GWAS Meta-Analysis of Neuroticism (N=449,484) Identifies Novel Genetic Loci and Pathways

Abstract

Neuroticism is an important risk factor for psychiatric traits including depression 1 , anxiety 2,3 , and schizophrenia 4–6 . Previous genome-wide association studies 7–12 (GWAS) reported 16 genomic loci 10–12 . Here we report the largest neuroticism GWAS meta-analysis to date (N=449,484), and identify 136 independent genome-wide significant loci (124 novel), implicating 599 genes. Extensive functional follow-up analyses show enrichment in several brain regions and involvement of specific cell-types, including dopaminergic neuroblasts ( P =3×10 -8 ), medium spiny neurons ( P =4×10 -8 ) and serotonergic neurons ( P =1×10 -7 ). Gene-set analyses implicate three specific pathways: neurogenesis ( P =4.4×10 -9 ), behavioural response to cocaine processes ( P =1.84×10 -7 ), and axon part (P=5.26×10 -8 ). We show that neuroticism’s genetic signal partly originates in two genetically distinguishable subclusters 13 ( depressed affect and worry , the former being genetically strongly related to depression, rg =0.84), suggesting distinct causal mechanisms for subtypes of individuals. These results vastly enhance our neurobiological understanding of neuroticism, and provide specific leads for functional follow-up experiments.