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Genome-wide association study in 404,302 individuals identifies 7 significant loci for reaction time variability

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Wootton, Olivia, Shadrin, Alexey A., Mohn, Christine, Susser, Ezra, Ramesar, Raj, Gur, Ruben C., Andreassen, Ole A., Stein, Dan J., Dalvie, Shareefa·2023·Molecular Psychiatry
DOI 10.1038/s41380-023-02292-9PMC PMC10730420

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Abstract

Reaction time variability (RTV), reflecting fluctuations in response time on cognitive tasks, has been proposed as an endophenotype for many neuropsychiatric disorders. There have been no large-scale genome-wide association studies (GWAS) of RTV and little is known about its genetic underpinnings. Here, we used data from the UK Biobank to conduct a GWAS of RTV in participants of white British ancestry ( n = 404,302) as well as a trans-ancestry GWAS meta-analysis ( n = 44,873) to assess replication. We found 161 genome-wide significant single nucleotide polymorphisms (SNPs) distributed across 7 genomic loci in our discovery GWAS. Functional annotation of the variants implicated genes involved in synaptic function and neural development. The SNP-based heritability ( h 2 SNP ) estimate for RTV was 3%. We investigated genetic correlations between RTV and selected neuropsychological traits using linkage disequilibrium score regression, and found significant correlations with several traits, including a positive correlation with mean reaction time and schizophrenia. Despite the high genetic correlation between RTV and mean reaction time, we demonstrate distinctions in the genetic underpinnings of these traits. Lastly, we assessed the predictive ability of a polygenic score (PGS) for RTV, calculated using PRSice and PRS-CS, and found that the RTV-PGS significantly predicted RTV in independent cohorts, but that the generalisability to other ancestry groups was poor. These results identify genetic underpinnings of RTV, and support the use of RTV as an endophenotype for neurological and psychiatric disorders.

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Metadata

Authors
Wootton, O., Shadrin, A. A., Mohn, C., Susser, E., Ramesar, R., Gur, R. C., Andreassen, O. A., Stein, D. J., & Dalvie, S.
Affiliations
  • University of Cape Town (ZA)
  • Oslo University Hospital (NO)
  • New York State Psychiatric Institute (US)
  • University of Pennsylvania (US)
  • South African Medical Research Council (ZA)
Corresponding author
Wootton, Olivia
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2023-09
Volume
28
Issue
9
Pages
4011-4019
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-023-02292-9
PMC
PMC10730420
OpenAlex
W4387814658
Cited by
5
References
9
Citations by year
2026: 2 · 2025: 1 · 2024: 2
FWCI
0.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (U01MH125053, 5UO1MH096754)
  • Norges Forskningsråd (275054, 26813, 223273, 324499)
  • EEA Grants (2018-0573)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
Keywords
reaction time variability, endophenotypes, neuropsychiatric disorders, genetic loci, single nucleotide polymorphisms, heritability, genetic correlation, schizophrenia, polygenic risk score, synaptic function, neural development, UK Biobank

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