Examination of Candidate Exonic Variants that Confer Susceptibility to Alzheimer Disease in the Amish

Abstract

Alzheimer disease (AD) is the most common cause of dementia. As with many complex diseases, the identified variants do not explain the total expected genetic risk that is based on heritability estimates for AD. Isolated founder populations, such as the Amish, are advantageous for genetic studies as they overcome limitations associated with complex population studies. Amish AD cases harbored a significantly higher burden of the known risk alleles compared to Amish cognitively normal controls, but a significantly lower burden when compared to cases from a cohort of unrelated individuals. These results suggest that known loci explain some of the genetic effects and that there may be different underlying genetic architectures between the two populations. Whole-exome sequencing of a selected subset of the overall study population was used as a screening tool to identify variants located in the regions of the genome that are most likely to contribute risk. By then genotyping the top candidate variants from the known AD genes and implicated linkage regions from previous studies in the full data set, new associations could be confirmed. The most significant result (p = 0.0012) was for rs73938538, a synonymous variant in LAMA1 within the previously identified linkage peak on chromosome 18, but this association did not generalize when tested in a dataset of unrelated individuals. These results indicate that exonic variation in a majority of previously associated LOAD genes, and regions implicated by previous linkage studies, does not contribute to risk for LOAD in the Amish.