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

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PROJECT SUMMARY Genome Wide Association Studies (GWAS) studies in AD have been very successful in identifying genetic regions contributing to the disease, but almost all have been in Non-Hispanic Whites (NHW). Most of these associated genetic regions lie in non-coding, regulatory areas of the genome. That means to understand how these associated loci influence the risk of getting AD, we must understand the regulatory architecture of the genome in these associated regions. Recent efforts from our group and others have sought to understand the genetic underpinning of AD in diverse, admixed populations such as African Americans (AA) and Hispanics (HI). These studies have shown that different ethnic and racial groups having distinct genetic architectures that can lead to differing genetic susceptibility. However, while studies like Encode and Gtex have mapped some of the regulatory architecture of the human genome, they lack information on diverse populations, as these regulatory mapping studies have also been almost exclusively in NHW, and not necessarily in the actual cell types that are affected in Alzheimer disease (AD). This proposal will use multiple avenues of investigation to map the regulatory architecture of the African and Amerindian Genomes, which, together with European, are the components that contribute to the admixed AA and HI genomes. Once we have this architecture mapped, we will use it to understand the mechanisms of disease associated with rare variants and associated non-coding loci identified in AA and HI association studies. To accomplish this, we will use inducible pluripotent stem cells from AA and HI (Peruvian) AD cases, chosen to maximize either African or Amerindian global ancestries, as well as brain tissue from AA and HI individuals. With our collaborator Dr. Fulai Jin at Case Western Reserve University, state of the art Hi-C techniques will be used to map interactions in both the differentiated iPSC lines (neurons, oligodendrocytes, astrocytes and microglia) as well as the frozen brain tissue. We will also use single nuclei RNAseq and single nuclei ATACseq to evaluate the brains, bulk ATAC and RNAseq for iPSC lines. All the genomic data will then be complied, along with supporting existing data from European genomes (NHW), to create the African and Amerindian regulatory maps. We will then take the identified associated haplotypes from the outside AA and HI GWAS and rare variant studies and “lay” them across our regulatory landscape to identify the interacting genes and subregions of the haplotypes affecting the risk for AD in these populations. Next we will use CRISPRa and CRISPRi techniques to verify these interactions. Finally, we will incorporate all this data with existing data to help identify high quality genetic targets for therapeutic intervention for AD.