Trans-ethnic meta-analysis and fine-mapping of Alzheimer’s Disease loci

Alzheimer’s disease (AD) is a leading cause of death and disability worldwide. Despite the tremendous burden of the disease and arduous research efforts in the field, there are currently no disease-modifying treatments. Better elucidation of the genetic etiology of AD is needed to drive further drug discovery. Although the largest genome-wide association study (GWAS) of AD included over one million individuals of European ancestry and identified 38 associated loci, previous studies have highlighted the disproportionate disease risk and differing genetic architecture for AD across global populations. We hypothesize that a trans-ancestry approach would improve the generalizability of GWAS results, increase statistical power for locus discovery, and improve fine-mapping resolution to identify putative causal variants. Using a method that accounts for ancestral heterogeneity, we plan to leverage published and de-novo GWAS from individuals of European, East Asian, African American, South Asian, and Caribbean Hispanic ancestry and performed the largest trans-ancestry meta-analysis of AD to date. This method has allowed us to identify a novel AD locus near the Lymphocyte Cytosolic Protein 1 (LCP1) gene and prioritize an intronic SNP, rs2146890, as likely driving the observed association. Our findings further support the involvement of immune-related pathways in AD pathogenesis and highlight the importance of multi-ancestry representation in genetic studies. We propose utilizing the LASI-DAD GWAS and Imputation dataset to further extend these results by completing additional trans-ancestry meta-analyses.

Alzheimer’s disease (AD) is a leading cause of death and disability worldwide. Although the largest genome-wide association study (GWAS) of AD included over one million individuals of European ancestry and identified 38 associated loci, previous studies have highlighted the disproportionate disease risk and differing genetic architecture for AD across global populations. Our findings have supported the involvement of immune-related pathways in AD pathogenesis and highlight the importance of multi-ancestry representation in genetic studies. We will use the LASI-DAD GWAS and Imputation data in conjunction with existing open datasets from individuals of European, East Asian, African American, South Asian, and Caribbean Hispanic ancestry to perform the largest trans-ancestry meta-analysis of Alzheimer’s disease to date.