Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; University Center for Primary Care and Public Health, Lausanne, Switzerland.
Am J Hum Genet. 2023 Sep 7;110(9):1549-1563. doi: 10.1016/j.ajhg.2023.07.006. Epub 2023 Aug 4.
There is currently little evidence that the genetic basis of human phenotype varies significantly across the lifespan. However, time-to-event phenotypes are understudied and can be thought of as reflecting an underlying hazard, which is unlikely to be constant through life when values take a broad range. Here, we find that 74% of 245 genome-wide significant genetic associations with age at natural menopause (ANM) in the UK Biobank show a form of age-specific effect. Nineteen of these replicated discoveries are identified only by our modeling framework, which determines the time dependency of DNA-variant age-at-onset associations without a significant multiple-testing burden. Across the range of early to late menopause, we find evidence for significantly different underlying biological pathways, changes in the signs of genetic correlations of ANM to health indicators and outcomes, and differences in inferred causal relationships. We find that DNA damage response processes only act to shape ovarian reserve and depletion for women of early ANM. Genetically mediated delays in ANM were associated with increased relative risk of breast cancer and leiomyoma at all ages and with high cholesterol and heart failure for late-ANM women. These findings suggest that a better understanding of the age dependency of genetic risk factor relationships among health indicators and outcomes is achievable through appropriate statistical modeling of large-scale biobank data.
目前几乎没有证据表明人类表型的遗传基础在整个生命周期中存在显著差异。然而，事件时间表型的研究还很不足，可以被认为反映了一种潜在的危险，当数值范围很广时，这种危险不太可能在整个生命周期中保持不变。在这里，我们发现，英国生物银行中与自然绝经年龄（ANM）相关的 245 个全基因组显著遗传关联中有 74%表现出一种特定年龄的效应。其中 19 个复制发现仅通过我们的建模框架确定，该框架确定了 DNA 变异起始年龄关联的时间依赖性，而不会显著增加多重检验负担。在早期到晚期绝经的整个范围内，我们发现了证据表明存在着显著不同的潜在生物学途径，ANM 与健康指标和结果的遗传相关性的标志发生了变化，以及因果关系的推断也存在差异。我们发现，只有在 ANM 早期的女性中，DNA 损伤反应过程才会影响卵巢储备和耗竭。通过 ANM 的遗传介导延迟与所有年龄段的乳腺癌和子宫肌瘤的相对风险增加以及晚期 ANM 女性的高胆固醇和心力衰竭相关。这些发现表明，通过对大型生物库数据进行适当的统计建模，可以更好地理解健康指标和结果之间遗传风险因素关系的年龄依赖性。
