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

23Andme Research Team

Research output: Contribution to JournalArticleAcademicpeer-review

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

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Genetic Loci
Genome-Wide Association Study
Meta-Analysis
Mendelian Randomization Analysis
Psychiatry
Genome
Serotonergic Neurons
Neurogenesis
Cocaine
Genes
Axons
Neuroticism
Neurons
Brain

Cite this

@article{97f94d8a7c1a441cb14ef7525d5a6073,
title = "Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways",
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.",
author = "Mats Nagel and Jansen, {Philip R} and Sven Stringer and Kyoko Watanabe and {de Leeuw}, {Christiaan A} and Julien Bryois and Savage, {Jeanne E} and Hammerschlag, {Anke R} and Skene, {Nathan G} and Mu{\~n}oz-Manchado, {Ana B} and Tonya White and Henning Tiemeier and Sten Linnarsson and Jens Hjerling-Leffler and Polderman, {Tinca J C} and Sullivan, {Patrick F} and {van der Sluis}, Sophie and Danielle Posthuma and {23Andme Research Team}",
year = "2018",
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language = "English",
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Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways. / 23Andme Research Team.

In: Nature Genetics, Vol. 50, No. 7, 01.07.2018, p. 920-927.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways

AU - Nagel, Mats

AU - Jansen, Philip R

AU - Stringer, Sven

AU - Watanabe, Kyoko

AU - de Leeuw, Christiaan A

AU - Bryois, Julien

AU - Savage, Jeanne E

AU - Hammerschlag, Anke R

AU - Skene, Nathan G

AU - Muñoz-Manchado, Ana B

AU - White, Tonya

AU - Tiemeier, Henning

AU - Linnarsson, Sten

AU - Hjerling-Leffler, Jens

AU - Polderman, Tinca J C

AU - Sullivan, Patrick F

AU - van der Sluis, Sophie

AU - Posthuma, Danielle

AU - 23Andme Research Team

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N2 - 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.

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