Examination of Candidate Exonic Variants for Association to Alzheimer Disease in the Amish

Laura N. D'Aoust, Anna C. Cummings, Renee Laux, Denise Fuzzell, Laura Caywood, Lori Reinhart-Mercer, William K. Scott, Margaret A. Pericak-Vance, Jonathan L. Haines, Yi-Hsiang Hsu
2015 PLoS ONE  
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 heterogeneity limitations associated with complex population studies. We determined that Amish AD cases harbored a significantly higher burden of the known risk alleles compared to
more » ... cognitively normal controls, but a significantly lower burden when compared to cases from a dataset of unrelated individuals. 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 from linkage regions implicated previous studies in the full dataset, 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. However, this association is specific to the Amish and did not generalize when tested in a dataset of unrelated individuals. These results suggest that additional risk variation in the Amish remains to be identified and likely resides outside of the classical protein coding gene regions. Percent female, age of exam and onset averages and standard deviations were calculated for 629 Amish samples and the 971 samples from the unrelated dataset which passed QC for follow-up genotyping. Percent female, age of exam and onset averages and standard deviations were calculated for the 921 samples which passed QC for follow-up genotyping.
doi:10.1371/journal.pone.0118043 pmid:25668194 pmcid:PMC4323242 fatcat:2bdnwv3twzgnxjolvjpcdiik4m