Evidence of Recessive Alzheimer Disease Loci in a Caribbean Hispanic Data Set
Identifieur interne : 000D79 ( Main/Exploration ); précédent : 000D78; suivant : 000D80Evidence of Recessive Alzheimer Disease Loci in a Caribbean Hispanic Data Set
Auteurs : Mahdi Ghani ; Christine Sato ; Joseph H. Lee ; Christiane Reitz ; Danielle Moreno ; Richard Mayeux ; Peter St George-Hyslop ; Ekaterina RogaevaSource :
- JAMA neurology [ 2168-6149 ] ; 2013.
Abstract
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.
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.
We used genome-wide array data to identify ROHs (>1 megabase) and conducted global burden and locus-specific ROH analyses.
A whole-genome case-control ROH study.
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.
Alzheimer disease risk genes.
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.
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 (
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.
Url:
DOI: 10.1001/jamaneurol.2013.3545
PubMed: 23978990
PubMed Central: 3991012
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Evidence of Recessive Alzheimer Disease Loci in a Caribbean Hispanic Data Set</title><author><name sortKey="Ghani, Mahdi" sort="Ghani, Mahdi" uniqKey="Ghani M" first="Mahdi" last="Ghani">Mahdi Ghani</name></author><author><name sortKey="Sato, Christine" sort="Sato, Christine" uniqKey="Sato C" first="Christine" last="Sato">Christine Sato</name></author><author><name sortKey="Lee, Joseph H" sort="Lee, Joseph H" uniqKey="Lee J" first="Joseph H." last="Lee">Joseph H. Lee</name></author><author><name sortKey="Reitz, Christiane" sort="Reitz, Christiane" uniqKey="Reitz C" first="Christiane" last="Reitz">Christiane Reitz</name></author><author><name sortKey="Moreno, Danielle" sort="Moreno, Danielle" uniqKey="Moreno D" first="Danielle" last="Moreno">Danielle Moreno</name></author><author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name></author><author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23978990</idno><idno type="pmc">3991012</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991012</idno><idno type="RBID">PMC:3991012</idno><idno type="doi">10.1001/jamaneurol.2013.3545</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">000769</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000769</idno><idno type="wicri:Area/Pmc/Curation">000769</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000769</idno><idno type="wicri:Area/Pmc/Checkpoint">000658</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000658</idno><idno type="wicri:Area/Ncbi/Merge">001550</idno><idno type="wicri:Area/Ncbi/Curation">001550</idno><idno type="wicri:Area/Ncbi/Checkpoint">001550</idno><idno type="wicri:doubleKey">2168-6149:2013:Ghani M:evidence:of:recessive</idno><idno type="wicri:Area/Main/Merge">000D91</idno><idno type="wicri:Area/Main/Curation">000D79</idno><idno type="wicri:Area/Main/Exploration">000D79</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Evidence of Recessive Alzheimer Disease Loci in a Caribbean Hispanic Data Set</title><author><name sortKey="Ghani, Mahdi" sort="Ghani, Mahdi" uniqKey="Ghani M" first="Mahdi" last="Ghani">Mahdi Ghani</name></author><author><name sortKey="Sato, Christine" sort="Sato, Christine" uniqKey="Sato C" first="Christine" last="Sato">Christine Sato</name></author><author><name sortKey="Lee, Joseph H" sort="Lee, Joseph H" uniqKey="Lee J" first="Joseph H." last="Lee">Joseph H. Lee</name></author><author><name sortKey="Reitz, Christiane" sort="Reitz, Christiane" uniqKey="Reitz C" first="Christiane" last="Reitz">Christiane Reitz</name></author><author><name sortKey="Moreno, Danielle" sort="Moreno, Danielle" uniqKey="Moreno D" first="Danielle" last="Moreno">Danielle Moreno</name></author><author><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name></author><author><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name></author><author><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name></author></analytic><series><title level="j">JAMA neurology</title><idno type="ISSN">2168-6149</idno><idno type="eISSN">2168-6157</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>IMPORTANCE</title><p id="P1">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.</p></sec><sec id="S2"><title>OBJECTIVE</title><p id="P2">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.</p></sec><sec id="S3"><title>DESIGN</title><p id="P3">We used genome-wide array data to identify ROHs (>1 megabase) and conducted global burden and locus-specific ROH analyses.</p></sec><sec id="S4"><title>SETTING</title><p id="P4">A whole-genome case-control ROH study.</p></sec><sec id="S5"><title>PARTICIPANTS</title><p id="P5">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.</p></sec><sec id="S6"><title>EXPOSURE</title><p id="P6">Alzheimer disease risk genes.</p></sec><sec id="S7"><title>MAIN OUTCOMES AND MEASURES</title><p id="P7">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.</p></sec><sec id="S8"><title>RESULTS</title><p id="P8">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 (<italic>P</italic> = .0039), and this association was stronger with familial AD (<italic>P</italic> = .0005). Among the European Hispanics, a consensus region at the <italic>EXOC4</italic> locus was significantly associated with AD even after correction for multiple testing (empirical <italic>P</italic> 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 <italic>CTNNA3</italic>, a well-known AD gene candidate (EMP1, .002; 10 AD cases vs 0 controls).</p></sec><sec id="S9"><title>CONCLUSIONS AND RELEVANCE</title><p id="P9">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.</p></sec></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Ghani, Mahdi" sort="Ghani, Mahdi" uniqKey="Ghani M" first="Mahdi" last="Ghani">Mahdi Ghani</name><name sortKey="Lee, Joseph H" sort="Lee, Joseph H" uniqKey="Lee J" first="Joseph H." last="Lee">Joseph H. Lee</name><name sortKey="Mayeux, Richard" sort="Mayeux, Richard" uniqKey="Mayeux R" first="Richard" last="Mayeux">Richard Mayeux</name><name sortKey="Moreno, Danielle" sort="Moreno, Danielle" uniqKey="Moreno D" first="Danielle" last="Moreno">Danielle Moreno</name><name sortKey="Reitz, Christiane" sort="Reitz, Christiane" uniqKey="Reitz C" first="Christiane" last="Reitz">Christiane Reitz</name><name sortKey="Rogaeva, Ekaterina" sort="Rogaeva, Ekaterina" uniqKey="Rogaeva E" first="Ekaterina" last="Rogaeva">Ekaterina Rogaeva</name><name sortKey="Sato, Christine" sort="Sato, Christine" uniqKey="Sato C" first="Christine" last="Sato">Christine Sato</name><name sortKey="St George Hyslop, Peter" sort="St George Hyslop, Peter" uniqKey="St George Hyslop P" first="Peter" last="St George-Hyslop">Peter St George-Hyslop</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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