Evidence of Inbreeding Depression on Human Height

Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

身高是一种经典且遗传度极高的复杂性状，其80%~90%的表型变异可由遗传因素解释。
近年来，全基因组关联研究（genome-wide association studies, GWAS）已成功鉴定出诸多影响人类身高的常见加性变异；但学界对隐性遗传效应的潜在作用却关注甚少。
本研究通过对21个不同人群样本、共35000余名成年人的身高进行近交衰退分析，探究了全基因组范围的隐性遗传效应。
本研究发现身高与全基因组纯合性之间存在极显著的负相关关联：与无关个体的后代相比，一级表亲的后代身高最多可降低3厘米；在控制了社会经济地位这一重要混杂因素后，该关联依然显著（χ²=83.89，自由度df=1；p=5.2×10⁻²⁰）。
但不同人群间存在高度异质性：尽管该效应的方向在大多数人群样本中保持一致，但效应量在人群间差异显著。
这种异质性很可能反映了真实的生物学差异：某一效应能否被观测到，既取决于人群中纯合性的变异程度，也取决于个体隐性基因型的随机遗传情况。
上述结果表明，多种罕见隐性变异会对人类身高产生影响。
尽管本探索性研究仅聚焦于身高，但所开发的方法学普遍适用于可遗传的数量性状（quantitative trait, QT），为探究一系列具有生物医学重要性的数量性状的近交效应及其遗传架构铺平了道路。