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Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals.

ABSTRACT: To identify novel loci for late-onset Alzheimer disease (LOAD) in Caribbean Hispanic individuals and to replicate the findings in a publicly available data set from the National Institute on Aging Late-Onset Alzheimer's Disease Family Study.Nested case-control genome-wide association study.The Washington Heights-Inwood Columbia Aging Project and the Estudio Familiar de Influencia Genetica de Alzheimer study.Five hundred forty-nine affected and 544 unaffected individuals of Caribbean Hispanic ancestry.The Illumina HumanHap 650Y chip for genotyping.Clinical diagnosis or pathologically confirmed diagnosis of LOAD.The strongest support for allelic association was for rs9945493 on 18q23 (P=1.7×10(-7)), but 22 additional single-nucleotide polymorphisms (SNPs) had a P value less than 9×10(-6) under 3 different analyses: unadjusted and stratified by the presence or absence of the APOE ?4 allele. Of these SNPs, 5 SNPs (rs4669573 and rs10197851 on 2p25.1; rs11711889 on 3q25.2; rs1117750 on 7p21.1; and rs7908652 on 10q23.1) were associated with LOAD in an independent cohort from the National Institute on Aging Late-Onset Alzheimer's Disease Family Study. We also replicated genetic associations for CLU, PICALM, and BIN1.Our genome-wide search of Caribbean Hispanic individuals identified several novel genetic variants associated with LOAD and replicated these associations in a white cohort. We also replicated associations in CLU, PICALM, and BIN1 in the Caribbean Hispanic cohort.

SUBMITTER: Lee JH

PROVIDER: S-EPMC3268783 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals.

Lee Joseph H JH Cheng Rong R Barral Sandra S Reitz Christiane C Medrano Martin M Lantigua Rafael R Jiménez-Velazquez Ivonne Z IZ Rogaeva Ekaterina E St George-Hyslop Peter H PH Mayeux Richard R

Archives of neurology 20101108 3

<h4>Objectives</h4>To identify novel loci for late-onset Alzheimer disease (LOAD) in Caribbean Hispanic individuals and to replicate the findings in a publicly available data set from the National Institute on Aging Late-Onset Alzheimer's Disease Family Study.<h4>Design</h4>Nested case-control genome-wide association study.<h4>Setting</h4>The Washington Heights-Inwood Columbia Aging Project and the Estudio Familiar de Influencia Genetica de Alzheimer study.<h4>Participants</h4>Five hundred forty ...[more]

PMID: 21059989

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Project description:IMPORTANCE The search for novel Alzheimer disease (AD) genes or pathologic mutations within known AD loci is ongoing. The development of array technologies has helped to identify rare recessive mutations among long runs of homozygosity (ROHs), in which both parental alleles are identical. Caribbean Hispanics are known to have an elevated risk for AD and tend to have large families with evidence of inbreeding. OBJECTIVE To test the hypothesis that the late-onset AD in a Caribbean Hispanic population might be explained in part by the homozygosity of unknown loci that could harbor recessive AD risk haplotypes or pathologic mutations. DESIGN We used genome-wide array data to identify ROHs (>1 megabase) and conducted global burden and locus-specific ROH analyses. SETTING A whole-genome case-control ROH study. PARTICIPANTS A Caribbean Hispanic data set of 547 unrelated cases (48.8% with familial AD) and 542 controls collected from a population known to have a 3-fold higher risk of AD vs non-Hispanics in the same community. Based on a Structure program analysis, our data set consisted of African Hispanic (207 cases and 192 controls) and European Hispanic (329 cases and 326 controls) participants. EXPOSURE Alzheimer disease risk genes. MAIN OUTCOMES AND MEASURES We calculated the total and mean lengths of the ROHs per sample. Global burden measurements among autosomal chromosomes were investigated in cases vs controls. Pools of overlapping ROH segments (consensus regions) were identified, and the case to control ratio was calculated for each consensus region. We formulated the tested hypothesis before data collection. RESULTS In total, we identified 17 137 autosomal regions with ROHs. The mean length of the ROH per person was significantly greater in cases vs controls (P?=?.0039), and this association was stronger with familial AD (P?=?.0005). Among the European Hispanics, a consensus region at the EXOC4 locus was significantly associated with AD even after correction for multiple testing (empirical P value 1 [EMP1], .0001; EMP2, .002; 21 AD cases vs 2 controls). Among the African Hispanic subset, the most significant but nominal association was observed for CTNNA3, a well-known AD gene candidate (EMP1, .002; 10 AD cases vs 0 controls). CONCLUSIONS AND RELEVANCE Our results show that ROHs could significantly contribute to the etiology of AD. Future studies would require the analysis of larger, relatively inbred data sets that might reveal novel recessive AD genes. The next step is to conduct sequencing of top significant loci in a subset of samples with overlapping ROHs.

Dataset Information

Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals.

Publications

Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals.

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