Gene expression in the human brain

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

An important unresolved general question in human genetics is how the majority of common genomic variation, much of which is associated with common diseases, changes gene function. Most variants that have been found in association with neurodegenerative diseases, for example, do not change protein coding regions. One reasonable hypothesis is that common variants change how genes are regulated in specific cells, perhaps under specific circumstances. We have addressed this by examining mRNA and miRNA expression, using gene expression microarrays, in the brains of a number of individuals who have been genotypes at a large number of genomic loci, tagged using using single nucleotide polymorphisms (SNPs). We find that for many genes, there is an association between genotype and gene expression and that this relationship is dependent on the physical distance between the SNP and the gene that is expressed. When we specifically examine genetic variants that are robustly associated with neurodegenerative diseases, we find that these impact gene expression in predictable and robust ways. This data begins to define the relationships between common variants and common disorders. Many such genotype-gene expression relationships hold over mutliple brain regions and, by comparison with other large datasets in the public domain, other tissue types. However, a small number of correlations appear to be specific to a single brain region and this is not explained by lack of detection in other regions. We are therefore extending these approaches by using laser capture microdissection to isolate defined neuronal populations and repeating the experiments.