From Rare Mutations to Normal Variation: Genetic Association Study of Mathematical, Spatial, and General Cognitive Abilities

Abstract

Background. Behavioral genetic fndings suggest that complex traits, such as mathemat-ical ability, general cognitive ability (intelligence; g), and spatial ability, are infuenced by many common genetic variants of very small efects that operate across the ability continuum. Common genetic variants may also be responsible for cognitive defcits as-sociated with rare genetic syndromes, in which whole genomic regions may be afected. To date, relatively few common genetic variants involved in cognitive traits have been identifed, and these only explain a small proportion of variance in these traits. Objective. Te aim of the study was to fnd associations between mathematics-re-lated traits and single-nucleotide polymorphisms (SNPs) within chromosomal regions involved in Williams and Prader-Willi disorders. Both disorders are characterized by patterns of weaknesses and strengths in cognitive abilities. Two types of analyses were performed (SNP-based and gene-based), using genotypic and phenotypic data available for 3000 participants from the UK. Results. SNP-based tests indicated that none of the SNPs passed the demanding multiple testing correction level for any of the phenotypes. Gene-based analysis sug-gested that 2 pseudogenes (i.e., GOLGA8I and WHAMMP3) were signifcantly asso-ciated with intelligence, and 1 gene (i.e., TUBGCP5) was signifcantly associated with mathematics at 16 years of age. Conclusion. Te results are consistent with other fndings demonstrating that cog-nitive traits are infuenced by many common genetic variants with very small efects. The results also suggest that a small number of these variants may be located in the chromo-somal regions afected in Prader-Willi and Williams syndrome regions.