Sex differences in the genetic architecture of obsessive-compulsive disorder
Sex differences in the genetic architecture of obsessive-compulsive disorder
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DOI：
10.1002/ajmg.b.32687
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发表时间：
2019-09-01
影响因子：
2.8
通讯作者：
Zai, Gwyneth
中科院分区：
文献类型：
--
作者：
Khramtsova, Ekaterina A.;Heldman, Raphael;Zai, Gwyneth
强迫症（OCD）是一种高度遗传的复杂表型，表现出发病年龄和临床表现的性别差异，这表明潜在的遗传结构可能存在性别差异。我们提出了第一个全基因组特征的性别特异性遗传结构的强迫症，利用最大的一组强迫症病例和控制可从精神病基因组学联盟。我们评估了可能导致性别差异的几种机制的证据，包括性别依赖的责任阈值，常染色体和X染色体上存在个体性别特异性风险变异，以及性别特异性多效性效应。此外，我们测试的假设，性别之间的遗传异质性可能会掩盖性别结合的全基因组关联研究的关联。我们观察到男性和女性强迫症之间有很强的遗传相关性，并且没有证据表明性别依赖的责任阈值模型，这表明性别组合分析不会因为性别之间的遗传异质性而遭受广泛的权力损失。虽然我们没有检测到任何显著的性别特异性全基因组单核苷酸多态性（SNP）关联，但我们确实在女性中发现了两个显著的基于基因的关联：GRID2和GRP135，这在男性中没有显示出关联。我们观察到，具有性别差异效应的SNPs显示了影响脑和免疫组织中基因表达的调节变体的富集。这些研究结果表明，未来的研究与更大的样本量有很大的希望，为确定性别特异性遗传风险因素的强迫症。
Obsessive-compulsive disorder (OCD) is a highly heritable complex phenotype that demonstrates sex differences in age of onset and clinical presentation, suggesting a possible sex difference in underlying genetic architecture. We present the first genome-wide characterization of the sex-specific genetic architecture of OCD, utilizing the largest set of OCD cases and controls available from the Psychiatric Genomics Consortium. We assessed evidence for several mechanisms that may contribute to sex differences including a sex-dependent liability threshold, the presence of individual sex-specific risk variants on the autosomes and the X chromosome, and sex-specific pleiotropic effects. Furthermore, we tested the hypothesis that genetic heterogeneity between the sexes may obscure associations in a sex-combined genome-wide association study. We observed a strong genetic correlation between male and female OCD and no evidence for a sex-dependent liability threshold model, suggesting that sex-combined analysis does not suffer from widespread loss of power because of genetic heterogeneity between the sexes. While we did not detect any significant sex-specific genome-wide single nucleotide polymorphisms (SNP) associations, we did identify two significant gene-based associations in females: GRID2 and GRP135, which showed no association in males. We observed that the SNPs with sexually differentiated effects showed an enrichment of regulatory variants influencing expression of genes in brain and immune tissues. These findings suggest that future studies with larger sample sizes hold great promise for the identification of sex-specific genetic risk factors for OCD.