Extended genome-wide association study employing the African Genome Resources Panel identifies novel susceptibility loci for Alzheimers Disease in individuals of African ancestry

Abstract

INTRODUCTIONDespite a two-fold increased risk, individuals of African ancestry have been significantly underrepresented in Alzheimers Disease (AD) genomics efforts. METHODSGWAS of 2,903 AD cases and 6,265 cognitive controls of African ancestry. Within-dataset results were meta-analyzed, followed by gene-based and pathway analyses, and analysis of RNAseq and whole-genome sequencing data. RESULTSA novel AD risk locus was identified in MPDZ on chromosome 9p23 (rs141610415, MAF=.002, P=3.68x10-9). Two additional novel common and nine novel rare loci approached genome-wide significance at P<9x10-7. Comparison of association and LD patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that the association is modulated by regional origin of local African ancestry. DISCUSSIONIncreased sample sizes and sample sets from Africa covering as much African genetic diversity as possible will be critical to identify additional disease-associated loci and improve deconvolution of local genetic ancestry effects.