Advertisement

Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics

Published:October 09, 2019DOI:https://doi.org/10.1016/j.jalz.2019.07.016

      Abstract

      Introduction

      Although the relationship between APOE and Alzheimer's disease (AD) is well established in populations of European descent, the effects of APOE and ancestry on AD risk in diverse populations is not well understood.

      Methods

      Logistic mixed model regression and survival analyses were performed in a sample of 3067 Caribbean Hispanics and 3028 individuals of European descent to assess the effects of APOE genotype, local ancestry, and genome-wide ancestry on AD risk and age at onset.

      Results

      Among the Caribbean Hispanics, individuals with African-derived ancestry at APOE had 39% lower odds of AD than individuals with European-derived APOE, after adjusting for APOE genotype, age, and genome-wide ancestry. While APOE E2 and E4 effects on AD risk and age at onset were significant in the Caribbean Hispanics, they were substantially attenuated compared with those in European ancestry individuals.

      Discussion

      These results suggest that additional genetic variation in the APOE region influences AD risk beyond APOE E2/E3/E4.

      Keywords

      To read this article in full you will need to make a payment
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      References

        • Hebert L.E.
        • Weuve J.
        • Scherr P.A.
        • Evans D.A.
        Alzheimer disease in the United States (2010-2050) estimated using the 2010 census.
        Neurology. 2013; 80: 1778-1783
        • Lane C.A.
        • Hardy J.
        • Schott J.M.
        Alzheimer's disease.
        Eur J Neurol. 2018; 25: 59-70
        • Gatz M.
        • Reynolds C.A.
        • Fratiglioni L.
        • Johansson B.
        • Mortimer J.A.
        • Berg S.
        • et al.
        Role of genes and environments for explaining Alzheimer disease.
        Arch Gen Psychiatry. 2006; 63: 168-174
        • Goate A.
        • Chartier-Harlin M.C.
        • Mullan M.
        • Brown J.
        • Crawford F.
        • Fidani L.
        • et al.
        Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
        Nature. 1991; 349: 704-706
        • Sherrington R.
        • Rogaev E.I.
        • Liang Y.
        • Rogaeva E.A.
        • Levesque G.
        • Ikeda M.
        • et al.
        Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
        Nature. 1995; 375: 754-760
        • Levy-Lahad E.
        • Wasco W.
        • Poorkaj P.
        • Romano D.M.
        • Oshima J.
        • Pettingell W.H.
        • et al.
        Candidate gene for the chromosome 1 familial Alzheimer's disease locus.
        Science. 1995; 269: 973-977
        • Levy-Lahad E.
        • Wijsman E.M.
        • Nemens E.
        • Anderson L.
        • Goddard K.A.
        • Weber J.L.
        • et al.
        A familial Alzheimer's disease locus on chromosome 1.
        Science. 1995; 269: 970-973
        • Corder E.H.
        • Saunders A.M.
        • Strittmatter W.J.
        • Schmechel D.E.
        • Gaskell P.C.
        • Small G.W.
        • et al.
        Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.
        Science. 1993; 261: 921-923
        • Hohman T.J.
        • Cooke-Bailey J.N.
        • Reitz C.
        • Jun G.
        • Naj A.
        • Beecham G.W.
        • et al.
        Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk.
        Alzheimers Dement. 2016; 12: 233-243
        • Popejoy A.B.
        • Fullerton S.M.
        Genomics is failing on diversity.
        Nature. 2016; 538: 161-164
        • MacArthur J.
        • Bowler E.
        • Cerezo M.
        • Gil L.
        • Hall P.
        • Hastings E.
        • et al.
        The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog).
        Nucleic Acids Res. 2017; 45: D896-D901
        • Farrer L.A.
        • Cupples L.A.
        • Haines J.L.
        • Hyman B.
        • Kukull W.A.
        • Mayeux R.
        • et al.
        Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium.
        JAMA. 1997; 278: 1349-1356
        • Jun G.R.
        • Chung J.
        • Mez J.
        • Barber R.
        • Beecham G.W.
        • Bennett D.A.
        • et al.
        Transethnic genome-wide scan identifies novel Alzheimer's disease loci.
        Alzheimers Dement. 2017; 13: 727-738
        • Chen H.Y.
        • Panegyres P.K.
        The role of ethnicity in Alzheimer's disease: findings from the C-PATH online data repository.
        J Alzheimers Dis. 2016; 51: 515-523
        • Benedet A.L.
        • Moraes C.F.
        • Camargos E.F.
        • Oliveira L.F.
        • Souza V.C.
