Sex differences in the genetic architecture of depression
Sex differences in the genetic architecture of depression
复制标题
DOI：
10.1038/s41598-020-66672-9
复制
发表时间：
2020-06-18
影响因子：
4.6
通讯作者：
Kim, Jae-Min
中科院分区：
文献类型：
--
作者：
Kang, Hee-Ju;Park, Yoomi;Kim, Jae-Min
抑郁障碍的患病率和临床特征在女性和男性之间有所不同；然而，基因对抑郁障碍性别差异的影响尚未阐明。为了评估抑郁症遗传结构的性别差异，对1000例抑郁症患者(70.7%为女性)的样本进行了全外显子组测序。对照数据来自无精神障碍的健康人(n=72，26.4%女性)和东亚亚群1000基因组计划数据(n=207，女性50.7%)。采用定性和定量研究设计，直接比较了男性和女性之间的基因变异。定性分析发现了5个可能与女性抑郁障碍风险增加相关的遗传标记，包括染色体19p13.2上的三个变异(PDE4A内的rs201432982和FDX1L内的rs62640397和rs79442975)以及染色体17p25.1上的MYO15B内的两个新变异(rs820182和rs820148)。与非纯合子(即杂合子和非关联等位基因的纯合子)相比，携带这些变异纯合子的抑郁症患者表现出更严重的抑郁症状和更高的自杀倾向。定量分析表明，即使在置换测试之后，蛋白质截断和有害变异的遗传负担在男性中也高于女性。我们的研究提供了新的遗传学证据，表明女性抑郁障碍的高患病率可能与遗传变异有关。
The prevalence and clinical characteristics of depressive disorders differ between women and men; however, the genetic contribution to sex differences in depressive disorders has not been elucidated. To evaluate sex-specific differences in the genetic architecture of depression, whole exome sequencing of samples from 1000 patients (70.7% female) with depressive disorder was conducted. Control data from healthy individuals with no psychiatric disorder (n=72, 26.4% female) and East-Asian subpopulation 1000 Genome Project data (n=207, 50.7% female) were included. The genetic variation between men and women was directly compared using both qualitative and quantitative research designs. Qualitative analysis identified five genetic markers potentially associated with increased risk of depressive disorder in females, including three variants (rs201432982 within PDE4A, and rs62640397 and rs79442975 within FDX1L) mapping to chromosome 19p13.2 and two novel variants (rs820182 and rs820148) within MYO15B at the chromosome 17p25.1 locus. Depressed patients homozygous for these variants showed more severe depressive symptoms and higher suicidality than those who were not homozygotes (i.e., heterozygotes and homozygotes for the non-associated allele). Quantitative analysis demonstrated that the genetic burden of protein-truncating and deleterious variants was higher in males than females, even after permutation testing. Our study provides novel genetic evidence that the higher prevalence of depressive disorders in women may be attributable to inherited variants.