and Technology (ES)
  • Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
Corresponding author
  • Navarro, Arcadi
  • Muntané, Gerard
ORCID
Venue
Nature Ecology & Evolution
Publisher
Springer Science and Business Media LLC
Published
2026-07-21
Volume
10
Issue
9
Pages
1774-1785
ISSN
2397-334X (ISSN-L)
DOI
10.1038/s41559-026-03140-z
PMC
PMC13541616
OpenAlex
W7169878769
Semantic Scholar
8220cf1b3fb6c69e1207d5a9ae837e0368b7a0b2
Cited by
6
References
91
Citations by year
2026: 5
FWCI
11.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Ecology & Evolution (publishedVersion, cc-by-nc-nd)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (publishedVersion, cc-by-nc-nd)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Funders
  • Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (PI21/00612)
  • Fundació la Marató de TV3 (202230-32)
  • Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (RYC2022-038136-I, PID2021-127792NB-I00, CEX2018-000792-M)
  • "la Caixa" Foundation (GRC 2021 SGR 0467)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Evolutionary Psychology and Human Behavior
Keywords
antagonistic pleiotropy, genetic trade-offs, fertility, longevity, complex diseases, disease risk alleles, genetic correlation, pleiotropy, life history theory, offspring number, early-onset disease, natural selection
MeSH terms
Alleles, Female, Fertility, Humans, Longevity, Selection, Genetic, Genetic Predisposition to Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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