| Title: | Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways |
| Journal: | Nature Genetics |
| Published: | 25 Jun 2018 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/29942085/ |
| DOI: | https://doi.org/10.1038/s41588-018-0151-7 |
| URL: | https://www.biorxiv.org/content/biorxiv/early/2017/09/05/184820.full.pdf |
| Citations: | 574 (167 in last 2 years) as of 8 Aug 2024 |
Publication 1970
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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.</p>
18 Keywords
- Adult
- Aged
- Anxiety Disorders
- Axons
- Depression
- Female
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Neurogenesis
- Neurons
- Neuroticism
- Polymorphism, Single Nucleotide
- Risk Factors
- Schizophrenia
19 Authors
- 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
- 23andMe Research Team
- Tonya White
- Henning Tiemeier
- Sten Linnarsson
- Jens Hjerling-Leffler
- Tinca J. C. Polderman
- Patrick F. Sullivan
- Sophie van der Sluis
- Danielle Posthuma
1 Application
| Application ID | Title |
|---|---|
| 16406 | Causes of individual differences in cognitive and mental health |
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