Association Analyses of Known Genetic Variants with Gene Expression in Brain.

[摘要] The availability of high through-put genome-wide expression technologies has resulted inan unprecedented ability to analyze the consequences of genetic mutations or variants onexpression. When a Mendelian disorder is caused by mutations in a gene encoding aprotein of unknown function, gene expression analysis can help define molecularpathways affected, and thus place the unknown gene product into functional context. Wehave used DNA microarray analysis to elucidate the functional deficits in two differentmouse models of ataxia. In a mouse model of Cayman ataxia, we found dysregulation ofglutamate signaling in the cerebellum. In the second ataxic mouse mutant, waddles, ouranalysis revealed calcium signaling as the most prominently affected pathway. In contrastto these single gene disorders, in complex disorders many genetic variants are involved,each with only a small contribution to the phenotype, and it is often unclear which varianthas functional consequences. Here, we hypothesized that gene expression studies may aidin defining gene targets, especially in the primary tissue of interest. Focusing on geneticmarkers that were significantly associated with bipolar disorder in several genome-wideassociation studies (GWAS), we combined expression and genotype information from~100 postmortem human brain samples. We identified genetic variants that significantlyaffect gene expression of a nearby gene, although these expression-associated variantswere not identical with the best GWAS findings.While each of the three studies addressed different biological questions, commonchallenges arose. The most prominent one was the heterogeneity and complexity of braintissue, which resulted in noisier and less striking expression changes than those typicallyseen from homogenous tissue or cell culture sources. In summary, we successfullyaddressed these and other technical issues and utilized microarray expression technologyto generate new specific biological hypotheses for follow-up studies.

[发布机构] University of Michigan

[效力级别] Genetics

[关键词] Microarray Gene Expression Analysis;Genetics;Science;Bioinformatics