GWAS of Genetic Resilience to Age‐Related Risk for Alzheimer’s Disease in Admixed African Ancestry Individuals

Abstract

AbstractBackgroundWe sought to identify genetic variants that confer resilience to age‐related Alzheimer’s disease (AD) risk in subjects of admixed African ancestry.MethodsParticipants were ages 60+, of African ancestry (> = 25%), and diagnosed as cases or controls. Genetic data were available from SNP arrays imputed to TOPMed, whole genome sequencing (WGS), or whole exome sequencing (WES). Genome‐wide association studies (GWAS) were performed per data type, split by Hispanic/non‐Hispanic participants (Table‐1), followed by meta‐analysis (Plink v2.0; GWAMA v2.2.2). GWAS performed multiple linear regression on an AD‐age score that models resilience to age‐related risk for AD (Le Guen & Belloy et al. 2021; Figure‐1). Models adjusted for sex, APOE*4/APOE*2 dosage, the first five genetic principal components (PC‐AiR; GENESIS; R v3.6), and array/sequencing center. Brain amyloid Positron Emission Tomography (PET) qualitative reads together with SNP array data imputed to TOPMed were also available for African American individuals in A4. These data were independent from the primary GWAS and were used to evaluate significant GWAS variants for their association with binarized amyloid outcome (negative/positive), using a consistent model that additionally adjusted for age‐at‐scan.ResultsWe found a novel protective genome‐wide significant intergenic variant (rs77450754) ∼200kb downstream of ATXN8OS/KLHL1 (Figure‐2‐3). It has a MAF of 13% in African ancestry samples, but is rare (0.1%) in Europeans and (<2%) Latino/Admixed Americans in gnomAD v.3. The latter may explain why effects appeared less pronounced in the considered Hispanic samples (since linkage to potential causal nearby variants may differ) (Figure‐3). The variant also displayed a protective, non‐significant, association with brain amyloid in African ancestry samples (Table‐2). Interestingly, KLHL1, also known as MRP2, is a member of the superfamily of ATP‐binding cassette (ABC) transporters, and has potential functions related to neurite outgrowth and efflux transport at the blood‐brain barrier, supporting its potential relevance to AD pathogenesis.ConclusionsOur results provide new insights into genetic resilience to AD across aging and emphasize the importance of including ancestrally‐diverse populations in genetic studies. Our results also highlight the need for the field to compose ancestrally‐diverse multi‐omics and endophenotype data to support further validation analyses of genetic risk loci prioritized from GWAS.