A new risk locus on chromosome 1 is suggested by genome‐wide association study in Peruvians for Alzheimer disease
Authors: Akgun Bilcag , Cornejo‐Olivas Mario , Custodio Nilton , Rajabli Farid , Soto‐Añari Marcio F. , Montesinos Rosa , Yang Zikun , Huaman Basilio C. , Reyes‐Dumeyer Dolly , Cedeno Jeffrey A , Rivero Joe , Mena Pedro R. , Adams Larry D. , Whitehead Patrice , Hamilton‐Nelson Kara L. , Rios‐Pinto Julia , Medina‐Colque Angel , Dalgard Clifton L. , Isasi Rosario , Cornejo‐Herrera Ivan , Illanes‐Manrique Maryenela , Ochoa‐Valle Edward , Sarapura‐Castro Elison , Mejía Koni K. , Milla‐Neyra Karina , Castro‐Suarez Sheila ,   The Alzheimer’s Disease Sequencing Project (ADSP), Martin Eden R. , Griswold Anthony J. , McInerney Katalina , Cuccaro Michael L. , Vance Jeffery M. , Beecham Gary W. , Pericak‐Vance Margaret A. , Tosto Giuseppe 
Published: December 2023

Background

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 (PE) population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI ancestry in AD. We performed the first genome‐wide association study (GWAS) in the PE population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.

Method

The PE dataset includes array‐genotype and phenotype data from 542 individuals (189 cases; 353 controls), imputed to the NHLBI TOPMedv5 haplotype reference panel. We used a generalized linear mixed‐model (SAIGE software) for the GWAS analysis. We analyzed two separate models; the first model accounted for sex, age, and population substructure, while the second model also included the dosage of APOEe4. In both models, we included a genetic relationship matrix as a random effect to account for any potential relatedness. To determine if the associations are specific to specific ancestries, we employed ancestry‐aware approaches using the RFMix software.

Result

APOE was significantly associated with AD with an effect size comparable to that found in non‐Hispanic white (NHW) populations (OR = 3.3(2.2‐4.8),pv = 8.0×10−10). Two additional known AD loci, TREML2 (pv = 0.008) and CLU (pv = 0.012), showed nominal significance Variants at three additional loci reached suggestive significance (pv<1×10−6): NFASC (pv = 9.4×10−8;chromosome 1), STK32A (pv = 9.3×10−7; chromosome 5), and LOC100132830 (pv = 6.7×10−7;chromosome 6). The NFASC locus neared genome‐wide significance in the APOE adjusted model (pv = 6.7×10−8). The haplotypes associated with AD at the NFASC locus were found to be of European origin. Additionally, the STK32A locus was found to have a protective effect specifically among individuals of AI background. We did not observe significant heterogeneity of effect at the APOE and LOC100132830 loci across different ancestral backgrounds.

Conclusion

PE GWAS identified a novel, promising AD susceptibility locus in the NFASC gene of European origin. We also detected a potential protective effect in the STK32A locus on AI background, emphasizing the importance of incorporating ancestry‐aware approaches in gene discovery in admixed populations.