Genome-wide association analysis of 19,629 individuals identifies variants influencing regional brain volumes and refines their genetic co-architecture with cognitive and mental health traits
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Abstract
Volumetric variations of the human brain are heritable and are associated with many brain-related complex traits. Here we performed genome-wide association studies (GWAS) of 101 brain volumetric phenotypes using the UK Biobank sample including 19,629 participants. GWAS identified 365 independent genetic variants exceeding a significance threshold of 4.9 × 10-10, adjusted for testing multiple phenotypes. A gene-based association study found 157 associated genes (124 new), and functional gene mapping analysis linked 146 additional genes. Many of the discovered genetic variants and genes have previously been implicated in cognitive and mental health traits. Through genome-wide polygenic-risk-score prediction, more than 6% of the phenotypic variance (P = 3.13 × 10-24) in four other independent studies could be explained by the UK Biobank GWAS results. In conclusion, our study identifies many new genetic associations at the variant, locus and gene levels and advances our understanding of the pleiotropy and genetic co-architecture between brain volumes and other traits.
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Other genes among the 34, including CADM2, ZIC4, GABRA2, NEGR1, and FURIN, have previously been identified in GWAS of behavioral or psychiatric traits.
“Other genes among the 34 have previously been identified in GWAS of behavioral or psychiatric traits: Cell Adhesion Molecule 2 (CADM2, previously identified in GWAS related to self-regulation, including drug use and risk tolerance17,33), Zic Family Member 4 (ZIC4, associated with brain volume34), Gamma-Aminobutyric Acid Type A Receptor Subunit Alpha 2 (GABRA2; the site of action for alcohol and”
From Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction. (2021) · cites this paper as [34]
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References 104 · Cited by 295
- Authors
- Zhao, B., Luo, T., Li, T., Li, Y., Zhang, J., Shan, Y., Wang, X., Yang, L., Zhou, F., Zhu, Z., Initiative, A. D. N., Pediatric Imaging, N. A. G., & Zhu, H.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Harvard University (US)
- ORCID
- Venue
- Nature Genetics
- Published
- 2019-11
- Volume
- 51
- Issue
- 11
- Pages
- 1637-1644
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6858580
- OpenAlex
- W2986919234
- Cited by
- 295
- References
- 104
- Citations by year
- 2026: 26 · 2025: 48 · 2024: 47 · 2023: 52 · 2022: 42 · 2021: 49 · 2020: 24 · 2019: 6 · 2018: 1
- FWCI
- 18.62
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, other-oa)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (MH086633, MH116527)
- Cancer Prevention Research Institute of Texas
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- brain volume, genetic variants, cognitive characteristics, pleiotropy, polygenic risk score, gene mapping, heritability, UK Biobank
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Mental Disorders, Brain, Child, Child, Preschool, Cognition Disorders, Female, Genetic Markers, United Kingdom, Humans, Male, Mental Health, Middle Aged, Phenotype, Cohort Studies, Linkage Disequilibrium, Quantitative Trait, Heritable, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Young Adult, Genetic Association Studies
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