Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits
Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits
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DOI：
10.1016/j.ajhg.2018.08.017
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发表时间：
2018-10-04
影响因子：
9.8
通讯作者：
Arboleda, Valerie A.
中科院分区：
文献类型：
--
作者：
Freund, Malika Kumar;Burch, Kathryn S.;Arboleda, Valerie A.
虽然最近的研究提供了证据，复杂的性状和孟德尔疾病之间的共同遗传基础，一个彻底的量化表型特异性的方式，他们的重叠仍然难以捉摸。在这里，我们量化了通过大规模全基因组关联研究（GWAS）确定的62种复杂性状和疾病的基因重叠，这些基因含有已知导致20大类孟德尔疾病的突变。我们在GWAS基因集中发现了与表型匹配的孟德尔疾病相关的基因的显著富集;在总共1，240个比较中，表型匹配或相关对的比例（n = 50/92 [54%]）高于表型不匹配对（n = 27/1，148 [2%]），证明了显著重叠，证实了表型特异性富集模式。此外，我们观察到与表型匹配的孟德尔疾病相关的基因附近的GWAS效应大小升高。最后，我们报告的例子GWAS变异定位在转录起始位点或物理相互作用的基因的启动子与表型匹配的孟德尔疾病。我们的研究结果与孟德尔疾病中被破坏的基因被复杂性状中的非编码变体失调的假设一致，并证明了如何利用来自相关孟德尔疾病和功能基因组数据集的发现来优先考虑被局部和远端非编码GWAS变体失调的基因。
Although recent studies provide evidence for a common genetic basis between complex traits and Mendelian disorders, a thorough quantification of their overlap in a phenotype-specific manner remains elusive. Here, we have quantified the overlap of genes identified through large-scale genome-wide association studies (GWASs) for 62 complex traits and diseases with genes containing mutations known to cause 20 broad categories of Mendelian disorders. We identified a significant enrichment of genes linked to phenotypically matched Mendelian disorders in GWAS gene sets; of the total 1,240 comparisons, a higher proportion of phenotypically matched or related pairs (n = 50 of 92 [54%]) than phenotypically unmatched pairs (n = 27 of 1,148 [2%]) demonstrated significant overlap, confirming a phenotype-specific enrichment pattern. Further, we observed elevated GWAS effect sizes near genes linked to phenotypically matched Mendelian disorders. Finally, we report examples of GWAS variants localized at the transcription start site or physically interacting with the promoters of genes linked to phenotypically matched Mendelian disorders. Our results are consistent with the hypothesis that genes that are disrupted in Mendelian disorders are dysregulated by non-coding variants in complex traits and demonstrate how leveraging findings from related Mendelian disorders and functional genomic datasets can prioritize genes that are putatively dysregulated by local and distal non-coding GWAS variants.