A genome-wide association study in Peruvians suggests new risk loci for Alzheimer Disease
Authors: Akgun Bilcag , Cornejo-Olivas Mario , Custodio Nilton , Mena Pedro R , Soto-Añari Marcio , Montesinos Rosa , Adams Larry D , Celis Katrina , Yang Zikun , Huaman Basilio C , Reyes-Dumeyer Dolly , Rivero Joe , Whitehead Patrice G , Hamilton-Nelson Kara L , Wang Liyong , Dykxhoorn Derek M , Rios-Pinto Julia , Medina-Colque Angel , Dalgard Clifton L , Martin Eden R , Cornejo-Herrera Ivan , Illanes-Manrique Maryenela , Ochoa-Valle Edward , Sarapura-Castro Elison , Ramirez Aura M , Moura Sofia , Xu Wanying , Mejía Koni K , Milla-Neyra Karina , Castro-Suarez Sheila ,   Alzheimer’s Disease Sequencing Project (ADSP), Jin Fulai , Griswold Anthony J , Beecham Gary W , Isasi Rosario , McInerney Katalina F , Cuccaro Michael L , Vance Jeffery M , Rajabli Farid , Pericak-Vance Margaret A , Tosto Giuseppe 
Published: November 2023

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 forAPOE-ε4allele 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 theNFASClocus. 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 ofNFASCin neurons and oligodendrocytes. We also replicated three known AD loci:APOE,TREML2, andCLU.

This study identified a novel locus associated with risk for AD in the Peruvian population. Functional studies strongly support thatNFASCis 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 theNFASCgene, 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 theNFASCgene 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.