Functional Gene Group Analysis Indicates No Role for Heterotrimeric G Proteins in Cognitive Ability

et al. (2014) Functional Gene Group Analysis Indicates No Role for Heterotrimeric G Proteins in Cognitive Ability. PLoS ONE 9(3): e91690. doi:10.1371/journal.pone.0091690 Functional Gene Group Analysis Indicates No Role for Heterotrimeric G Proteins in Cognitive Ability W. David Hill 0 Christiaan de Leeuw 0 Gail Davies 0 David Cherry McLachlan Liewald 0 Anthony Payton 0 Leone C. A. Craig 0 Lawrence J. Whalley 0 Mike Horan 0 William Ollier 0 John M. Starr 0 Neil Pendleton 0 Danielle Posthuma 0 Timothy C. Bates 0 Ian J. Deary 0 Reiner Albert Veitia, Institut Jacques Monod, France 0 1 Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh , Edinburgh , United Kingdom , 2 Department of Psychology, University of Edinburgh , Edinburgh , United Kingdom , 3 Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Complex Trait Genetics, VU University Amsterdam , Amsterdam , The Netherlands , 4 Institute for Computing and Information Sciences, Radboud University Nijmegen , Nijmegen , The Netherlands , 5 Centre for Integrated Genomic Medical Research, University of Manchester , Manchester , United Kingdom , 6 Public Health Nutrition Group, Institute of Applied Health Sciences, University of Aberdeen , Aberdeen , United Kingdom, 7 Institute of Applied Health Sciences, University of Aberdeen , Aberdeen , United Kingdom, 8 Centre for Clinical and Cognitive Neurosciences, Institute of Brain , Behaviour and Mental Health , University of Manchester , Manchester , United Kingdom , 9 Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands, 10 Department of Child and Adolescent Psychiatry, Erasmus University Rotterdam, Sophia Child Hospital , Rotterdam , The Netherlands Previous functional gene group analyses implicated common single nucleotide polymorphisms (SNPs) in heterotrimeric G protein coding genes as being associated with differences in human intelligence. Here, we sought to replicate this finding using five independent cohorts of older adults including current IQ and childhood IQ, and using both gene- and SNP-based analytic strategies. No significant associations were found between variation in heterotrimeric G protein genes and intelligence in any cohort at either of the two time points. These results indicate that, whereas G protein systems are important in cognition, common genetic variation in these genes is unlikely to be a substantial influence on human intelligence differences. - Funding: This work was supported by the Engineering and Physical research council (EPSRC), the Biological Sciences Research Council (BBSRC), the Medical Research Council (MRC), the Wellcome Trust, the Economic and Social Research Council (ESRC), and Netherlands Organization of Scientific Research NWO 645000-003. The work was undertaken in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (G0700704/84698). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. People who do well on one type of cognitive test tend to do well on others, giving rise to the concept of general cognitive ability (intelligence) as an important human phenotype [1]. The strong heritability [2], and significant practical impact of general intelligence on factors such as education, occupational status, and health, has motivated research seeking to discover molecular genetic factors influencing cognitive differences [3]. However, specific genetic variants remain elusive, other than a small effect of APOE variation on cognitive ageing [4]. The failure of candidate gene designs to identify genetic variants being involved in intelligence differences has led researchers to adopt new approaches as well as motivating the efforts dedicated to the attempted replication of reported associations [4,5]. Methods to increase the power to detect causal variants focus on combining the effects of multiple SNPs. At the largest level, Genome-Wide Complex Trait Analysis (GCTA) can be used to combine the effect of every available SNP across the genome [68], whilst GCTA provides a heritability estimate based on all SNPs it cannot be used to detect which SNPs are associated with the trait. GCTA has been used to show that common variants jointly tag 51% of the variance in fluid cognitive ability and 40% of crystallised ability in a cohort of older adults [4], and around 40% of childhood IQ variance [9]. Pathway analyses have been introduced as a method to increase statistical power and test for the joint effect of multiple SNPs [10]. Typically, SNPs are grouped together based on their role in biological pathways or according to the cellular function of their gene product. Using this method, genetic (...truncated)