Evidence of Recessive Alzheimer Disease Loci in a Caribbean Hispanic Data Set Genome-wide Survey of Runs of Homozygosity

被引:34
|
作者
Ghani, Mandi [1 ]
Sato, Christine [1 ]
Lee, Joseph H. [2 ,3 ,4 ,5 ]
Reitz, Christiane [2 ,3 ,4 ]
Moreno, Danielle [1 ]
Mayeux, Richard [2 ,3 ,4 ]
St George-Hyslop, Peter [1 ,6 ,7 ,8 ]
Rogaeva, Ekaterina [1 ,6 ]
机构
[1] Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada
[2] Columbia Univ, Coll Phys & Surg, Taub Inst Res Alzheimers Dis & Aging Brain, Gertrude H Sergievsky Ctr,Dept Neurol, New York, NY USA
[3] Columbia Univ, Coll Phys & Surg, Taub Inst Res Alzheimers Dis & Aging Brain, Gertrude H Sergievsky Ctr,Dept Psychiat, New York, NY USA
[4] Columbia Univ, Coll Phys & Surg, Taub Inst Res Alzheimers Dis & Aging Brain, Gertrude H Sergievsky Ctr,Dept Med, New York, NY USA
[5] Columbia Univ, Sch Publ Hlth, Dept Epidemiol, New York, NY USA
[6] Univ Toronto, Dept Med, Toronto, ON, Canada
[7] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England
[8] Univ Cambridge, Dept Clin Neurosci, Cambridge, England
基金
美国国家卫生研究院; 英国惠康基金; 英国医学研究理事会; 加拿大健康研究院;
关键词
GENETIC ASSOCIATION; IDENTIFIES VARIANTS; EXTENDED TRACTS; COMMON VARIANTS; CANDIDATE GENES; CLU; AUTOZYGOSITY; PICALM; REPLICATION; MEMBRANE;
D O I
10.1001/jamaneurol.2013.3545
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 17137 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.
引用
收藏
页码:1261 / 1267
页数:7
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