Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals 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 G. Skene, Ana B. Muñoz-Manchado, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Bethann S. HromatkaKaren E. Huber, Aaron Kleinman, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, Catherine H. Wilson, Tonya White, Henning Tiemeier, Sten Linnarsson, Jens Hjerling-Leffler, Tinca J.C. Polderman, Patrick F. Sullivan, Sophie Van Der Sluis, Danielle Posthuma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Neuroticism is an important risk factor for psychiatric traits, including depression 1 , anxiety 2,3 , and schizophrenia 4-6 . At the time of analysis, previous genome-wide association studies 7-12 (GWAS) reported 16 genomic loci associated to neuroticism 10-12 . 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 subclusters 13 ('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
Issue number7
Publication statusPublished - 1 Jul 2018

Cite this