        • Lins T.C.
        • et al.
        Amerindian genetic ancestry protects against Alzheimer's disease.
        Dement Geriatr Cogn Disord. 2012; 33: 311-317
        • Moreno D.J.
        • Pino S.
        • Rios A.
        • Lopera F.
        • Ostos H.
        • Via M.
        • et al.
        Genetic ancestry and susceptibility to late-onset Alzheimer disease (LOAD) in the admixed colombian population.
        Alzheimer Dis Assoc Disord. 2017; 31: 225-231
        • Teruel B.M.
        • Rodriguez J.J.
        • McKeigue P.
        • Mesa T.T.
        • Fuentes E.
        • Cepero A.A.
        • et al.
        Interactions between genetic admixture, ethnic identity, APOE genotype and dementia prevalence in an admixed Cuban sample; a cross-sectional population survey and nested case-control study.
        BMC Med Genet. 2011; 12: 43
        • Tang M.X.
        • Stern Y.
        • Marder K.
        • Bell K.
        • Gurland B.
        • Lantigua R.
        • et al.
        The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics.
        JAMA. 1998; 279: 751-755
        • Tang M.X.
        • Maestre G.
        • Tsai W.Y.
        • Liu X.H.
        • Feng L.
        • Chung W.Y.
        • et al.
        Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City.
        Am J Hum Genet. 1996; 58: 574-584
        • Sahota A.
        • Yang M.
        • Gao S.
        • Hui S.L.
        • Baiyewu O.
        • Gureje O.
        • et al.
        Apolipoprotein E-associated risk for Alzheimer's disease in the African-American population is genotype dependent.
        Ann Neurol. 1997; 42: 659-661
        • Corbo R.M.
        • Scacchi R.
        Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele?.
        Ann Hum Genet. 1999; 63: 301-310
        • Lek M.
        • Karczewski K.J.
        • Minikel E.V.
        • Samocha K.E.
        • Banks E.
        • Fennell T.
        • et al.
        Analysis of protein-coding genetic variation in 60,706 humans.
        Nature. 2016; 536: 285-291
        • Lee J.H.
        • Cheng R.
        • Graff-Radford N.
        • Foroud T.
        • Mayeux R.
        National institute on aging late-onset Alzheimer's disease family study G. analyses of the National Institute on Aging late-onset Alzheimer's disease family study: implication of additional loci.
        Arch Neurol. 2008; 65: 1518-1526
        • Blue E.E.
        • Yu C.E.
        • Thornton T.A.
        • Chapman N.H.
        • Kernfeld E.
        • Jiang N.
        • et al.
        Variants regulating ZBTB4 are associated with age-at-onset of Alzheimer's disease.
        Genes Brain Behav. 2018; 17: e12429
        • Saykin A.J.
        • Shen L.
        • Yao X.
        • Kim S.
        • Nho K.
        • Risacher S.L.
        • et al.
        Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans.
        Alzheimers Dement. 2015; 11: 792-814
        • Blacker D.
        • Albert M.S.
        • Bassett S.S.
        • Go R.C.
        • Harrell L.E.
        • Folstein M.F.
        Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative.
        Arch Neurol. 1994; 51: 1198-1204
        • Cruchaga C.
        • Haller G.
        • Chakraverty S.
        • Mayo K.
        • Vallania F.L.
        • Mitra R.D.
        • et al.
        Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.
        PLoS One. 2012; 7: e31039
        • International HapMap C.
        • Altshuler D.M.
        • Gibbs R.A.
        • Peltonen L.
        • Altshuler D.M.
        • Gibbs R.A.
        • et al.
        Integrating common and rare genetic variation in diverse human populations.
        Nature. 2010; 467: 52-58
        • Jakobsson M.
        • Scholz S.W.
        • Scheet P.
        • Gibbs J.R.
        • VanLiere J.M.
        • Fung H.C.
        • et al.
        Genotype, haplotype and copy-number variation in worldwide human populations.
        Nature. 2008; 451: 998-1003
        • Li J.Z.
        • Absher D.M.
        • Tang H.
        • Southwick A.M.
        • Casto A.M.
        • Ramachandran S.
        • et al.
        Worldwide human relationships inferred from genome-wide patterns of variation.
        Science. 2008; 319: 1100-1104
        • Purcell S.
        • Neale B.
        • Todd-Brown K.
        • Thomas L.
        • Ferreira M.A.
        • Bender D.
        • et al.
        PLINK: a tool set for whole-genome association and population-based linkage analyses.
        Am J Hum Genet. 2007; 81: 559-575
        • Therneau T.
        A Package for Survival Analysis in S. version. 2.38 ed.
        2015 (Available at)
        https://CRAN.R-project.org/package=survival
        Date accessed: October 16, 2019
        • Terry M.
        • Therneau P.M.G.
