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Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

G DaviesN ArmstrongJ C BisJ BresslerVincent ChourakiS GiddaluruE HoferC A Ibrahim-VerbaasM KirinJ LahtiS J van der LeeS Le HellardT LiuR E MarioniC OldmeadowI PostmusA V SmithJ A SmithA ThalamuthuR ThomsonV VitartJ WangL YuL ZgagaW ZhaoR BoxallS E HarrisW D HillD C LiewaldM LucianoHieab H H AdamsD AmesN AminPhillippe AmouyelA A AssarehR AuJ T BeckerA BeiserC BerrL BertramE BoerwinkleB M BuckleyH CampbellJ CorleyP L De JagerC DufouilJ G ErikssonT EspesethJ D FaulI Fordnull nullR F GottesmanM E GriswoldV GudnasonT B HarrisG HeissA HofmanE G HollidayJennifer E HuffmanS L R KardiaN KochanD S KnopmanJ B KwokJ-C LambertT LeeG LiS-C LiM LoitfelderO L LopezA J LundervoldA LundqvistK A MatherS S MirzaL NybergB A OostraA PalotieG PapenbergA PattieK PetrovicO PolasekB M PsatyP RedmondS ReppermundJ I RotterH SchmidtM SchuurP W SchofieldR J ScottV M SteenD J StottJ C van SwietenK D TaylorJ TrollorS TrompetA G UitterlindenG WeinsteinE WidenB G WindhamJ W JukemaA F WrightM J WrightQ YangH AmievaJ R AttiaD A BennettH BrodatyA J M de CraenC HaywardM A IkramU LindenbergerL-G NilssonD J PorteousK RäikkönenI ReinvangIgor RudanP S SachdevR SchmidtP R SchofieldV SrikanthJ M StarrS T TurnerD R WeirJ F WilsonC van DuijnL LaunerA L FitzpatrickS SeshadriT H MosleyI J Deary
Published in: Molecular psychiatry (2015)
General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
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