RT Journal Article
SR Electronic
T1 GWAS Meta-Analysis of Neuroticism (N=449,484) Identifies Novel Genetic Loci and Pathways
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 184820
DO 10.1101/184820
A1 Nagel, Mats
A1 Jansen, Philip R
A1 Stringer, Sven
A1 Watanabe, Kyoko
A1 de Leeuw, Christiaan A
A1 Bryois, Julien
A1 Savage, Jeanne E
A1 Hammerschlag, Anke R
A1 Skene, Nathan
A1 Muñoz-Manchado, Ana B
A1 ,
A1 Linnarsson, Sten
A1 Hjerling-Leffler, Jens
A1 White, Tonya JH
A1 Tiemeier, Henning
A1 Polderman, Tinca JC
A1 Sullivan, Patrick F
A1 van der Sluis, Sophie
A1 Posthuma, Danielle
YR 2017
UL http://biorxiv.org/content/early/2017/09/05/184820.abstract
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.