Genome-wide strategies for discovering genetic influences on cognition and cognitive disorders: methodological considerations.

Introduction: Genes play a well-documented role in determining normal cognitive function. This paper focuses on reviewing strategies for the identification of common genetic variation in genes that modulate normal and abnormal cognition with a genome-wide association scan (GWAS). GWASs make it possible to survey the entire genome to discover important but unanticipated genetic influences.
Methods: The use of a quantitative phenotype in combination with a GWAS provides many advantages over a case-control design, both in power and in physiological understanding of the underlying cognitive processes. We review the major features of this approach, and show how, using a General Linear Model method, the contribution of each Single Nucleotide Polymorphism (SNP) to the phenotype is determined, and adjustments then made for multiple tests. An example of the strategy is presented, in which fMRI measures of cortical inefficiency while performing a working memory task are used as the quantitative phenotype. We estimate power under different effect sizes (10-30%) and variations in allelic frequency for a Quantitative Trait (QT) (10-20%), and compare them to a case-control design with an Odds Ratio (OR) of 1.5, showing how a QT approach is superior to a traditional case-control. In the presented example, this method identifies putative susceptibility genes for schizophrenia which affect prefrontal efficiency and have functions related to cell migration, forebrain development and stress response.
Conclusion: The use of QT as phenotypes provide increased statistical power over categorical association approaches and when combined with a GWAS creates a strategy for identification of unanticipated genes that modulate cognitive processes and cognitive disorders.