30 Aug Alzheimer Disease: Homozygous Genetic Loci Identified
Ekaterina Rogaeva, PhD
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, CanadaDepartment of Medicine, University of Toronto, Toronto, Ontario, CanadaCambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, England
MedicalResearch.com: What are the main findings of the study?
Answer: We tested the hypothesis that late-onset Alzheimer disease (AD) might be in part explained by the homozygosity of unknown loci. In a genome-wide study of a Caribbean Hispanic population with noticeable inbreeding and high risk of AD we assessed the presence of long runs of homozygosity (ROHs) – regions where the alleles inherited from both parents are identical. Our results suggest the existence of recessive AD loci, since the mean length of the ROH per person was significantly longer in AD cases versus controls, and this association was stronger in familial AD.
The association of ROHs with AD could either reflect the cumulative risk effects of multiple ROHs or the contribution of specific loci harboring recessive mutations in a subset of AD patients. To address the latter possibility we identified overlapping ROH segments (consensus regions) and calculated the case/control ratio for each of 1,415 consensus regions. The most significant association with AD was observed for two genes: EXOC4, encoding a component of the exocyst complex involved in the trafficking of the NMDA receptor; and CTNNA3, encoding alpha catenin interacting with PSEN1 (known AD gene).
MedicalResearch.com: Were any of the findings unexpected?
Answer: Thus far, all known causal AD genes (APP, PSEN1 and PSEN2) are responsible for an autosomal dominant inheritance of disease For the first time we showed that autosomal recessive inheritance could also contribute to AD, when one copy of a mutant allele cause the disease..
MedicalResearch.com: What should clinicians and patients take away from your report?
Answer: Knowledge about the genetics of AD is important to manage the challenges of aging populations, since it is the most prevalent form of dementia. The results of our ROH-study is especially important for clinicians assessing AD patients from regions where consanguineous marriages are frequently practised (e.g. the Middle East) or from populations with a noticeable degree of inbreeding (e.g. Caribbean Hispanics). Families with both history of AD and an inbred background should be included in genetic studies to search for recessive defects as described above.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Answer: Future studies would require the analysis of large independent and relatively inbred data sets that might confirm the loci detected in our study and/or reveal novel recessive AD genes. In order to characterize the molecular defects underlying AD, the first step is to conduct deep sequencing of the top significant loci in a subset of samples with ROHs overlapping EXOC4 and CTNNA3 loci, followed-up by segregation studies in AD families and the assessment of potential pathological mutations in different ethnic groups.
Evidence of Recessive Alzheimer Disease Loci in a Caribbean Hispanic Data Set Genome-wide Survey of Runs of HomozygosityGhani M, Sato C, Lee JH, et al. Evidence of Recessive Alzheimer Disease Loci in a Caribbean Hispanic Data Set: Genome-wide Survey of Runs of Homozygosity.
JAMA Neurol. 2013;():-. doi:10.1001/jamaneurol.2013.3545.