Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency <1%) putatively functional single-nucleotide polymorphisms (SNPs) present on the Illumina PsychArray genotyping array in 2,672 USGRS suicide deaths of non-Finnish European (NFE) ancestry and 51,583 NFE controls from the Genome Aggregation Database. Secondary analyses used an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. Five novel, high-impact, rare SNPs were identified with significant associations with suicide death (SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). 119 suicide decedents carried these high-impact SNPs. Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and psychiatric associations exist for PER1 (bipolar disorder, schizophrenia), and for TNKS1BP1 and ESS2 (schizophrenia). Three of the genes (PER1, TNKS1BP1, and ADGRF5), together with additional genes implicated by genome-wide association studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. No specific diagnostic phenotypes were associated with the subset of suicide deaths with the identified rare variants. These findings suggest an important role for rare variants in suicide risk and implicate genes and gene pathways for targeted replication.

中文翻译：

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罕见的蛋白质编码变体暗示与自杀死亡风险相关的基因

识别导致自杀死亡风险增加的遗传因素对于应对自杀率上升至关重要，然而，只有一小部分影响风险的遗传变异被考虑在内。为了解决这一限制，我们利用最大的自杀死亡生物库犹他州自杀遗传风险研究 (USGRS)，对自杀死亡中罕见的遗传变异进行了首次综合分析。我们对 Illumina PsychArray 基因分型阵列上存在的 2,672 名非芬兰欧洲 (NFE) 血统的 USGRS 自杀死亡和 51,583来自基因组聚合数据库的 NFE 控制。二次分析使用了 21 个独立的对照样本，来自 Psychiatric Genomics Consortium 的 324 个 NFE 对照。五个新的、高影响的、罕见的 SNP 与自杀死亡显着相关。SNAPC1 , rs75418419 ; TNKS1BP1，rs143883793 ；ADGRF5 , rs149197213 ; PER1 , rs145053802; 和ESS2 , rs62223875)。119 名自杀者携带这些高影响 SNP。PER1和SNAPC1都有其他支持自杀风险的基因水平证据，并且PER1（双相情感障碍、精神分裂症）以及TNKS1BP1和ESS2（精神分裂症）存在精神病学关联。三个基因（PER1、TNKS1BP1和ADGRF5)，连同与自杀行为的全基因组关联研究有关的其他基因，显示出免疫系统、稳态和信号转导过程的显着富集。没有特定的诊断表型与已确定的罕见变异的自杀死亡子集相关。这些发现表明罕见变异在自杀风险中的重要作用，并暗示了靶向复制的基因和基因途径。