On the Effect Heterogeneity of Established Disease Susceptibility Loci for Alzheimer's Disease Across Different Genetic Ancestries

INTRODUCTION Genome-wide association studies have identified numerous disease susceptibility loci (DSLs) for Alzheimer's disease (AD). However, only a limited number of studies have investigated the dependence of the genetic effect size of established DSLs on genetic ancestry. METHODS We utilized the whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) including 35,569 participants. A total of 25,459 subjects in four distinct populations (African ancestry, non-Hispanic White, admixed Hispanic, and Asian) were analyzed. RESULTS We found that nine DSLs showed significant heterogeneity across populations. Single nucleotide polymorphism (SNP) rs2075650 in translocase of outer mitochondrial membrane 40 (TOMM40) showed the largest heterogeneity (Cochran's Q = 0.00, I-2 = 90.08), followed by other SNPs in apolipoprotein C1 (APOC1) and apolipoprotein E (APOE). Two additional loci, signal-induced proliferation-associated 1 like 2 (SIPA1L2) and solute carrier 24 member 4 (SLC24A4), showed significant heterogeneity across populations. DISCUSSION We observed substantial heterogeneity for the APOE-harboring 19q13.32 region with TOMM40/APOE/APOC1 genes. The largest risk effect was seen among African Americans, while Asians showed a surprisingly small risk effect.