The ATXN1 and TRIM31 genes are related to intelligence in an ADHD background: Evidence from a large collaborative study totaling 4,963 Subjects

Thais S. Rizzi, Alejandro Arias‐Vasquez, Nanda Rommelse, Jonna Kuntsi, Richard Anney, Philip Asherson, Jan Buitelaar, Tobias Banaschewski, Richard Ebstein, Dina Ruano, Sophie Van der Sluis, Christina A. Markunas, Melanie E. Garrett, Allison E. Ashley‐Koch, Scott H. Kollins, Arthur D. Anastopoulos, Narelle K. Hansell, Margaret J. Wright, Grant W. Montgomery, Nicholas G. Martin, Sarah E. Harris, Gail Davies, Albert Tenesa, David J. Porteous, John M. Starr, Ian J. Deary, Beate St. Pourcain, George Davey Smith, Nicholas J. Timpson, David M. Evans, Michael Gill, Ana Miranda, Fernando Mulas, Robert D. Oades, Herbert Roeyers, Aribert Rothenberger, Joseph Sergeant, Edmund Sonuga‐Barke, Hans Christoph Steinhausen, Eric Taylor, Stephen V. Faraone, Barbara Franke, Danielle Posthuma

Intelligence is a highly heritable trait for which it has proven difficult to identify the actual genes. In the past decade, five whole-genome linkage scans have suggested genomic regions important to human intelligence; however, so far none of the responsible genes or variants in those regions have been identified. Apart from these regions, a handful of candidate genes have been identified, although most of these are in need of replication. The recent growth in publicly available data sets that contain both whole genome association data and a wealth of phenotypic data, serves as an excellent resource for fine mapping and candidate gene replication. We used the publicly available data of 947 families participating in the International Multi-Centre ADHD Genetics (IMAGE) study to conduct an in silico fine mapping study of previously associated genomic locations, and to attempt replication of previously reported candidate genes for intelligence. Although this sample was ascertained for attention deficit/hyperactivity disorder (ADHD), intelligence quotient (IQ) scores were distributed normally. We tested 667 single nucleotide polymorphisms (SNPs) within 15 previously reported candidate genes for intelligence and 29451 SNPs in five genomic loci previously identified through whole genome linkage and association analyses. Significant SNPs were tested in four independent samples (4,357 subjects), one ascertained for ADHD, and three population-based samples. Associations between intelligence and SNPs in the ATXN1 and TRIM31 genes and in three genomic locations showed replicated association, but only in the samples ascertained for ADHD, suggesting that these genetic variants become particularly relevant to IQ on the background of a psychiatric disorder.