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GWAS Meta-Analysis of Neuroticism (N=449,484) Identifies Novel Genetic Loci and Pathways
Philip R Jansen,
Christiaan A de Leeuw,
Jeanne E Savage,
Anke R Hammerschlag,
Ana B Muñoz-Manchado,
the 23andMe Research Team,
Tonya JH White,
Tinca JC Polderman,
Patrick F Sullivan,
Sophie van der Sluis,
Posted 05 Sep 2017
bioRxiv DOI: 10.1101/184820 (published DOI: 10.1038/s41588-018-0151-7)
Posted 05 Sep 2017
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.
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