Functional genomic studies in diverse populations to characterize risk loci for Alzheimer Disease

Abstract

AbstractBackgroundAs part of the ADSP Functional Genomics consortium, we aim to unravel ancestry specific effects of genomic regulation of AD loci. African Americans (AA) and Hispanics (HI) are at higher risk for Alzheimer’s disease (AD) compared to non‐Hispanic whites (NHW). Even though AA, HI and other diverse groups make up 40% of the US population, over 90% of participants in large‐scale genomic research studies have been NHW, representing European (EU) ancestry. Recent AD research including diverse groups has shown that genes and variants contributing to disease can have different risk effect dependent on the ancestral background they reside on (i.e. APOE). Together these clearly indicate a need to expand genome‐wide and gene‐specific analyses of genomic organization and regulation for other ancestries contributing to diverse, admixed populations, such as African (AF) or Amerindian (AI) ancestries.MethodWe analyzed interaction of variants in the APOE region with AD risk in WGS of diverse populations to identify modifiers of the APOEɛ4 risk effect. Additionally, to assess overall differences in chromatin regulation genome‐wide across ancestries, we performed bulk and single cell chromatin accessibility (ATAC‐seq) and bulk chromatin interaction (Hi‐C) assays in brains from admixed individuals with high EU, AF (>95%) or AI (>75%) ancestry contribution.ResultWe identified both close‐by and distant modifier variants (in the downstream PSG gene family region) inferring protection against the APOEɛ4 risk on the AF ancestry. Single cell ATAC‐seq data in brain showed higher accessibility of the APOE region and large regions of chr19 in astrocytes, but not microglia, of EU versus AF ancestry. Lastly, bulk Hi‐C analyses in brain strongly supported the hypothesis of ancestry dependent regulation by genome‐wide detection of differential chromatin interactions comparing EU to AF ancestry.ConclusionOur analyses using complementary functional genomic assay methods show clear differences of genome regulation between EU and AF ancestry. Overall, these data support genome regulation to be strongly influenced by ancestral origin. The generated data on samples with high single ancestral contributions will help elucidate risk effects seen for AD related genes in different population groups, as we describe for the APOE region.