GWAS of cognitive function using UK Biobank data

Written by: Stephen Hsu

Primary Source: Information Processing

This paper is based on analysis of UK Biobank data. The phenotypes (cognitive scores) were obtained via brief on-screen tests. Although there is significant noise in the scores obtained (see test-retest correlations in the table at bottom), there was enough signal to obtain a number of genome-wide significant SNP hits.

Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112,151)

Nature Molecular Psychiatry 5 April 2016 doi: 10.1038/mp.2016.45

People’s differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal–numerical reasoning (N=36 035), memory (N=112 067), reaction time (N=111 483) and for the attainment of a college or a university degree (N=111 114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal–numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer’s disease and schizophrenia.

Discussion

The results of the present study make novel contributions to three scientific aims of GWAS: helping towards identifying specific mechanisms of genomic variation; describing the genetic architecture of complex traits; and predicting phenotypic variation in independent samples. The most important novel contribution of the present study is the discovery of many new genome-wide significant genetic variants associated with reasoning ability, cognitive processing speed and the attainment of a college or university degree. The study provided robust estimates of the SNP-based heritability of the four cognitive variables and their genetic correlations. The study makes important steps toward genetic consilience, because several of the genomic regions identified by the present analyses have previously been associated in GWASs of general cognitive function, executive function, educational attainment, intracranial volume, neurodegenerative disorders and Alzheimer’s disease. The study was successful in using the GWAS results from UK Biobank to predict cognitive variation in new samples. …

 

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Stephen Hsu
Stephen Hsu is vice president for Research and Graduate Studies at Michigan State University. He also serves as scientific adviser to BGI (formerly Beijing Genomics Institute) and as a member of its Cognitive Genomics Lab. Hsu’s primary work has been in applications of quantum field theory, particularly to problems in quantum chromodynamics, dark energy, black holes, entropy bounds, and particle physics beyond the standard model. He has also made contributions to genomics and bioinformatics, the theory of modern finance, and in encryption and information security. Founder of two Silicon Valley companies—SafeWeb, a pioneer in SSL VPN (Secure Sockets Layer Virtual Private Networks) appliances, which was acquired by Symantec in 2003, and Robot Genius Inc., which developed anti-malware technologies—Hsu has given invited research seminars and colloquia at leading research universities and laboratories around the world.