Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank.
Sex-stratified genome-wide association study of multisite chronic pain in UK Biobank.
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DOI：
10.1371/journal.pgen.1009428
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发表时间：
2021-04
期刊：
影响因子：
4.5
通讯作者：
Bailey MES
中科院分区：
文献类型：
--
作者：
Johnston KJA;Ward J;Ray PR;Adams MJ;McIntosh AM;Smith BH;Strawbridge RJ;Price TJ;Smith DJ;Nicholl BI;Bailey MES
慢性疼痛在世界范围内非常普遍，并造成重大的社会经济和公共卫生负担。影响慢性疼痛易感性的因素和机制尚不完全清楚，但性别被认为起着重要作用，慢性疼痛在女性中比男性更普遍。为了研究慢性疼痛的性别差异，我们在英国生物银行对178,556名男性和209,093名女性进行了一项性别分层的多位点慢性疼痛（MCP）全基因组关联研究，MCP是一种衍生的慢性疼痛表型，同时调查了一系列精神、自身免疫和人体测量表型的性别特异性遗传相关性，以及性别特异性MCP多基因风险评分与慢性广泛性疼痛之间的关系。我们还评估了mcp相关基因是否在组织中表现出表达模式富集。在男性中，5个独立位点上共有123个snp与MCP显著相关。在女性中，在10个独立位点上发现了286个全基因组显著snp。对性别分层的GWAS结果进行荟萃分析，发现了另外87个独立的相关snp。基因水平分析显示性别特异性MCP相关，31个基因在女性中显著相关，37个基因在男性中相关，一个基因DCC在两性中都相关。我们发现了性别特异性多效性的证据，发现MCP的风险与慢性广泛性疼痛以性别差异的方式相关。男性和女性MCP呈高度遗传相关，但rg显著小于1（0.92）。37个雄性mcp相关基因和31个雌性mcp相关基因均在背根神经节中表达，且在性别特异性组织中有一定程度的表达富集。总体而言，研究结果表明慢性疼痛的性别差异存在于SNP、基因和转录物丰度水平上，并突出了MCP可能的性别特异性多效性。研究结果支持了中枢神经系统在两性慢性疼痛中的重要作用，并强调了DRG和伤害感觉的潜在作用。慢性疼痛是一种非常普遍和使人衰弱的疾病，在女性中比在男性中更常见。这种情况下的性别差异可能是几个因素的结果，包括与慢性疼痛相关的遗传变异的性别差异和与性别相关的基因表达差异。为了从遗传角度探讨慢性疼痛的性别差异，我们在一个大型的普通人群队列中分别寻找与男性和女性慢性疼痛相关的遗传变异，并比较了我们在性别之间发现的变异。我们评估了与男女慢性疼痛相关的基因变异和与其他广泛特征相关的基因变异之间的重叠程度，包括重度抑郁症、体重指数和自杀倾向。我们还研究了与慢性疼痛相关的基因在不同性别的一系列组织中的表达模式，特别是检查了神经和非神经人类和小鼠组织中的表达，并评估了背根神经节（DRG）的富集程度，背根神经节是参与慢性疼痛的重要外周神经系统成分。这项工作有助于理解慢性疼痛作为一种特征和慢性疼痛在遗传和基因表达水平上的性别差异。
Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception. Chronic pain is a highly prevalent and debilitating condition, which is more common in women than in men. Sex differences in this condition may be a result of several factors, including differences between the sexes in genetic variation related to chronic pain and gene expression differences related to sex. To explore sex differences in chronic pain from a genetic perspective, we looked for genetic variants associated with chronic pain in men and women separately in a large general-population cohort, and compared the variants we identified between the sexes. We assessed the degree of overlap between genetic variants associated with chronic pain in each sex and those associated with a wide range of other traits, including major depression, body-mass index and suicidality. We also investigated gene expression patterns across a range of tissues for genes associated with chronic pain in each sex, in particular examining expression in neural and non-neural human and mouse tissues and assessing the degree of Dorsal Root Ganglion (DRG) enrichment, an important peripheral nervous system component involved in chronic pain. This work contributes to understanding of chronic pain as a trait and of sex differences in chronic pain at the levels of genetics and gene expression.
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影响因子：
6.2
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
16.6
作者：
Cordell HJ;Han Y;Mells GF;Li Y;Hirschfield GM;Greene CS;Xie G;Juran BD;Zhu D;Qian DC;Floyd JA;Morley KI;Prati D;Lleo A;Cusi D;Canadian-US PBC Consortium;Italian PBC Genetics Study Group;UK-PBC Consortium;Gershwin ME;Anderson CA;Lazaridis KN;Invernizzi P;Seldin MF;Sandford RN;Amos CI;Siminovitch KA
通讯作者：
Siminovitch KA
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.