Heritability and rare variant contributions to Alzheimer disease in the Midwestern Amish.

Background The genetic architecture of Alzheimer disease remains incompletely understood. Founder populations such as the Amish offer a unique opportunity to identify additional genetic variation influencing the disease. Method Using extensive pedigree and genomic data from Midwestern Amish communities, we estimated both pedigree- and SNP- based heritability of AD. In addition, genome-wide association studies and gene-based rare variant tests were performed. Results Heritability estimates suggested that common variants explain much of genetic risk among APOE-ε4 carriers, while unexplained heritability remains in non-carriers in the Amish. GWAS confirmed APOE-ε4 as the strongest genetic determinant of AD in the Amish. Rare variant analyses identified RIN3 and PILRA as significantly associated with risk of cognitive impairment; suggestive signals including CYP24A1 were also identified. Discussion These findings highlight the contributions of common and rare variants to Alzheimer disease and suggest factors beyond common variants may contribute to disease susceptibility particularly among the APOE-ε4 non-carriers.