Genetic reports abstractDissecting the role of Amerindian genetic ancestry and the ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population
Introduction
Alzheimer disease (AD) is a neurodegenerative disease accounting for over 70% of dementia cases in individuals ≥70 years of age (Alzheimer's Association 2011). AD has a multifactorial etiology, with both genetic and nongenetic risk factors, with liability-scale heritability estimates based on twin studies ranging between 0.58 and 0.79, and with over 25 genetic risk factors contributing to AD risk (Gatz et al., 2006; Kunkle et al., 2019).
The apolipoprotein E (ApoE) gene (19q13.32) is the strongest known genetic risk factor for AD explaining up to 6% of the liability-scale phenotypic variance (Corder et al., 1993, 1994). ApoE codes for a protein that transports cholesterol through the interaction with cell surface receptors (Holtzman et al., 2012). There are 3 ApoE alleles, ε2, ε3, and ε4, defined by 2 polymorphisms rs429358 and rs7412, that code for 3 protein isoforms ApoE2 (Cys130, Cys176), ApoE3 (Cys130, Arg176), and ApoE4 (Arg130, Arg176) (Aleshkov et al., 1997).
The association of ApoE with AD risk differs across the ethnic or racial groups. The strongest association of ApoE and AD risk has been observed in East Asian (EA) populations (ε3 ε4 odds ratio (OR): 3.1–5.6; ε4 ε4 OR: 11.8–33.1) followed by non-Hispanic white populations (ε3/ε4 OR: 3.2; ε4/ε4 OR: 14.9) (Farrer et al., 1997; Liu et al., 2014). Its effect is weaker in African-descent and Hispanic populations (ε 3 ε4 OR: 1.1–2.2; ε4 ε4 OR: 2.2–5.7) (Hendrie et al., 2014; Sahota et al., 1997; Tang et al., 1996, 1998, 2001). Genetic studies examining the interaction of genetic ancestry and risk effect of the ApoE in Caribbean Hispanic populations (Puerto Rican and Dominican Republic) showed that the effect of the ε4 is correlated with the ancestral background around ApoE with the attenuated effect on African-originated haplotypes (Blue et al., 2019; Rajabli et al., 2018). However, the relationship between ApoE and AD risk in Amerindian (AI) descent populations is not well established. Thus, the inclusion of populations with high AI genetic ancestry is critical to understand the effects of ApoE and AI ancestry on AD risk.
Genetically, the Peruvian population has approximately 80% AI ancestral background, higher than other Latin American populations, such as Mexico (50%), Chile (40%), Colombia (28%), Argentina (28%), and Puerto Rico (16%) (Homburger et al., 2015; Norris et al., 2018, 2019). Native Americans in Peru show ancestry from 3 ancestral groups, likely that originated by the split of an ancient group that migrated from EA, across the Bering Strait, and down the Americas (Harris et al., 2018). Through admixture with non-native inhabitants that arrived after Peru's Spanish colonization, these AI groups gave rise to the current Peruvian mestizo population, resulting in an admixed population with European (EU), EA, and African (AF) components (Harris et al., 2018; Homburger et al., 2015; Norris et al., 2018). Studies in a sample of mestizo Peruvian population suggest high allele frequency of the ApoE ε3 allele (93.9%), with low ε4 (5 %) and ε2 (1.1 %) allele frequencies (Marca et al., 2011). No previous published studies have examined the association of ApoE and AD in the Peruvian population.
Our goal is to use data from the Peruvian population to assess the role of AI genetic ancestry and the ApoE gene on AD. Peruvians with the high AI genetic ancestry provide a unique opportunity to study the correlation of AI genetic ancestry with the effect of the ε4 allele over the risk of AD.
Section snippets
Study samples and ascertainment
Unrelated cases and controls were ascertained from the Instituto Nacional de Ciencias Neurologicas in Lima, Peru as part of a larger genetics study of AD. All cases were assessed by trained neurologists following NINCDS-ADRDA criteria for possible and probable AD (McKhann et al., 1984). Cognitively intact controls were screened using the clock drawing test and the Pfeffer functional activities questionnaire (Manos et al., 1994; Pfeffer et al., 1982). Controls were defined as individuals with no
Results
The supervised ADMIXTURE analysis showed that Peruvians are a 4-way admixed population with the 63.6% AI, 29.7% EU, 3.8% AF, and 2.9% EA ancestral background. This confirms recent studies showing similar distribution of admixture in Peruvians (Harris et al., 2018). Fig. 1A shows the boxplot of the average ancestry across all individuals in the data set. The ancestral proportion of each individual is illustrated in the bar plot Fig. 1B, where each column reflects the admixture structure of a
Discussion
The ApoE ε4 allele is the most significant genetic risk factor for late-onset AD with the differences in effect size among the populations. Our results showed that the risk for AD from the ApoE ε4 allele in Peruvians is higher than we have observed in non-Hispanic white populations. Given the high admixture of AI in the Peruvian population, it suggests that the AI local ancestry is contributing to a strong risk for AD in ApoE ε4 carriers. This would align with the current believed migration
Disclosure statement
No conflicts of interest exist.
CRediT authorship contribution statement
Maria Victoria Marca-Ysabel: Conceptualization, Methodology, Formal analysis, Writing - original draft. Farid Rajabli: Conceptualization, Methodology, Software, Formal analysis, Writing - original draft, Visualization. Mario Cornejo-Olivas: Conceptualization, Methodology, Writing - original draft, Data curation. Patrice G. Whitehead: Resources, Writing - review & editing. Natalia K. Hofmann: Resources, Writing - review & editing. Maryenela Zaida Illanes Manrique: Resources, Writing - review &
Acknowledgements
Research reported in this publication was supported in part by the Fogarty International Center of the National Institutes of Health and the National Institute of Neurological Disorders and Stroke under grant #D43TW009345 awarded to the Northern Pacific Global Health Fellows Program from National Institutes of Health, grant #D43TW009137 awarded to the Interdisciplinary Cerebrovascular Diseases Training Program in South America from National Institutes of Health, the AG054074 grant from the
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