Leveraging genetic overlap between irritability and psychiatric disorders to identify genetic variants of major psychiatric disorders

Abstract

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. Psychiatry: Genetic associations between irritability and major psychiatric disordersIdentifying genetic variants associated with irritability, a heritable condition, has revealed some variants that are also associated with major psychiatric disorders. Researchers in Seoul, South Korea, led by Hong-Hee Won at Sungkyunkwan University and Woojae Myung at Seoul National University, performed a genome-wide association study with 379,506 individuals of European ancestry from the UK Biobank database. The study compared millions of genetic variants between 105,975 people with self-reported irritability and 273,531 controls. Multiple genetic analyses illustrated the genetic overlap between irritability and psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia. The study also investigated specific biological pathways associated with these variants. The findings help shed light on the genetic basis of psychiatric disorders, which may pave the way for new treatment.