Abstract

Neuroticism is an important risk factor for psychiatric traits, including depression1, anxiety2,3, and schizophrenia4,5,6. At the time of analysis, previous genome-wide association studies7,8,9,10,11,12 (GWAS) reported 16 genomic loci associated to neuroticism10,11,12. 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.

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Acknowledgements

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).

Author information

Author notes

  1. These authors contributed equally: Mats Nagel, Philip R. Jansen.

  2. These authors jointly supervised this work: Sophie van der Sluis, Danielle Posthuma.

  3. A list of members and affiliations appears at the end of the paper.

Affiliations

  1. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

    • Mats Nagel
    • , Philip R. Jansen
    • , Sven Stringer
    • , Kyoko Watanabe
    • , Christiaan A. de Leeuw
    • , Jeanne E. Savage
    • , Anke R. Hammerschlag
    • , Tinca J. C. Polderman
    • , Sophie van der Sluis
    •  & Danielle Posthuma
  2. Department of Clinical Genetics, Section of Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands

    • Mats Nagel
    • , Sophie van der Sluis
    •  & Danielle Posthuma
  3. Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands

    • Philip R. Jansen
    • , Tonya White
    •  & Henning Tiemeier
  4. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    • Julien Bryois
    •  & Patrick F. Sullivan
  5. Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    • Nathan G. Skene
    • , Ana B. Muñoz-Manchado
    • , Sten Linnarsson
    •  & Jens Hjerling-Leffler
  6. Department of Social and Behavioral Science, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Henning Tiemeier
  7. UCL Institute of Neurology, Queen Square, London, UK

    • Jens Hjerling-Leffler
  8. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    • Patrick F. Sullivan
  9. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    • Patrick F. Sullivan
  10. 23andMe, Inc, Mountain View, CA, USA

    • Michelle Agee
    • , Babak Alipanahi
    • , Adam Auton
    • , Robert K. Bell
    • , Katarzyna Bryc
    • , Sarah L. Elson
    • , Pierre Fontanillas
    • , Nicholas A. Furlotte
    • , David A. Hinds
    • , Bethann S. Hromatka
    • , Karen 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

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Consortia

  1. 23andMe Research Team

Contributions

S.v.d.S. and D.P. conceived the study; M.N. and P.R.J. performed the analyses; S.S. performed the quality control on the UKB data and wrote a pipeline to facilitate data processing; K.W. constructed the tool for biological annotation and ran the analyses; H.T. and T.W. read and commented on the pre-final version of the manuscript; A.R.H., C.A.d.L., J.E.S., and T.J.C.P. wrote part of the analysis pipeline and assisted in interpreting results; N.G.S., A.B.M.-M., S.L., and J.H.-L. provided single-cell RNA-seq data for mouse brain cell types; J.B. and P.F.S. performed the single-cell gene expression analysis; and M.N., P.R.J., S.v.d.S., and D.P. wrote the paper. All authors discussed the results and commented on the paper.

Competing interests

J.H.-L. is a scientific advisor at Cartana and has received a grant from Roche. P.F. has received a grant from Lundbeck and is currently a member of the advisory committee. Over the last 3 years, P.F. has been on the scientific advisory board at Pfizer, received a consultation fee from Element Genomics, and received speaker reimbursement fees from Roche.

Corresponding author

Correspondence to Danielle Posthuma.

Supplementary information

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    Supplementary Note, Supplementary Results and Supplementary Figures 1–17

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  3. Supplementary Tables 1–42

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DOI

https://doi.org/10.1038/s41588-018-0151-7

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