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GWAS Meta-Analysis of Neuroticism (N=449,484) 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 Skene, Ana B Muñoz-Manchado, the 23andMe Research Team, Sten Linnarsson, Jens Hjerling-Leffler, Tonya JH White, Henning Tiemeier, Tinca JC Polderman, Patrick F Sullivan, Sophie van der Sluis, Danielle Posthuma
doi: https://doi.org/10.1101/184820
Mats Nagel
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
2Department of Clinical Genetics, Section Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
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Philip R Jansen
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
3Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
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Sven Stringer
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
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Kyoko Watanabe
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
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Christiaan A de Leeuw
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
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Julien Bryois
4Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Jeanne E Savage
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
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Anke R Hammerschlag
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
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Nathan Skene
5Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Ana B Muñoz-Manchado
5Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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623andMe, Inc., Mountain View, CA, USA
Sten Linnarsson
5Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Jens Hjerling-Leffler
5Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Tonya JH White
3Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
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Henning Tiemeier
3Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
7Department of Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands
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Tinca JC Polderman
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
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Patrick F Sullivan
4Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
8Department of Genetics, University of North Carolina, Chapel Hill, USA
9Department of Psychiatry, University of North Carolina, Chapel Hill, USA
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Sophie van der Sluis
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
2Department of Clinical Genetics, Section Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
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Danielle Posthuma
1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, The Netherlands
2Department of Clinical Genetics, Section Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
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  • For correspondence: d.posthuma@vu.nl
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Abstract

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.

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GWAS Meta-Analysis of Neuroticism (N=449,484) 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 Skene, Ana B Muñoz-Manchado, the 23andMe Research Team, Sten Linnarsson, Jens Hjerling-Leffler, Tonya JH White, Henning Tiemeier, Tinca JC Polderman, Patrick F Sullivan, Sophie van der Sluis, Danielle Posthuma
bioRxiv 184820; doi: https://doi.org/10.1101/184820
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GWAS Meta-Analysis of Neuroticism (N=449,484) 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 Skene, Ana B Muñoz-Manchado, the 23andMe Research Team, Sten Linnarsson, Jens Hjerling-Leffler, Tonya JH White, Henning Tiemeier, Tinca JC Polderman, Patrick F Sullivan, Sophie van der Sluis, Danielle Posthuma
bioRxiv 184820; doi: https://doi.org/10.1101/184820

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