Extreme Polygenicity of Complex Traits Is Explained by Negative Selection
Extreme Polygenicity of Complex Traits Is Explained by Negative Selection
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DOI：
10.1016/j.ajhg.2019.07.003
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发表时间：
2019-09-05
影响因子：
9.8
通讯作者：
Price, Alkes L.
中科院分区：
文献类型：
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作者：
O'Connor, Luke J.;Schoech, Armin P.;Price, Alkes L.
复杂性状和常见疾病都是多基因的，它们的遗传力分布在数千个基因座上。一种可能的解释是，成千上万的基因和位点在突变时具有类似的重要生物学效应。然而，我们假设，对于大多数复杂的性状，相对较少的基因和位点是关键的，负选择清除这些区域中的大效应突变，在数千个不太重要的区域中留下共同的变异关联。我们把这种现象称为扁平化。为了量化其影响，我们引入了多基因性的数学定义，即独立相关SNP（M-e）的有效数量，它描述了性状的遗传力在基因组中分布的均匀程度。我们开发了一种方法，分层LD四阶矩回归（S-LD 4 M），估计M-e，M-验证，它产生强大的估计在模拟中。通过分析33个复杂性状（平均N = 361 k），我们确定遗传力在常见SNP之间的分布比在低频SNP之间的分布均匀4倍。这种差异，加上新突变的进化模型，表明如果没有负选择的影响，复杂性状的多基因性将降低几个数量级。我们还确定，遗传力分布更均匀的功能重要的区域内的比例，其遗传力富集;功能重要的区域不窝藏常见的SNP大大增加的因果效应大小，由于选择性约束。我们的研究结果表明，对于大多数复杂的性状，具有最关键生物学效应的基因和位点往往与具有最强共同变异关联的基因和位点不同。
Complex traits and common diseases are extremely polygenic, their heritability spread across thousands of loci. One possible explanation is that thousands of genes and loci have similarly important biological effects when mutated. However, we hypothesize that for most complex traits, relatively few genes and loci are critical, and negative selection-purging large-effect mutations in these regions-leaves behind common-variant associations in thousands of less critical regions instead. We refer to this phenomenon as flattening. To quantify its effects, we introduce a mathematical definition of polygenicity, the effective number of independently associated SNPs (M-e), which describes how evenly the heritability of a trait is spread across the genome. We developed a method, stratified LD fourth moments regression (S-LD4M), to estimate M-e,M- validating that it produces robust estimates in simulations. Analyzing 33 complex traits (average N = 361k), we determined that heritability is spread similar to 4 x more evenly among common SNPs than among low-frequency SNPs. This difference, together with evolutionary modeling of new mutations, suggests that complex traits would be orders of magnitude less polygenic if not for the influence of negative selection. We also determined that heritability is spread more evenly within functionally important regions in proportion to their heritability enrichment; functionally important regions do not harbor common SNPs with greatly increased causal effect sizes, due to selective constraint. Our results suggest that for most complex traits, the genes and loci with the most critical biological effects often differ from those with the strongest common-variant associations.