American University of Antigua College of Medicine, Osbourn, Antigua and Barbuda.
Forensic Science Program, University of Toronto, Mississauga, ON, Canada.
Mol Psychiatry. 2023 Mar;28(3):1064-1071. doi: 10.1038/s41380-022-01929-5. Epub 2023 Jan 6.
Genome-wide association studies (GWAS) of suicidal thoughts and behaviors support the existence of genetic contributions. Continuous measures of psychiatric disorder symptom severity can sometimes model polygenic risk better than binarized definitions. We compared two severity measures of suicidal thoughts and behaviors at the molecular and functional levels using genome-wide data. We used summary association data from GWAS of four traits analyzed in 122,935 individuals of European ancestry: thought life was not worth living (TLNWL), thoughts of self-harm, actual self-harm, and attempted suicide. A new trait for suicidal thoughts and behaviors was constructed first, phenotypically, by aggregating the previous four traits (termed "suicidality") and second, genetically, by using genomic structural equation modeling (gSEM; termed S-factor). Suicidality and S-factor were compared using SNP-heritability (h) estimates, genetic correlation (r), partitioned h, effect size distribution, transcriptomic correlations (ρ) in the brain, and cross-population polygenic scoring (PGS). The S-factor had good model fit (χ = 0.21, AIC = 16.21, CFI = 1.00, SRMR = 0.024). Suicidality (h = 7.6%) had higher h than the S-factor (h = 2.54, P = 4.78 × 10). Although the S-factor had a larger number of non-null susceptibility loci (π = 0.010), these loci had small effect sizes compared to those influencing suicidality (π = 0.005, P = 0.045). The h of both traits was enriched for conserved biological pathways. The r and ρ support highly overlapping genetic and transcriptomic features between suicidality and the S-factor. PGS using European-ancestry SNP effect sizes strongly associated with TLNWL in Admixed Americans: Nagelkerke's R = 8.56%, P = 0.009 (PGS) and Nagelkerke's R = 7.48%, P = 0.045 (PGS). An aggregate suicidality phenotype was statistically more heritable than the S-factor across all analyses and may be more informative for future genetic study designs interested in common genetic factors among different suicide related phenotypes.
全基因组关联研究（GWAS）表明自杀意念和行为存在遗传因素。连续的精神障碍症状严重程度测量有时可以比二分定义更好地模拟多基因风险。我们使用来自欧洲血统 122935 人的四个特征的 GWAS 的汇总关联数据，在分子和功能水平上比较了自杀意念和行为的两种严重程度测量。我们首先通过聚合以前的四个特征（称为“自杀意念”）来构建一个新的自杀意念和行为特征，然后使用基因组结构方程建模（gSEM；称为 S 因子）在遗传上构建该特征。使用 SNP 遗传度（h）估计值、遗传相关性（r）、分区 h、效应大小分布、大脑中的转录组相关性（ρ）和跨人群多基因评分（PGS）比较了自杀意念和 S 因子。S 因子具有良好的模型拟合（χ=0.21，AIC=16.21，CFI=1.00，SRMR=0.024）。自杀意念（h=7.6%）的 h 高于 S 因子（h=2.54，P=4.78×10）。尽管 S 因子具有更多的非零易感性基因座（π=0.010），但与影响自杀意念的基因座相比，这些基因座的效应大小较小（π=0.005，P=0.045）。两个特征的 h 都富集了保守的生物学途径。r 和 ρ 支持自杀意念和 S 因子之间具有高度重叠的遗传和转录组特征。使用欧洲血统 SNP 效应大小的 PGS 与混合美国人的 TLNWL 强烈相关：Nagelkerke 的 R=8.56%，P=0.009（PGS）和 Nagelkerke 的 R=7.48%，P=0.045（PGS）。在所有分析中，聚合自杀意念表型在统计学上比 S 因子更具遗传性，并且对于未来对不同自杀相关表型之间共同遗传因素感兴趣的遗传研究设计可能更具信息性。
