A Genome-Wide Association Study in Peruvians Suggests New Risk Loci for Alzheimer Disease

Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI ancestry in AD. We aimed to conduct a genome-wide association study and comprehensive analyzes to identify novel ancestry-specific AD susceptibility loci and characterize the known AD genetic risk loci in the Peruvian population. 528 individuals were included in these analyses (175 AD, 353 cognitively unimpaired). Array genotype was imputed to the NHLBI TOPMedv5 haplotype reference panel. We used a generalized linear mixed model adjusting for sex, age, and population substructure (model-1), and adjusting for APOE-ε4 allele dosage (model-2). Both models included a genetic relationship matrix as a random effect to account for cryptic relatedness. To determine if the associations were ancestry-specific, we further explored interactions between top genetic variants and local ancestry. Single nuclei ATACseq and RNAseq, and Hi-C analysis was performed to identify potential interactions with the associated locus. We identified a novel genome-wide significant signal (rs2625222; P =3.5×10-8) within the Neurofascin gene ( NFASC) on chromosome 1. Local ancestry approach estimated both European and African ancestral backgrounds at the NFASC locus. Functional studies found that rs2625222 lies within an open ATAC peak and is expressed in oligodendrocytes and neurons. Hi-C studies revealed strong loops between rs2625222 region and the promoter of NFASC in neurons and oligodendrocytes. We also replicated three known AD loci: APOE , TREML2 , and CLU . This study identified a novel locus associated with risk for AD in the Peruvian population. Functional studies strongly support that NFASC is the targeted gene of this risk association. These findings emphasize the importance of including diverse populations in genetic studies of AD. Author summary Alzheimer Disease (AD), the most common type of dementia in older adults, has a complex etiology with a strong genetic predisposition. Despite Genome-Wide Association Studies (GWAS) identifying over 75 loci associated with AD, these have predominantly focused on the non-Hispanic White population. Genetic studies of diverse populations, such as the Peruvian population with its significant Amerindian ancestral background, are crucial for identifying ancestry-specific genetic risk and protective loci associated with AD. Our objective in this study was to conduct a GWAS and comprehensive analyses of 528 Peruvian individuals to identify new ancestry-specific AD risk loci. In this study, we identified a genome-wide significant novel signal within the NFASC gene, which has a crucial role in central and peripheral nervous systems, on chromosome 1. This locus showed both European and African ancestral backgrounds. Our functional analyses strongly support that the NFASC gene itself is the primary gene tagged by the risk-associated signal. These findings emphasize the inclusion of admixed populations in genetic studies provides an important opportunity to assess the role of different ancestries in AD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This investigation was supported by grants R01AG070864 (MAPV, GWB, FR), RF1AG082009 (GT), U19AG074865 (MAPV, GT, JMV), R56AG069118 (GT), U01AG058654 (ERM, MAPV), RF1AG054074 (MAPV, GWB), U01AG057659 (MAPV), RF1AG059018 (JMV), and U01AG072579 (JMV, DMD, AJG) from the National Institutes on Aging of NIH, A2018556F (FR) grant from the BrightFocus Foundation, and 21A18 (KC) grant from the Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Informed consent was obtained from all participants, and the study protocols were approved by the Ethical Research Committee of the Instituto Nacional de Ciencias Neurologicas (INCN), and Instituto Peruano de Neurociencias (IPN) Lima, the University of Miami's Institutional Review Board, and the Columbia University Review Board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available through the National Institute on Aging Genetics of Alzheimers Disease Data Storage Site (NIAGADS) Data Sharing Service (DSS).