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Cited by 43Genetic Associations and EpidemiologyCognitive Abilities and TestingGenetic Mapping and Diversity in Plants and Animals

Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions

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Hill, W D, Davies, G, Harris, S E, Hagenaars, S P, The neuroCHARGE Cognitive Working group, Davies, Gail, Deary, Ian J, Debette, Stephanie +16 more·2016·Translational Psychiatry
DOI 10.1038/tp.2016.246PMC PMC5290340

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Abstract

Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with several psychiatric and physical disease states. However, to date, few single-nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium ( n =53 949) and UK Biobank ( n =36 035), to partition the genome into 52 functional annotations and an additional 10 annotations describing tissue-specific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ~2.6% of the SNPs from each GWAS but accounted for ~40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions.

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  • Conserved and regulatory regions have previously been implicated in cognitive functioning, but coding regions have not.

    “Conserved and regulatory regions have previously been implicated in cognitive functioning 22 , but coding regions have not.”

    From Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence (2018) · cites this paper as [22]

    The Results (Partitioned heritability; page unavailable) report enrichment for cognitive-function heritability in conserved regions and in regulatory annotations, including weak enhancers and DNase hypersensitivity sites. The paper does not establish the broader claim that coding regions have not been implicated in cognitive functioning. (LLM, conf=0.82)

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Authors
Hill, W. D., Davies, G., Harris, S. E., Hagenaars, S. P., The neuroCHARGE Cognitive Working group, Davies, G., Deary, I. J., Debette, S., Verbaas, C. I., Bressler, J., Schuur, M., Smith, A. V., Bis, J. C., Bennett, D. A., Ikram, M. A., Launer, L. J., Fitzpatrick, A. L., Seshadri, S., van Duijn, C. M., Mosley Jr, T. H., Liewald, D. C., Penke, L., Gale, C. R., & Deary, I. J.
Affiliations
  • University of Edinburgh (GB)
  • Western General Hospital (GB)
  • Erasmus MC (NL)
  • The University of Texas Health Science Center at Houston (US)
  • Icelandic Heart Association (IS)
  • University of Washington (US)
  • Rush University Medical Center (US)
  • National Institutes of Health (US)
  • Leibniz ScienceCampus Primate Cognition (DE)
  • MRC Lifecourse Epidemiology Unit (GB)
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2016-12-13
Volume
6
Issue
12
Pages
e980-e980
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2016.246
PMC
PMC5290340
OpenAlex
W2951443932
Cited by
43
References
5
Citations by year
2026: 3 · 2022: 6 · 2021: 5 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 4 · 2016: 1
FWCI
5.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
  • National University of Singapore (submittedVersion, cc-by)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • GRO (submittedVersion, cc-by)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • School of Medicine, Boston University
  • University of Washington
  • Rush University
  • University of Texas Health Science Center at Houston
  • National Institute for Health and Care Research (NF-SI-0508-10082, NF-SI-0513-10085)
  • University of Edinburgh (MR/K026992/1)
  • Institut National de la Santé et de la Recherche Médicale
  • Háskóli Íslands
  • Université de Bordeaux
  • Hjartavernd
  • Centre for Cognitive Ageing and Cognitive Epidemiology (MR/K026992/1)
  • Directorate for Biological Sciences
  • School of Public Health, University of Texas Health Science Center at Houston
  • Medical Research Council (MR/K026992/1, MC_UU_12011/2, MC_UU_12011/1)
  • Biotechnology and Biological Sciences Research Council (MR/K026992/1, BB/F019394/1)
  • Erasmus Universitair Medisch Centrum Rotterdam
  • National Institute on Aging (R01AG017917, P30AG010129, U01AG049505, R01AG015819, P30AG010161, R01AG033193, RF1AG015819)
  • National Institute of Neurological Disorders and Stroke (R01NS017950)
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
general intelligence, single nucleotide polymorphisms, evolutionary conservation, negative selection, linkage disequilibrium score regression, heritability, pleiotropy, histone modifications, functional genomic annotation, genetic correlation
MeSH terms
Aged, Brain, Cognition, Female, Humans, Male, Middle Aged, Molecular Biology, Neuropsychological Tests, Phenotype, Problem Solving, Statistics as Topic, Genetic Variation, Linkage Disequilibrium, Conserved Sequence, Evolution, Molecular, Polymorphism, Single Nucleotide, Genome-Wide Association Study

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