        Modeling Survival Data: Extending the Cox Model.
        Springer, New York2000
        • Team R.C.R.
        R: A Language and Environment for Statistical Computing.
        the R Foundation for Statistical Computing, Vienna, Austria2011 (Available at)
        https://www.r-project.org
        Date accessed: September 16, 2019
        • Delaneau O.
        • Marchini J.
        • Genomes Project C.
        • Genomes Project C.
        Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel.
        Nat Commun. 2014; 5: 3934
        • Delaneau O.
        • Howie B.
        • Cox A.J.
        • Zagury J.F.
        • Marchini J.
        Haplotype estimation using sequencing reads.
        Am J Hum Genet. 2013; 93: 687-696
        • O'Connell J.
        • Gurdasani D.
        • Delaneau O.
        • Pirastu N.
        • Ulivi S.
        • Cocca M.
        • et al.
        A general approach for haplotype phasing across the full spectrum of relatedness.
        PLoS Genet. 2014; 10: e1004234
        • Maples B.K.
        • Gravel S.
        • Kenny E.E.
        • Bustamante C.D.
        RFMix: a discriminative modeling approach for rapid and robust local-ancestry inference.
        Am J Hum Genet. 2013; 93: 278-288
        • Gogarten S.M.
        • Sofer T.
        • Chen H.
        • Yu C.
        • Brody J.A.
        • Thornton T.A.
        • et al.
        Genetic association testing using the GENESIS R/Bioconductor package.
        Bioinformatics. 2019; ([Epub ahead of print]. https://doi.org/10.1093/bioinformatics/btz567.)
        • Conomos M.P.
        • Miller M.B.
        • Thornton T.A.
        Robust inference of population structure for ancestry prediction and correction of stratification in the presence of relatedness.
        Genet Epidemiol. 2015; 39: 276-293
        • Conomos M.P.
        • Reiner A.P.
        • Weir B.S.
        • Thornton T.A.
        Model-free estimation of recent genetic relatedness.
        Am J Hum Genet. 2016; 98: 127-148
        • Babenko V.N.
        • Afonnikov D.A.
        • Ignatieva E.V.
        • Klimov A.V.
        • Gusev F.E.
        • Rogaev E.I.
        Haplotype analysis of APOE intragenic SNPs.
        BMC Neurosci. 2018; 19: 16
        • Fullerton S.M.
        • Clark A.G.
        • Weiss K.M.
        • Nickerson D.A.
        • Taylor S.L.
        • Stengard J.H.
        • et al.
        Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism.
        Am J Hum Genet. 2000; 67: 881-900
        • Radwan Z.H.
        • Wang X.
        • Waqar F.
        • Pirim D.
        • Niemsiri V.
        • Hokanson J.E.
        • et al.
        Comprehensive evaluation of the association of APOE genetic variation with plasma lipoprotein traits in U.S. whites and African blacks.
        PLoS One. 2014; 9: e114618
        • Liu J.
        • Zhao W.
        • Ware E.B.
        • Turner S.T.
        • Mosley T.H.
        • Smith J.A.
        DNA methylation in the APOE genomic region is associated with cognitive function in African Americans.
        BMC Med Genomics. 2018; 11: 43
        • Zaitlen N.
        • Pasaniuc B.
        • Sankararaman S.
        • Bhatia G.
        • Zhang J.
        • Gusev A.
        • et al.
        Leveraging population admixture to characterize the heritability of complex traits.
        Nat Genet. 2014; 46: 1356-1362
        • Kim M.S.
        • Patel K.P.
        • Teng A.K.
        • Berens A.J.
        • Lachance J.
        Genetic disease risks can be misestimated across global populations.
        Genome Biol. 2018; 19: 179
        • Rajabli F.
        • Feliciano B.E.
        • Celis K.
        • Hamilton-Nelson K.L.
        • Whitehead P.L.
        • Adams L.D.
        • et al.
        Ancestral origin of ApoE epsilon4 Alzheimer disease risk in Puerto Rican and African American populations.
        PLoS Genet. 2018; 14: e1007791
        • Levran O.
        • Awolesi O.
        • Shen P.H.
        • Adelson M.
        • Kreek M.J.
        Estimating ancestral proportions in a multi-ethnic US sample: implications for studies of admixed populations.
        Hum Genomics. 2012; 6: 2
        • Halder I.
        • Yang B.Z.
        • Kranzler H.R.
        • Stein M.B.
        • Shriver M.D.
        • Gelernter J.
        Measurement of admixture proportions and description of admixture structure in different U.S. populations.
        Hum Mutat. 2009; 30: 1299-1309
        • Mathias R.A.
        • Taub M.A.
        • Gignoux C.R.
        • Fu W.
        • Musharoff S.
        • O'Connor T.D.
        • et al.
        A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome.
        Nat Commun. 2016; 7: 12522

      CHORUS Manuscript

      View Open Manuscript