Relationships between estimated autozygosity and complex traits in the UK Biobank
Relationships between estimated autozygosity and complex traits in the UK Biobank
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DOI：
10.1371/journal.pgen.1007556
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发表时间：
2018-07-01
期刊：
影响因子：
4.5
通讯作者：
Keller, Matthew C.
中科院分区：
文献类型：
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作者：
Johnson, Emma C.;Evans, Luke M.;Keller, Matthew C.
近亲繁殖增加了人类患某些孟德尔疾病的风险，但也可能通过其对复杂性状和疾病的影响而降低健康。这种近亲繁殖衰退被认为是由于在适合度方面隐性的因果变体处的纯合性增加而发生的。直到最近，它一直很难积累足够大的样本量，以调查复杂的性状，使用全基因组单核苷酸多态性（SNP）数据在人口为基础的样本近交衰退的影响。此外，在将近亲繁殖程度与复杂性状相关联的分析中难以推断因果关系，因为混杂变量（例如，教育）可能会影响父母远系繁殖的可能性和后代的性状值。本研究使用英国生物库中多达40万个个体的全基因组SNP数据中的纯合性运行来估计存在于基因组的纯合片段中的常染色体的比例，这些片段由于共享的共同祖先而相同。经过多次测试校正和控制可能的社会人口学混杂因素，我们发现估计的自体接合性和我们调查的26个特征中的3个之间的预测方向有显着关系：第一次性交时的年龄，液体智力和1秒用力呼气量。我们的发现证实了几项已发表的研究。这些结果可能意味着，这些性状已与达尔文的适应性在进化的时间。然而，在控制了背景社会人口学特征后，一些自合子-性状关系减弱，这表明这些关联的其他解释尚未消除。在设计和解释ROH研究时需要小心，以便收集有关复杂性状的遗传结构和进化历史的可靠信息。
Inbreeding increases the risk of certain Mendelian disorders in humans but may also reduce fitness through its effects on complex traits and diseases. Such inbreeding depression is thought to occur due to increased homozygosity at causal variants that are recessive with respect to fitness. Until recently it has been difficult to amass large enough sample sizes to investigate the effects of inbreeding depression on complex traits using genome-wide single nucleotide polymorphism (SNP) data in population-based samples. Further, it is difficult to infer causation in analyses that relate degree of inbreeding to complex traits because confounding variables (e.g., education) may influence both the likelihood for parents to outbreed and offspring trait values. The present study used runs of homozygosity in genome-wide SNP data in up to 400,000 individuals in the UK Biobank to estimate the proportion of the autosome that exists in autozygous tracts-stretches of the genome which are identical due to a shared common ancestor. After multiple testing corrections and controlling for possible sociodemographic confounders, we found significant relationships in the predicted direction between estimated autozygosity and three of the 26 traits we investigated: age at first sexual intercourse, fluid intelligence, and forced expiratory volume in 1 second. Our findings corroborate those of several published studies. These results may imply that these traits have been associated with Darwinian fitness over evolutionary time. However, some of the autozygosity-trait relationships were attenuated after controlling for background sociodemographic characteristics, suggesting that alternative explanations for these associations have not been eliminated. Care needs to be taken in the design and interpretation of ROH studies in order to glean reliable information about the genetic architecture and evolutionary history of complex traits.