Affiliation:
1. Department of Medical Consilience Division of Medicine Graduate school Dankook University Yongin‐si Gyeonggi‐do South Korea
2. Channing Division of Network Medicine Brigham and Women's Hospital Boston Massachusetts USA
3. Department of Biostatistics Harvard T.H. Chan School of Public Health Boston Massachusetts USA
4. Genetics and Aging Unit and McCance Center for Brain Health Department of Neurology Massachusetts General Hospital Charlestown Massachusetts USA
5. Department of Population Medicine Harvard Medical School and Harvard Pilgrim Healthcare Institute Boston Massachusetts USA
Abstract
AbstractINTRODUCTIONGenome‐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.METHODSWe 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.RESULTSWe 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, I2 = 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.DISCUSSIONWe 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.
Funder
Cure Alzheimer's Fund
National Institutes of Health