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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222 Citations (Scopus)


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
Issue number2
Publication statusPublished - 2015

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