Human Molecular Genetics Advance Access originally published online on September 4, 2009
Human Molecular Genetics 2009 18(23):4650-4661; doi:10.1093/hmg/ddp413
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A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB
1 Center for Human Genome Variation, Institute for Genome Sciences and Policy and 2 Genomic Analysis Facility, Institute for Genome Sciences and Policy, Duke University, 450 Research Drive, Box 91009, Durham, NC 27708, USA, 3 Division of Neurology and Division of Medical Psychology, Duke University Medical Center, Durham, NC 27705, USA, 4 Department of Genetics, Gardner Hall, North Carolina State University, Raleigh, NC 27695, USA, 5 Department of Medical and Molecular Genetics, King's College London, Guy's Hospital Campus, London SE1 9RT, UK and 6 Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Hospital Campus, London, UK
* To whom correspondence should be addressed at: Tel: +1 9196840896; Fax: +1 9196686787; Email: d.goldstein{at}duke.edu
Received April 10, 2009; Revised July 7, 2009; Accepted August 25, 2009
Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the Cambridge Neuropsychological Test Automated Battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in 
750 subjects, and for spatial and verbal recognition memory, we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants. Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower than expected P-values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.