Meta‐analysis employing the African Genome Resources panel identifies novel Alzheimer disease risk loci in African Americans

Abstract Background In the largest Alzheimer disease (AD) genome‐wide association studies to date for African‐Americans (AA; Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified in addition to APOE several novel susceptibility loci, including ABCA7, API5, RBFOX1 and IGF1R . We followed up these analyses with an increased sample size (2,913 cases, 5,802 controls) employing the African Genome Resource (AGR) panel. Method Single‐variant association analysis was conducted adjusting for age, sex, principal components and subsequently APOE , applying logistic regression for case‐control and general estimating equations for family‐based datasets. Within‐study results were meta‐analyzed using METAL. Gene‐based and pathway analyses were conducted via MAGMA. Result In addition to the previously reported AA risk loci, we identified three novel signals reaching genome‐wide significance at chromosomes 3p24 ( TOP2B ; P = 4.7×10 −8 ), 3q26 ( NCEH1 ; P = 3.7×10 −8 ) and 9p23 ( MPDZ ; P = 1.7×10 −8 ), and seventeen novel loci reaching suggestive significance at p ≤ 9×10 −7 . NCEH1 modulates cholesterol metabolism and is neuroprotective against α‐synuclein toxicity; MPDZ encodes a scaffolding protein involved in cytoskeleton remodeling. Top2B encodes a DNA topoisomerase involved in DNA transcription. Gene‐based analyses identified SLC39A3 (P = 2.9×10 −6 ), involved in zinc transport, as a novel candidate gene. Pathway analyses support the notion that besides immunity, synaptic function, transcription/DNA repair, lipid processing, and intracellular trafficking, which overlap with the major AD‐associated pathways in non‐Hispanic Whites, also renal function is involved in AD etiology in African Americans. Conclusion We identified several novel candidate loci for AD in AA. While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non‐Hispanic White individuals, the disease‐associated loci within these pathways differ. Identification of a significant number of loci at suggestive significance indicates that future studies with further increased sample size will be valuable to identify additional disease‐associated loci in this ethnic group.