Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways

23Andme Research Team

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Abstract

Neuroticism is an important risk factor for psychiatric traits, including depression1, anxiety2,3, and schizophrenia4-6. At the time of analysis, previous genome-wide association studies7-12 (GWAS) reported 16 genomic loci associated to neuroticism10-12. Here we conducted a large GWAS meta-analysis (n = 449,484) of neuroticism and identified 136 independent genome-wide significant loci (124 new at the time of analysis), which implicate 599 genes. Functional follow-up analyses showed enrichment in several brain regions and involvement of specific cell types, including dopaminergic neuroblasts (P = 3.49 × 10-8), medium spiny neurons (P = 4.23 × 10-8), and serotonergic neurons (P = 1.37 × 10-7). Gene set analyses implicated three specific pathways: neurogenesis (P = 4.43 × 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'), suggesting distinct causal mechanisms for subtypes of individuals. Mendelian randomization analysis showed unidirectional and bidirectional effects between neuroticism and multiple psychiatric traits. These results enhance neurobiological understanding of neuroticism and provide specific leads for functional follow-up experiments.

Original languageEnglish
Pages (from-to)920-927
Number of pages8
JournalNature Genetics
Volume50
Issue number7
DOIs
Publication statusPublished - 1 Jul 2018

Funding

We would like to thank the participants, including the 23andMe customers who consented to participate in research, and the researchers who collected and contributed to the data. This work was funded by the Netherlands Organization for Scientific Research through the following grants: NWO Brain and Cognition 433-09-228 (D.P.), NWO MagW VIDI 452-12-014 (S.v.d.S.), NWO VICI 435-13-005 (D.P.) and 645-000-003) (D.P.). P.R.J. was funded by the Sophia Foundation for Scientific Research (SSWO, grant no. S14-27). J.H.-L. was funded by the Swedish Research Council (Vetenskapsrådet, award 2014-3863), StratNeuro, the Wellcome Trust (108726/Z/15/Z), and the Swedish Brain Foundation (Hjärnfonden). N.G.S. was supported by the Wellcome Trust (108726/Z/15/Z). J.B. was funded by the Swiss National Science Foundation. The work of H.T. was supported by a NWO–VICI grant (NWO-ZonMW 016.VICI.170.200). Analyses were carried out on the Genetic Cluster computer, which is financed by the Netherlands Scientific Organization (NWO award 480-05-003 to D.P.), VU University (Amsterdam, The Netherlands), and the Dutch Brain Foundation and is hosted by the Dutch National Computing and Networking Services, SurfSARA. This research has been conducted using the UK Biobank resource (application 16406).

FundersFunder number
Dutch Brain Foundation
Dutch National Computing and Networking Services
Netherlands Organization for Scientific Research645-000-003, VICI 435-13-005, MagW VIDI 452-12-014
Netherlands Scientific Organization480-05-003
SSWOS14-27
Sophia Foundation for Scientific Research
Swedish Brain Foundation
Wellcome Trust108726/Z/15/Z
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungNWO-ZonMW 016
Vrije Universiteit Amsterdam
Vetenskapsrådet2014-3863

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