“GWAS Meta-Analysis of Neuroticism (n = 449,484) Identifies Novel Genetic Loci and Pathways”, Mats Nagel, Philip R. Jansen, Sven Stringer, Kyoko Watanabe, Christiaan A. de Leeuw, Julien Bryois, Jeanne E. Savage, Anke R. Hammerschlag, Nathan Skene, Ana B. Muñoz-Manchado, the 23andMe Research Team, Sten Linnarsson, Jens Hjerling-Leffler, Tonya J. H. White, Henning Tiemeier, Tinca J. C. Polderman, Patrick F. Sullivan, Sophie van der Sluis, Danielle Posthuma2017-09-05 (, , , ; similar)⁠:

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 statistically-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 3 specific pathways: neurogenesis (p = 4.4×10−9), behavioral 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.