Genome‐wide association study on Alzheimer’s disease related cognitive, fluid, and neuropathology biomarkers in the African American population

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder that progresses over time, but its exact cause remains unknown. While risk genomic loci for AD‐related biomarkers have been identified in previous studies, these findings have mostly been based on European cohorts. As a result, there is limited research on the African American (AA) population. To address this research gap, we conducted a Genome‐Wide Association Study (GWAS) using whole genome sequencing (WGS) data from Alzheimer’s Disease Sequencing Project (ADSP) to identify AD‐related variants in the AA population.MethodWGS data and harmonized phenotypes from the cognitive, fluid biomarker, and neuropathology domains were downloaded from the ADSP database. Quality control (QC) was performed on the WGS data through removing high missing call rate SNPs, rare genetic variants, genetically closely related subjects, subjects with high missing call rate, and genomic loci that failed the Hardy‐Weinberg equilibrium among cognitive normal cohort. After QC 9,815,631 SNPs and 33,324 subjects were preserved. A total of 5,397 subjects in AA population were selected for the subsequent GWAS analysis. Scalable and Accurate Implementation of Generalized mixed model (SAIGE) was used to perform association tests between genetic variants and 39 phenotypic traits controlled for age, sex, and the first 10 principal components. Functional mapping and annotation (FUMA) was used to perform the post GWAS annotations.ResultThirty‐nine phenotypic traits from cognitive, fluid biomarker, and neuropathology domains were screened but only the “infarcts and lacunes”, “PD braak (dichotomous)”, and “whole brain vascular disease” of the neuropathology data had significant GWAS signals. We identified one risk locus for each of the phenotypic traits: lead SNP rs7604487 significantly associated with “infarcts and lacunes”; lead SNP rs7093080 significantly associated with “PD braak (dichotomous)”; and lead SNP rs623123 significantly associated with “whole brain vascular disease” (Figure 1). These associations were insignificant in the ADSP cohort with European ancestry.ConclusionOur GWAS on AD related biomarkers identified three genetic loci associated with multiple neuropathological processes among the AA population. These findings have a potential to contribute to a better understanding of the AD genetic risk in the AA population. It warrants further investigation to replicate the discovery in independent cohorts.