Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

Gail Davies(University of Edinburgh), Nicola J. Armstrong(The University of Sydney), Joshua C. Bis(University of Washington), Jan Bressler(The University of Texas Health Science Center at Houston), Vincent Chouraki(Inserm), Sudheer Giddaluru(Haukeland University Hospital), Edith Hofer(Medical University of Graz), Carla A. Ibrahim‐Verbaas(Erasmus MC), Mirna Kirin(University of Edinburgh), Jari Lahti(University of Helsinki), S J van der Lee(Erasmus MC), Stéphanie Le Hellard(Haukeland University Hospital), Tsan Liu(Max Planck Institute for Human Development), Riccardo E. Marioni(The University of Queensland), Christopher Oldmeadow(Hunter Medical Research Institute), Iris Postmus(Leiden University Medical Center), Albert V. Smith(University of Iceland), Jennifer A. Smith(University of Michigan), Anbupalam Thalamuthu(UNSW Sydney), Russell Thomson(Menzies School of Health Research), Véronique Vitart(Institute of Genetics and Cancer), Jiao Wang(Framingham Heart Study), Lei Yu(Rush University Medical Center), Lina Zgaga(University of Zagreb), Wei Zhao(University of Michigan), Ruth Boxall(Western General Hospital), Sarah E. Harris(Western General Hospital), W. David Hill(University of Edinburgh), David C. Liewald(University of Edinburgh), Michelle Luciano(University of Edinburgh), Hieab H.H. Adams(Erasmus MC), David Ames(The Royal Melbourne Hospital), Najaf Amin(Erasmus MC), Philippe Amouyel(Inserm), Amelia A. Assareh(UNSW Sydney), Rhoda Au(Framingham Heart Study), James T. Becker(University of Pittsburgh), Alexa Beiser(Framingham Heart Study), Claudine Berr(Inserm), Lars Bertram(Max Planck Institute for Molecular Genetics), Eric Boerwinkle(Baylor College of Medicine), B. M. Buckley(University College Cork), Harry Campbell(University of Edinburgh), Janie Corley(University of Edinburgh), Philip L. De Jager(Broad Institute), Carole Dufouil(Inserm), Johan G. Eriksson(University of Helsinki), Thomas Espeseth(Oslo University Hospital), Jessica D. Faul(University of Michigan), Ian Ford(The Robertson Trust), Generation Scotland(Western General Hospital), Rebecca F. Gottesman(Johns Hopkins University), M E Griswold(University of Mississippi Medical Center), Vilmundur Guðnason(University of Iceland), Tamara B. Harris(National Institutes of Health), G. Heiss(University of North Carolina at Chapel Hill), A Hofman(Erasmus MC), E.G. Holliday(Hunter Medical Research Institute), Jennifer E. Huffman(Institute of Genetics and Cancer), Sharon L. R. Kardia(University of Michigan), Nicole A. Kochan(New South Wales Department of Health), D S Knopman(Mayo Clinic), John B. Kwok(UNSW Sydney), J-C Lambert(Inserm), Teresa Lee(New South Wales Department of Health), G. Li(University of Washington), Shu Li(Max Planck Institute for Human Development), M Loitfelder(Medical University of Graz), O L Lopez(University of Pittsburgh), Astri J. Lundervold(University of Bergen), Annamari Lundqvist(Umeå University), Karen A. Mather(UNSW Sydney), S S Mirza(Erasmus MC), Lars Nyberg(Umeå University), Ben A. Oostra(Erasmus MC), Aarno Palotie(University of Helsinki), Goran Papenberg(Stockholm University), Alison Pattie(University of Edinburgh), Katja Petrovic(Medical University of Graz), Ozren Polašek(University of Split), Bruce M. Psaty(Group Health Cooperative), Paul Redmond(University of Edinburgh), Simone Reppermund(UNSW Sydney), Jerome I. Rotter(UCLA Medical Center), Helena Schmidt(Medical University of Graz), Maaike Schuur(Erasmus MC), P W Schofield(University of Newcastle Australia), Rodney J. Scott(Hunter Medical Research Institute), V M Steen(Haukeland University Hospital), David J. Stott(University of Glasgow), John C. van Swieten(Erasmus MC), Kent D. Taylor(UCLA Medical Center), Julian N. Trollor(UNSW Sydney), Stella Trompet(Leiden University Medical Center), André G. Uitterlinden(Erasmus MC), Galit Weinstein(Framingham Heart Study), Elisabeth Widén(University of Helsinki), B. Gwen Windham(University of Mississippi Medical Center), J. Wouter Jukema(Leiden University Medical Center), A F Wright(Institute of Genetics and Cancer), Margaret J. Wright(QIMR Berghofer Medical Research Institute), Qi Yang(Framingham Heart Study), Hélène Amieva(Inserm), J R Attia(Hunter Medical Research Institute), David A. Bennett(Rush University Medical Center), H Brodaty(UNSW Sydney), Anton J. M. de Craen(Leiden University Medical Center), C Hayward(Institute of Genetics and Cancer), M. Arfan Ikram(Erasmus MC), U Lindenberger(Max Planck Institute for Human Development), L-G Nilsson(Karolinska Institutet), David J. Porteous(Western General Hospital), Katri Räikkönen(University of Helsinki), Ivar Reinvang(University of Oslo), Igor Rudan(University of Edinburgh), Perminder S. Sachdev(New South Wales Department of Health), Reinhold Schmidt(Medical University of Graz), Peter R. Schofield(UNSW Sydney), Velandai Srikanth(University of Tasmania), John M. Starr(Alzheimer Scotland), S. T. Turner(Mayo Clinic), David R. Weir(University of Michigan), J F Wilson(University of Edinburgh), C van Duijn(Erasmus MC), L. J. Launer(National Institutes of Health), Annette L. Fitzpatrick(University of Washington), Sudha Seshadri(Framingham Heart Study), Tom Mosley(University of Mississippi Medical Center), Ian J. Deary(University of Edinburgh)
Molecular Psychiatry
February 1, 2015
10.1038/mp.2014.188
Cited by 410Open Access
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Abstract

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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