Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans
Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans
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DOI：
10.1001/jamapsychiatry.2022.3896
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发表时间：
2022-12-14
期刊：
影响因子：
25.8
通讯作者：
Hauser, Michael A.
中科院分区：
文献类型：
--
作者：
Kimbrel, Nathan A.;Ashley-Koch, Allison E.;Hauser, Michael A.
重要性
自杀是一个主要的死亡原因；然而，自杀想法和行为（SITB）的分子遗传基础仍然未知。
目的
确定SITB新的、可重复的基因组风险位点。
设计、环境和参与者
这项全基因组关联研究包括633778名有和没有SITB的美国退伍军人，通过电子健康记录确定。全基因组关联分析（GWAS）按血统分别进行，控制性别、年龄和遗传亚结构。通过荟萃分析确定跨血统风险位点。研究于2011年开始招募，目前仍在进行中。数据于2021年11月至2022年8月进行分析。
主要结果和测量指标
SITB
结果
共有633778名美国退伍军人被纳入分析（57152名[9%]为女性；121118名[19.1%]为非洲血统，8285名[1.3%]为亚洲血统，452767名[71.4%]为欧洲血统，51608名[8.1%]为西班牙裔血统），其中包括121211名有SITB的个体（19.1%）。荟萃分析确定了200多个全基因组显著（P < 5×10⁻⁸）的跨血统SITB风险单核苷酸变异，集中在2号、6号、9号、11号、14号、16号和18号染色体的7个区域。主要的单核苷酸变异大多为内含子性质；5个在国际自杀遗传学联盟（ISGC）中独立重复，包括ESR1中的rs6557168、DRD2中的rs12808482、EXD3中的rs77641763、DCC中的rs10671545和TRAF3中的rs36006172。FBXL19和.2的关联未被重复。基于基因的分析涉及另外24个全基因组显著的跨血统风险基因，包括弗林蛋白酶（FURIN）、TSNARE1以及神经细胞黏附分子1 - TTC12 - 锚蛋白重复和激酶结构域1 - 多巴胺受体D2（NCAM1 - TTC12 - ANKK1 - DRD2）基因簇。跨血统富集分析显示在脑和垂体组织表达、突触和泛素化过程、安非他命成瘾、甲状旁腺激素合成、轴突导向和多巴胺能通路中显著富集。还确定了7个其他独特的欧洲血统特异性全基因组显著位点，其中2个（POM121L2和METTL15/LINC02758）被重复。在非洲血统（PET112/GATB）和西班牙裔血统（4号染色体上的基因间位点）亚组中确定了另外2个全基因组显著的血统特异性位点，两者都被重复。在亚洲血统亚组中未确定全基因组显著位点；然而，在所有血统中观察到轴突导向、环磷酸腺苷信号传导、黏着斑、谷氨酸能突触和催产素信号通路的显著富集。在欧洲血统亚组中，观察到SITB表型与仅自杀未遂表型、抑郁症和创伤后应激障碍之间的遗传相关性（r > 0.75）。此外，多基因风险评分分析显示，百万退伍军人计划多基因风险评分在欧洲和非洲血统退伍军人的2个独立样本中具有名义上显著的主效应。
结论和相关性
这项分析的结果可能会促进对SITB分子遗传基础的理解，并为ESR1、DRD2、TRAF3和DCC作为跨血统候选风险基因提供证据。需要更多的工作来重复这些发现，并确定这些基因是否以及如何影响临床护理。
IMPORTANCE Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown. OBJECTIVE To identify novel, replicable genomic risk loci for SITB. DESIGN, SETTING, AND PARTICIPANTS This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022. Main Outcome and Measures SITB. RESULTS A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 x 10(-8)) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and .2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry-specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry. CONCLUSIONS AND RELEVANCE The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.