Sex-Specific Genetic and Transcriptomic Liability to Neuroticism.
Sex-Specific Genetic and Transcriptomic Liability to Neuroticism.
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DOI：
10.1016/j.biopsych.2022.07.019
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发表时间：
2023-02-01
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
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精神疾病的表现、病因和相对风险很大程度上受生物性别的影响。神经质是精神疾病的跨诊断特征，表现出显着的性别差异。我们分别对男性和女性的神经质进行了全基因组关联研究（GWAS），以确定性别特异性的遗传和转录组谱。神经质评分源自艾森克人格量表神经质量表。考虑到常染色体和 X 染色体变异，对英国生物银行的 145,669 名女性和 129,229 名男性进行了 GWAS。双边 Z 检验用于测试范德比尔特大学生物库（BioVu，39,692 名女性和 31,268 名男性）中发现的基因座、遗传相关性（N=673 性状）、组织和基因转录组谱以及健康结果之间的多基因关联的性别特异性影响。神经质的SNP遗传力在男性(h2=10.6%)和女性(h2=11.85%)之间没有统计学差异。四个女性特异性（rs10736549-CNTN5、rs6507056-ASXL3、rs2087182-MMS22L 和 rs72995548-HSPB2）和两个男性特异性（rs10507274-MED13L 和 rs7984597）神经质风险位点达到全基因组显着性。男性和女性特异性神经质多基因评分与“情绪障碍”最显着相关（男性 OR=1.11，P=1.40x10−9；女性 OR=1.14，P=6.05x10−22）。他们还与与红细胞计数、分布和血红蛋白浓度相关的性别特异性实验室测量相关。男性神经质位点的垂体基因表达变异丰富（男性 b=0.026，P=0.002），基因调控的转录组变化突出了 RAB7L1、TEX26 和 PLOT1 的影响。通过对神经质遗传风险和相关生物过程的全面评估，这项研究确定了几种分子途径，可以部分解释神经质症状及其精神合并症的已知性别差异。
The presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric disorders displaying prominent sex differences. We performed genome-wide association studies (GWAS) of neuroticism separately in males and females to identify sex-specific genetic and transcriptomic profiles. Neuroticism scores were derived from the Eysenck Personality Inventory Neuroticism scale. GWAS were performed in 145,669 females and 129,229 males from the UK Biobank considering autosomal and X-chromosomal variation. Two-sided Z-tests were used to test for sex-specific effects of discovered loci, genetic correlates (N=673 traits), tissue and gene transcriptomic profiles, and polygenic associations across health outcomes in the Vanderbilt University Biobank (BioVu, 39,692 females and 31,268 males). The SNP-heritability of neuroticism was not statistically different between males (h2=10.6%) and females (h2=11.85%). Four female-specific (rs10736549-CNTN5, rs6507056-ASXL3, rs2087182-MMS22L, and rs72995548-HSPB2) and two male-specific (rs10507274-MED13L and rs7984597) neuroticism risk loci reached genome-wide significance. Male- and female-specific neuroticism polygenic scores were most significantly associated with “mood disorders” (male OR=1.11, P=1.40x10−9; female OR=1.14, P=6.05x10−22). They also associated with sex-specific laboratory measures related to erythrocyte count, distribution, and hemoglobin concentration. Gene expression variation in the pituitary was enriched for neuroticism loci in males (males b=0.026, P=0.002) and genetically-regulated transcriptomic changes highlighted the effect of RAB7L1, TEX26, and PLOT1. Through a comprehensive assessment of genetic risk for neuroticism and the associated biological processes, this study identified several molecular pathways that can partially explain the known sex differences in neurotic symptoms and their psychiatric comorbidities.
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影响因子：
12.3
作者：
Dennis JK;Sealock JM;Straub P;Lee YH;Hucks D;Actkins K;Faucon A;Feng YA;Ge T;Goleva SB;Niarchou M;Singh K;Morley T;Smoller JW;Ruderfer DM;Mosley JD;Chen G;Davis LK
通讯作者：
Davis LK
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
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.
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
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