Abstract
Abstract Background Although African Americans are twice as likely to develop Alzheimer’s Disease (AD), individuals with African ancestry are under‐represented in genetic research of the disease. In the largest AD genome‐wide association studies to date for African‐Americans (Reitz et al. JAMA 2013; Kunkle at al. JAMA Neurol 2021) we previously identified several novel susceptibility loci in addition to APOE , including ABCA7, API5, RBFOX1 , and IGF1R . Method We performed a genome‐wide association meta‐analysis of 2,844 AD cases and 6,251 cognitively healthy controls of African ancestry (AA) assembled across 17 different cohorts. 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, and followed by gene‐based, pathway, scRNA‐seq, and colocalization analyses. Result Single variant meta‐analysis identified a novel genome‐wide significant AD risk locus in the MPDZ gene on chromosome 9p23 (rs141610415, MAF = .002, P = 3.68×10 −9 ). MPDZ (MUPP1) is a vital component of the NMDAR signaling complex in excitatory synapses of hippocampal neurons critical for learning and memory. Two additional novel common loci and 9 novel rare loci approached genome‐wide significance at P <9×10 −7 . Genes at these loci are acting in biologically plausible pathways: signal transduction ( PLEKHG1 ), synaptic transmission ( CNTNAP4) , synaptic connectivity ( SDK1 ), neural development/function ( SRGAP3, KIDINS220, UNC5C, TSSC1, TANC2 ), and neuronal differentiation ( ASCL1 ). Single‐cell RNA‐sequence analysis shows that all genes are expressed in the brain, and that expression of the orthologs of SRGAP3 , TANC2 , and MMP16 is upregulated with amyloid toxicity in zebrafish. Pathway analyses support the notion that immune response, transcription/DNA repair, lipid processing, and intracellular trafficking are major AD‐associated pathways in African Americans. Except for SIPA1L2 and ACER3 , all previously reported loci, including ABCA7 , API5 , RBFOX1 and IGF1R , remain genome‐wide or close to genome‐wide significant. Conclusion We identified several novel loci for AD in individuals with African ancestry with the strongest association observed for MPDZ involved in hippocampal synaptic signaling. Identification of a significant number of loci at suggestive significance indicates that future studies with further increased sample size will be critical to identify additional disease‐associated loci in individuals of African ancestry.