Sex-heterogeneous SNPs disproportionately influence gene expression and health.
Sex-heterogeneous SNPs disproportionately influence gene expression and health.
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性别异质SNP不成比例地影响基因表达和健康。
DOI：
10.1371/journal.pgen.1010147
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发表时间：
2022-05
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
两性间的表型差异是普遍存在的，但表型内和表型间性别差异的遗传结构大多是未知的。在本研究中，我们旨在提高对先前被证明在疾病关联中富集的性别差异snp的检测能力，并研究它们在健康、病理生理和遗传功能方面的功能。我们利用GIANT和UK Biobank的汇总统计数据，定义了一组2320个独立的snp，这些snp在生物特征内部和之间具有性别二态效应（MAF为0.001,P < 5x10-8）。生物特征性状性别异质snp （sex- heet SNPs）在33种疾病/性状中有20种的关联信号在5% α时富集（empP < 0.001），并且在肌肉、骨骼和干细胞发育过程以及钙通道和微管复合物中显著过度表达（FDR < 0.05, empP < 0.05）。有趣的是，我们发现，与性别同质的snp相比，性别同源的snp显著地映射到大脑和其他组织的预测表达数量性状位点（Pr-eQTLs）、发育过程中的甲基化数量性状位点（meQTLs）和转录起始位点。最后，我们验证了性别等位疾病/性状的富集不能仅仅用Pr-eQTL的富集来解释，因为性别等位的Pr-eQTL比匹配的性别同质的Pr-eQTL更富集。我们的结论是，对生物特征具有两性二态效应的遗传多态性不仅有助于基本的胚胎发生过程，而且在生命的后期在疾病风险中起着巨大的作用。与其他表达调控变异相比，这些性别敏感的snp不成比例地影响基因表达，对身体和大脑疾病的影响更大。总之，我们的数据强调了两性异形的遗传基础及其在人类健康中的作用。许多疾病和相关表现的风险因性别而异。在此，我们以先前的工作为基础，研究了大量的人体测量学和生物测量学特征，这些特征可以告知性别之间的健康差异。我们定义了一个由2320个性别单核苷酸多态性组成的强大列表，显示了多个性状的性别异质性。我们发现性别敏感的snp影响了大量的疾病和与健康相关的特征。性别敏感snp位于或靠近与骨骼和肌肉发育有关的基因中，并参与调节基因表达和DNA甲基化，这是基因组的两个重要功能。我们的结论是，对生物特征具有两性二态效应的遗传变异不仅有助于基本的胚胎发生过程，而且在生命后期的疾病风险中发挥作用，并参与基因表达和表观遗传过程的调节。我们的研究结果表明，性别异质性snp与人类生理和病理有关。
Phenotypic differences across sexes are pervasive, but the genetic architecture of sex differences within and across phenotypes is mostly unknown. In this study, we aimed to improve detection power for sex-differentially contributing SNPs previously demonstrated to be enriched in disease association, and we investigate their functions in health, pathophysiology, and genetic function. We leveraged GIANT and UK Biobank summary statistics and defined a set of 2,320 independent SNPs having sexually dimorphic effects within and across biometric traits (MAF > 0.001, P < 5x10-8). Biometric trait sex-heterogeneous SNPs (sex-het SNPs) showed enrichment in association signals for 20 out of 33 diseases/traits at 5% alpha compared to sex-homogeneous matched SNPs (empP < 0.001), and were significantly overrepresented in muscle, skeletal and stem cell development processes, and in calcium channel and microtubule complexes (FDR < 0.05, empP < 0.05). Interestingly, we found that sex-het SNPs significantly map to predicted expression quantitative trait loci (Pr-eQTLs) across brain and other tissues, methylation quantitative trait loci (meQTLs) during development, and transcription start sites, compared to sex-homogeneous SNPs. Finally, we verified that the sex-het disease/trait enrichment was not explained by Pr-eQTL enrichment alone, as sex-het Pr-eQTLs were more enriched than matched sex-homogeneous Pr-eQTLs. We conclude that genetic polymorphisms with sexually dimorphic effects on biometric traits not only contribute to fundamental embryogenic processes, but later in life play an outsized role in disease risk. These sex-het SNPs disproportionately influence gene expression and have a greater influence on disorders of body and brain than other expression-regulatory variation. Together, our data emphasize the genetic underpinnings of sexual dimorphism and its role in human health. Risk for many diseases and related manifestations differs by sex. Here, we build on prior work to study a large set of anthropometric and biometric traits that could inform health differences by sex. We define a well-powered list of 2,320 sex-het SNPs showing sex-heterogeneity across multiple traits. We find that sex-het SNPs influence a large set of diseases and health-related traits. The sex-het SNPs are in/near genes with roles in skeletal and muscle development and are involved in regulating gene expression and DNA methylation, two important functions of the genome. We conclude that genetic variation with sexually dimorphic effects on biometric traits not only contributes to fundamental embryogenic processes but plays a role in disease risk later in life and is involved in the regulation of gene expression and epigenetic processes. Our results suggest that sex-heterogeneous SNPs link human physiology and pathology.
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基因发现和多基因预测，从基因组全基因组协会的教育程度研究中，有110万个人。
影响因子：
30.8
作者：
Lee JJ;Wedow R;Okbay A;Kong E;Maghzian O;Zacher M;Nguyen-Viet TA;Bowers P;Sidorenko J;Karlsson Linnér R;Fontana MA;Kundu T;Lee C;Li H;Li R;Royer R;Timshel PN;Walters RK;Willoughby EA;Yengo L;23andMe Research Team;COGENT (Cognitive Genomics Consortium);Social Science Genetic Association Consortium;Alver M;Bao Y;Clark DW;Day FR;Furlotte NA;Joshi PK;Kemper KE;Kleinman A;Langenberg C;Mägi R;Trampush JW;Verma SS;Wu Y;Lam M;Zhao JH;Zheng Z;Boardman JD;Campbell H;Freese J;Harris KM;Hayward C;Herd P;Kumari M;Lencz T;Luan J;Malhotra AK;Metspalu A;Milani L;Ong KK;Perry JRB;Porteous DJ;Ritchie MD;Smart MC;Smith BH;Tung JY;Wareham NJ;Wilson JF;Beauchamp JP;Conley DC;Esko T;Lehrer SF;Magnusson PKE;Oskarsson S;Pers TH;Robinson MR;Thom K;Watson C;Chabris CF;Meyer MN;Laibson DI;Yang J;Johannesson M;Koellinger PD;Turley P;Visscher PM;Benjamin DJ;Cesarini D
通讯作者：
Cesarini D
影响因子：
16.6
作者：
Huan, Tianxiao;Joehanes, Roby;Leyy, Daniel
通讯作者：
Leyy, Daniel
影响因子：
9.8
作者：
Ferreira, Manuel A. R.;Mathur, Riddhima;Almqvist, Catarina
通讯作者：
Almqvist, Catarina
影响因子：
12.3
作者：
Gaunt TR;Shihab HA;Hemani G;Min JL;Woodward G;Lyttleton O;Zheng J;Duggirala A;McArdle WL;Ho K;Ring SM;Evans DM;Davey Smith G;Relton CL
通讯作者：
Relton CL
影响因子：
5.2
作者：
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通讯作者：
Begeer, Sander