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

Gail Davies, Nicola Armstrong, Joshua C Bis, Jan Bressler, Vincent Chouraki, Sudheer Giddaluru, Edith Hofer, Carla A Ibrahim-Verbaas, Mirna Kirin, Jari Marko Lahti, Sven J van der Lee, Stephanie Le Hellard, Tian Liu, Riccardo E Marioni, Christopher Oldmeadow, Iris Postmus, Albert Vernon Smith, Jennifer Ann Smith, Anbupalam Thalamuthu, Russell ThomsonVeronique Vitart, Jing Wang, Lei Yu, Lina Zgaga, Wei Zhao, Ruth Boxall, Sarah E Harris, William David Hill, David C Liewald, Michelle Luciano, Hieab H H Adams, David J Ames, Najaf Amin, Philippe Amouyel, Amelia A Assareh, Rhoda Au, James T Becker, Alexa Beiser, Claudine Berr, Lars Bertram, Eric Boerwinkle, Brendan M Buckley, Harry Campbell, Janie Corley, Philip Laurence De Jager, Carole Dufouil, Johan Gunnar Eriksson, Thomas Espeseth, Jessica D Faul, Ian Ford, Rebecca F Gottesman, Michael E Griswold, Vilmundur G Gudnason, Tamara B Harris, Gerardo Heiss, Albert Hofman, Elizabeth G Holliday, Jennifer Huffman, Sharon L R Kardia, Nicole Kochan, David S Knopman, John B J Kwok, Jean-Charles Lambert, Teresa Lee, Guo Li, Shu-Chen Li, Marisa Loitfelder, Oscar L Lopez, Astri Johansen Lundervold, Anders Lundqvist, Karen A Mather, Saira Saeed Mirza, Lars Nyberg, Ben A Oostra, Aarno Palotie, Goran Papenberg, Alison Pattie, Katja Elisabeth Petrovic, Ozren Polasek, Bruce M Psaty, Paul Redmond, Simone Reppermund, Jerome I Rotter, Helena Schmidt, Maaike Schuur, Peter W Schofield, Rodney J Scott, Vidar M Steen, David J Stott, John C van Swieten, Kent D Taylor, Julian Norman Trollor, Stella Trompet, Andre G Uitterlinden, Galit Weinstein, Elisabeth Widen, Beverly Gwen Windham, J Wouter Jukema, Alan F Wright, Margaret J Wright, Qiong Yang, Helene Amieva, John R Attia, David A Bennett, Henry Brodaty, Anton J M de Craen, Caroline Hayward, Mohammed Arfan Ikram, Lars-Goran Nilsson, Ulman Lindenberger, David J Porteous, Katri Raikkonen, Ivar Reinvang, Igor Rudan, Perminder Singh Sachdev, Reinhold Schmidt, Peter R Schofield, Velandai Srikanth, John M Starr, Stephen T Turner, David R Weir, Jim F Wilson, Cornelia M van Duijn, Lenore J Launer, Annette L Fitzpatrick, Sudha Seshadri, Thomas H Mosley, Ian J Deary

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182 Citations (Scopus)

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 x 10(-9), MIR2113; rs17522122, P=2.55 x 10(-8), AKAP6; rs10119, P=5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 x 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 x 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.
Original languageEnglish
Pages (from-to)183 - 192
Number of pages10
JournalMolecular Psychiatry
Volume20
Issue number2
DOIs
Publication statusPublished - 2015

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