@article {Nagel184820, author = {Mats Nagel and Philip R Jansen and Sven Stringer and Kyoko Watanabe and Christiaan A de Leeuw and Julien Bryois and Jeanne E Savage and Anke R Hammerschlag and Nathan Skene and Ana B Mu{\~n}oz-Manchado and the 23andMe Research Team and Sten Linnarsson and Jens Hjerling-Leffler and Tonya JH White and Henning Tiemeier and Tinca JC Polderman and Patrick F Sullivan and Sophie van der Sluis and Danielle Posthuma}, title = {GWAS Meta-Analysis of Neuroticism (N=449,484) Identifies Novel Genetic Loci and Pathways}, elocation-id = {184820}, year = {2017}, doi = {10.1101/184820}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Neuroticism is an important risk factor for psychiatric traits including depression1, anxiety2,3, and schizophrenia4{\textendash}6. Previous genome-wide association studies7{\textendash}12 (GWAS) reported 16 genomic loci10{\textendash}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{\texttimes}10-8), medium spiny neurons (P=4{\texttimes}10-8) and serotonergic neurons (P=1{\texttimes}10-7). Gene-set analyses implicate three specific pathways: neurogenesis (P=4.4{\texttimes}10-9), behavioural response to cocaine processes (P=1.84{\texttimes}10-7), and axon part (P=5.26{\texttimes}10-8). We show that neuroticism{\textquoteright}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.}, URL = {https://www.biorxiv.org/content/early/2017/09/05/184820}, eprint = {https://www.biorxiv.org/content/early/2017/09/05/184820.full.pdf}, journal = {bioRxiv} }