PT  - JOURNAL ARTICLE
AU  - Mats Nagel
AU  - Philip R Jansen
AU  - Sven Stringer
AU  - Kyoko Watanabe
AU  - Christiaan A de Leeuw
AU  - Julien Bryois
AU  - Jeanne E Savage
AU  - Anke R Hammerschlag
AU  - Nathan Skene
AU  - Ana B Muñoz-Manchado
AU  - the 23andMe Research Team
AU  - Sten Linnarsson
AU  - Jens Hjerling-Leffler
AU  - Tonya JH White
AU  - Henning Tiemeier
AU  - Tinca JC Polderman
AU  - Patrick F Sullivan
AU  - Sophie van der Sluis
AU  - Danielle Posthuma
TI  - GWAS Meta-Analysis of Neuroticism (N=449,484) Identifies Novel Genetic Loci and Pathways
AID  - 10.1101/184820
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 184820
4099  - http://biorxiv.org/content/early/2017/09/05/184820.short
4100  - http://biorxiv.org/content/early/2017/09/05/184820.full
AB  - Neuroticism is an important risk factor for psychiatric traits including depression1, anxiety2,3, and schizophrenia4–6. Previous genome-wide association studies7–12 (GWAS) reported 16 genomic loci10–12. 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 subclusters13 (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.