biostudies-literatureLee SCure Alzheimer's FundNIMH NIH HHSCure Alzheimer&apos;s FundNational Institutes of HealthNIH HHS3397-3405https://www.ebi.ac.uk/biostudies/studies/S-EPMC11095441biostudies-literatureUnknown20(5)<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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, 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.<h4>Discussion</h4>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.Alzheimer's & dementia : the journal of the Alzheimer's AssociationOn the effect heterogeneity of established disease susceptibility loci for Alzheimer's disease across different genetic ancestries.PMC11095441R01MH129337R01 MH129337Alzheimer's Disease Neuroimaging Initiative (ADNI)Lutz SMLee SHecker JHahn GProkopenko DLange CTanzi REMullin KfalseOn the effect heterogeneity of established disease susceptibility loci for Alzheimer's disease across different genetic ancestries.<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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, 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.<h4>Discussion</h4>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.2024-01-01T00:00:00Z2024 May2026-06-03T03:58:38.165Z2026-04-24T03:09:48.241ZS-EPMC110954413856350810.1002/alz.13796