Paper

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

Van Der Sluis, Sophie, Hjerling-Leffler, Jens, Polderman, Tinca Jc, De Leeuw, Christiaan A, Munoz-Manchado, Ana B, Skene, Nathan, Linnasrsson, Sten, Savage, Jeanne E, Sullivan, Patrick F, 23andme Research Team, Posthuma, Danielle, Hammerschlag, Anke R, Tiemeier, Henning, Watanabe, Kyoko, Jansen, Philip R, Stringer, Sven, Bryois, Julien, Nagel, Mats, White, Tonya

2017

Overview

Neuroticism is an important risk factor for psychiatric traits including depression, anxiety, and schizophrenia. Previous genome-wide association studies (GWAS) reported 16 genomic loci. 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=3E-8), medium spiny neurons (P=4E-8) and serotonergic neurons (P=1E-7). Gene-set analyses implicate three specific pathways: neurogenesis (P=4.4E-9), behavioural response to cocaine processes (P=1.84E-7), and axon part (P=5.26E-8). We show that neuroticism's genetic signal partly originates in two genetically distinguishable subclusters (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.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Anxiety / Cocaine / Dopamine receptors / Gene loci / Genetics / Genome-wide association studies / Genomes / Mental depression / Mental disorders / Neuroblasts / Neurogenesis / Neurosis / Risk factors / Schizophrenia / Serotonin / Spiny neurons