We previously conducted a genome-wide association study (GWAS) of attempted suicide within bipolar disorder, which implicated common variation in the 2p25 region primarily in males. The top association signal from our GWAS occurred in an intergenic region of 2p25 (p = 5.07 × 10-8) and was supported by two independent studies. In the current study, to better characterize the association of the 2p25 region with attempted suicide, we sequenced the entire 350kb 2p25 region in 476 bipolar suicide attempters and 473 bipolar non-attempters using targeted next-generation sequencing. This fine-mapping project identified 4,681 variants in the 2p25 region. We performed both gene-level and individual-variant tests on our sequencing results and identified 375 variants which were nominally significant (p < 0.05) and three common variants that were significantly associated with attempted suicide in males (corrected p = 0.035, odds ratio (OR) = 2.13). These three variants are in strong linkage disequilibrium with the top variant from our GWAS. Our top five variants are also predicted expression quantitative trait loci (eQTL) for three genes in the 2p25 region based on publicly available brain expression databases. Our sequencing and eQTL data implicate these three genes - SH3YL1, ACP1, and FAM150B - and three additional pathways - androgen receptor, Wnt signaling, and glutamatergic/GABAergic signaling - in the association of the 2p25 region with suicide. The current study provides additional support for an association of the 2p25 region with attempted suicide in males and identifies several candidate genes and pathways that warrant further investigation to understand their role in suicidal behavior.

中文翻译：

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2p25 区域与双相情感障碍自杀企图的男性特异性关联。

我们之前对双相情感障碍中的自杀未遂进行了全基因组关联研究 (GWAS)，这表明主要在男性中存在 2p25 区域的常见变异。来自我们 GWAS 的最高关联信号发生在 2p25 的基因间区域（p = 5.07 × 10-8），并得到两项独立研究的支持。在目前的研究中，为了更好地表征 2p25 区域与自杀未遂的关联，我们使用靶向下一代测序对 476 名双相自杀未遂者和 473 名双相非自杀未遂者的整个 350kb 2p25 区域进行了测序。这个精细映射项目确定了 2p25 区域中的 4,681 个变体。我们对测序结果进行了基因水平和个体变异测试，并确定了 375 个名义上显着的变异（p < 0. 05）和三个与男性自杀未遂显着相关的常见变体（校正后的 p = 0.035，优势比 (OR) = 2.13）。这三个变体与我们 GWAS 的顶级变体处于强连锁不平衡状态。我们的前五个变体也是基于公开可用的大脑表达数据库的 2p25 区域中三个基因的预测表达数量性状基因座 (eQTL)。我们的测序和 eQTL 数据表明这三个基因 - SH3YL1、ACP1 和 FAM150B - 以及另外三个途径 - 雄激素受体、Wnt 信号传导和谷氨酸能/GABA 能信号传导 - 在 2p25 区域与自杀的关联中。