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Original Investigation |

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

Mahdi Ghani, PhD1; Christine Sato, MSc1; Joseph H. Lee, PhD2,3; Christiane Reitz, PhD2; Danielle Moreno, BSc1; Richard Mayeux, MD2; Peter St George-Hyslop, MD1,4,5; Ekaterina Rogaeva, PhD1,4
[+] Author Affiliations
1Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
2Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
3Department of Epidemiology, School of Public Health, Columbia University, New York, New York
4Department of Medicine, University of Toronto, Toronto, Ontario, Canada
5Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, England
JAMA Neurol. 2013;70(10):1261-1267. doi:10.1001/jamaneurol.2013.3545.
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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.

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Figure.
Runs of Homozygosity (ROHs) in a Subset of Caribbean Hispanic Samples

Runs of homozygosity intersect the EXOC4 gene (A) and the CTNNA3 gene (B). Light blue bars represent ROHs in cases with Alzheimer disease; dark blue bars, ROHs in controls. The arrows represent the physical ROH consensus.

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