Barr Peter B, Bigdeli Tim B, Meyers Jacquelyn L, Peterson Roseann E, Sanchez-Roige Sandra, Mallard Travis T, Dick Danielle M, Paige Harden K, Wilkinson Anna, Graham David P, Nielsen David A, Swann Alan, Lipsky Rachele K, Kosten Thomas, Aslan Mihaela, Harvey Philip D, Kimbrel Nathan A, Beckham Jean C
VA New York Harbor Healthcare System, Brooklyn, NY.
Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY.
medRxiv. 2023 Jul 11:2023.03.22.23286865. doi: 10.1101/2023.03.22.23286865.
Many psychiatric outcomes are thought to share a common etiological pathway reflecting behavioral disinhibition, generally referred to as externalizing disorders (EXT). Recent genome-wide association studies (GWAS) have demonstrated the overlap between EXT and important aspects of veterans' health, such as suicide-related behaviors, substance use disorders, and other medical conditions.
We conducted a series of phenome-wide association studies (PheWAS) of polygenic scores (PGS) for EXT, and comorbid psychiatric problems (depression, schizophrenia, and suicide attempt) in an ancestrally diverse cohort of U.S. veterans ( = 560,824), using diagnostic codes from electronic health records. We conducted ancestry-specific PheWASs of EXT PGS in the European, African, and Hispanic/Latin American ancestries. To determine if associations were driven by risk for other comorbid problems, we performed a conditional PheWAS, covarying for comorbid psychiatric problems (European ancestries only). Lastly, to adjust for unmeasured confounders we performed a within-family analysis of significant associations from the main PheWAS in full-siblings (N = 12,127, European ancestries only).
The EXT PGS was associated with 619 outcomes across all bodily systems, of which, 188 were independent of risk for comorbid problems of PGS. Effect sizes ranged from OR = 1.02 (95% CI = 1.01, 1.03) for overweight/obesity to OR = 1.44 (95% CI = 1.42, 1.47) for viral hepatitis C. Of the significant outcomes 73 (11.9%) and 26 (4.5%) were significant in the African and Hispanic/Latin American results, respectively. Within-family analyses uncovered robust associations between EXT and consequences of substance use disorders, including liver disease, chronic airway obstruction, and viral hepatitis C.
Our results demonstrate a shared polygenic basis of EXT across populations of diverse ancestries and independent of risk for other psychiatric problems. The strongest associations with EXT were for diagnoses related to substance use disorders and their sequelae. Overall, we highlight the potential negative consequences of EXT for health and functioning in the US veteran population.
许多精神疾病结局被认为共享一条反映行为抑制的共同病因途径，通常称为外化性障碍（EXT）。最近的全基因组关联研究（GWAS）已证明EXT与退伍军人健康的重要方面存在重叠，如自杀相关行为、物质使用障碍和其他医疗状况。
我们在美国退伍军人的一个具有不同祖先的队列（n = 560,824）中，使用电子健康记录中的诊断代码，对EXT的多基因评分（PGS）以及共病的精神问题（抑郁症、精神分裂症和自杀未遂）进行了一系列全表型组关联研究（PheWAS）。我们在欧洲、非洲和西班牙裔/拉丁裔血统中对EXT PGS进行了特定血统的PheWAS。为了确定关联是否由其他共病问题的风险驱动，我们进行了条件PheWAS，对共病的精神问题进行协变量调整（仅欧洲血统）。最后，为了调整未测量的混杂因素，我们对全同胞（N = 12,127，仅欧洲血统）中主要PheWAS的显著关联进行了家系内分析。
EXT PGS与所有身体系统的619种结局相关，其中188种独立于PGS共病问题的风险。效应大小范围从超重/肥胖的OR = 1.02（95%CI = 1.01, 1.（此处原文有误，应为1.03））到丙型病毒性肝炎的OR = 1.44（95%CI = 1.42, 1.47）。在显著结局中，73种（11.9%）和26种（4.5%）分别在非洲和西班牙裔/拉丁裔血统的结果中显著。家系内分析发现EXT与物质使用障碍的后果之间存在强关联，包括肝病、慢性气道阻塞和丙型病毒性肝炎。
我们的结果表明，EXT在不同祖先的人群中具有共同的多基因基础，且独立于其他精神问题的风险。与EXT最强的关联是与物质使用障碍及其后遗症相关的诊断。总体而言，我们强调了EXT对美国退伍军人健康和功能的潜在负面影响。
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