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

TitleMolecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions.
Publication TypeJournal Article
Year of Publication2016
AuthorsHill WD, Davies G, Harris SE, Hagenaars SP, Liewald DC, Penke L, Gale CR
Secondary AuthorsDeary IJ
Corporate AuthorsneuroCHARGE Cognitive Working group
JournalTransl Psychiatry
Volume6
Issue12
Paginatione980
Date Published2016 12 13
ISSN2158-3188
KeywordsAged, Brain, Cognition, Conserved Sequence, Evolution, Molecular, Female, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Middle Aged, Molecular Biology, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Problem Solving, Statistics as Topic
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.

DOI10.1038/tp.2016.246
Alternate JournalTransl Psychiatry
PubMed ID27959336
PubMed Central IDPMC5290340
Grant ListRF1 AG015819 / AG / NIA NIH HHS / United States
MC_U147585827 / MRC_ / Medical Research Council / United Kingdom
MC_U147574232 / MRC_ / Medical Research Council / United Kingdom
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12011/2 / MRC_ / Medical Research Council / United Kingdom
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
MC_UP_A620_1014 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12011/1 / MRC_ / Medical Research Council / United Kingdom
P30 AG010129 / AG / NIA NIH HHS / United States
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
G0400491 / MRC_ / Medical Research Council / United Kingdom
MC_U147585824 / MRC_ / Medical Research Council / United Kingdom
U01 AG049505 / AG / NIA NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
MC_UP_A620_1015 / MRC_ / Medical Research Council / United Kingdom
MC_U147585819 / MRC_ / Medical Research Council / United Kingdom
R01 AG017917 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States