Fine‐mapping of chromosome 9p21 linkage in Puerto Rican Alzheimer disease families.

Abstract

AbstractBackgroundWe previously reported strong linkage on chromosome 9p21 in multiplex Alzheimer disease (AD) families from Puerto Rico. Nine families had the highest linkage contribution. 3/9 families shared seven coding variants with displayed evidence for AD association in similar ancestral. Although these variants reside in genes with neuronal expression and functionality, they do not explain the linkage signal in all families. Here, we performed a fine‐mapping analysis to identify non‐coding variants that can contribute to the AD trait previously observed.MethodWe analyzed whole genome sequencing (WGS) from 9 families, 43 AD and 15 cognitively intact individuals. Chromatin interaction and cis‐regulatory element (CREs) were used to prioritized relevant non‐coding variants. Induced pluripotent stem cells (iPSC) derived neurons were generated from five individuals for characterization.ResultWe found an average of 300,000 non‐coding variants per family. Following filtering steps including segregation, allele frequency and chromatin association, we identified ∼400 variants per family. These variants were analyzed using the CREs derived from ENCODE, which left us with 31 (8%) variants falling in promoters. 5/31 variants were shared among four or more families, and fall in the promoter of genes FBXO10, ACO1, NDUFB6 and DNAJA1. Six families shared variants in FBXO10 making it our top candidate gene, a F‐box protein family with a role in apoptosis and immunity. Interestingly, another F‐box protein (FBXL7) has been associated with AD in a Caribbean Hispanic population.ConclusionThese results reiterate the importance of family‐based studies and fine‐mapping as a resourceful tool to identified functional variants in AD. Transcriptomic profile and functional characterization of iPSC derived neurons will aid to understand the implication of prioritized genes in the linkage association previously observed.