Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, 06355, South Korea.
Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, 13620, South Korea.
Exp Mol Med. 2023 Jun;55(6):1193-1202. doi: 10.1038/s12276-023-01005-0. Epub 2023 Jun 1.
Irritability is a heritable core mental trait associated with several psychiatric illnesses. However, the genomic basis of irritability is unclear. Therefore, this study aimed to 1) identify the genetic variants associated with irritability and investigate the associated biological pathways, genes, and tissues as well as single-nucleotide polymorphism (SNP)-based heritability; 2) explore the relationships between irritability and various traits, including psychiatric disorders; and 3) identify additional and shared genetic variants for irritability and psychiatric disorders. We conducted a genome-wide association study (GWAS) using 379,506 European samples (105,975 cases and 273,531 controls) from the UK Biobank. We utilized various post-GWAS analyses, including linkage disequilibrium score regression, the bivariate causal mixture model (MiXeR), and conditional and conjunctional false discovery rate approaches. This GWAS identified 15 independent loci associated with irritability; the total SNP heritability estimate was 4.19%. Genetic correlations with psychiatric disorders were most pronounced for major depressive disorder (MDD) and bipolar II disorder (BD II). MiXeR analysis revealed polygenic overlap with schizophrenia (SCZ), bipolar I disorder (BD I), and MDD. Conditional false discovery rate analyses identified additional loci associated with SCZ (number [n] of additional SNPs = 105), BD I (n = 54), MDD (n = 107), and irritability (n = 157). Conjunctional false discovery rate analyses identified 85, 41, and 198 shared loci between irritability and SCZ, BD I, and MDD, respectively. Multiple genetic loci were associated with irritability and three main psychiatric disorders. Given that irritability is a cross-disorder trait, these findings may help to elucidate the genomics of psychiatric disorders.
易激惹是一种与多种精神疾病相关的遗传性核心精神特征。然而，易激惹的基因组基础尚不清楚。因此，本研究旨在：1）鉴定与易激惹相关的遗传变异，并研究相关的生物学途径、基因和组织以及基于单核苷酸多态性（SNP）的遗传率；2）探索易激惹与包括精神障碍在内的各种特征之间的关系；3）确定易激惹和精神障碍的额外和共享遗传变异。我们使用来自英国生物库的 379,506 名欧洲样本（105,975 例病例和 273,531 名对照）进行了全基因组关联研究（GWAS）。我们利用了各种 GWAS 后分析，包括连锁不平衡评分回归、双变量因果混合模型（MiXeR）以及条件和联合虚假发现率方法。该 GWAS 确定了 15 个与易激惹相关的独立位点；SNP 总遗传率估计值为 4.19%。与精神障碍的遗传相关性在重度抑郁症（MDD）和双相情感障碍 II 型（BD II）中最为明显。MiXeR 分析显示与精神分裂症（SCZ）、双相情感障碍 I 型（BD I）和 MDD 存在多基因重叠。条件虚假发现率分析确定了与 SCZ（附加 SNP 数量[n] = 105）、BD I（n = 54）、MDD（n = 107）和易激惹（n = 157）相关的额外位点。联合虚假发现率分析分别在易激惹与 SCZ、BD I 和 MDD 之间确定了 85、41 和 198 个共享位点。多个遗传位点与易激惹和三种主要精神障碍相关。鉴于易激惹是一种跨疾病特征，这些发现可能有助于阐明精神障碍的基因组学。
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