Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease

Late-onset Alzheimer disease (LOAD) is the most common cause of dementia in the elderly.1 Despite a substantial estimated genetic component,2 APOE e4 is the only universally accepted risk factor for LOAD.3–5 Endophenotypes are biologically relevant intermediate quantitative phenotypes.6–8 Gene expression levels may be particularly useful endophenotypes. Polymorphisms in genomic regulatory regions could underlie the genetic basis of complex diseases.9 Analysis of genetic variants that influence gene expression may significantly enhance our understanding of this genetic basis. Recent genome-wide association studies (GWAS) utilizing expression levels in human cells and tissues10–13 suggest a substantial genetic influence on human gene expression levels. We hypothesized that there may be variants that influence AD risk by influencing gene expression levels in the brain. If correct, such variants would associate with both AD risk and brain gene expression levels. We performed a pilot study using cerebellar gene expression levels of 12 LOAD candidate genes and their cis-single nucleotide polymorphism (SNP) genotypes extracted from our LOAD GWAS.14 Most of these 12 messenger RNAs (mRNAs) encode proteins that are likely to be involved in neurodegeneration. We identified 3 IDE cis-SNP/transcript associations with study-wide significance. One of these cis-SNPs showed an association with genome-wide significance. This SNP also associated significantly with LOAD risk. Our findings suggest that joint analysis of transcriptome and disease risk with genome data could identify candidate functional variants that influence disease risk by influencing gene expression. The use of brain expression endophenotypes may be a potentially powerful approach in uncovering the genetics of neurologic diseases like LOAD.