Summary: Researchers estimate carriers of a gene that is significantly enriched in Icelanders have a six fold increased risk of developing Alzheimer’s disease.
Source: Baylor College of Medicine.
This is a wild-type Drosophila a. (top) and human TM2D3 (middle) genomic constructs rescue the aberrant nervous system overgrowth seen in embryos laid by mutant females (bottom, no rescue construct). Blue: nuclei, Green: membranes, Red: cytoskeleton. NeuroscienceNews.com image is credited to S. Yamamoto, J. Schuman, H. Bellen, Baylor College of Medicine.
Scientists at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital are part of a multicenter collaborative study that has identified a novel genetic risk factor for late-onset Alzheimer’s disease. The study appears in the journal PLoS Genetics.
Alzheimer’s disease is the most common cause of dementia among older adults, and the presence of certain genetic variants increases an individual’s risk for developing this disease.
Baylor researchers Dr. Shinya Yamamoto, assistant professor of molecular and human genetics; Dr. Joshua M. Shulman, assistant professor of neurology, neuroscience, and molecular and human genetics, and Dr. Hugo J. Bellen, professor and director of the program in developmental biology and also an investigator at the Howard Hughes Medical Institute, were part of an international team that analyzed samples from 1,393 subjects with late-onset Alzheimer’s disease and compared the results with those of 8,141 neurologically healthy individuals.
The consortium found a variant in TM2D3, a gene that has never been studied in human or other vertebrate species. Interestingly, while the probability of this variant was very rare among people of European ancestry, it was significantly enriched among Icelanders (but still less than 1 percent frequency). The researchers estimated that carriers of this variant would have an approximately six-fold increased risk of developing Alzheimer’s disease.
To further understand the impact of the discovered mutation and its potential link to processes that lead to Alzheimer’s disease, the Baylor researchers studied the function of TM2D3 in the fruit fly model system.
They found that loss-of-function of theTM2D3 gene causes abnormal development of the fly’s nervous system. They next showed that human normal TM2D3 could functionally substitute for its fly counterpart and rescue the neurodevelopmental defect, whereas introduction of the Alzheimer’s disease-associated variant was unable to restore the normal function.
In summary, this study has identified a novel, rare genetic variant in the TM2D3 gene to be a risk factor in the development of late-onset Alzheimer’s disease among Icelanders. This gene has not been previously linked to Alzheimer’s, andresearchers are hopeful that further investigations may lead to new and more effective therapies.
Other Baylor contributors to this work are Dr. David Li-Kroeger, postdoctoral fellow in the Bellen Lab, José Salazar, graduate student in the Bellen Lab, and Dr. Eric Boerwinkle at Baylor’s Human Genome Sequencing Center.
Source: Allison Huseman – Baylor College of Medicine
Image Source: NeuroscienceNews.com image is credited to S. Yamamoto, J. Schuman, H. Bellen, Baylor College of Medicine.
Original Research: Full open access research for “Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer’s Disease” by Johanna Jakobsdottir, Sven J. van der Lee, Joshua C. Bis, Vincent Chouraki, David Li-Kroeger, Shinya Yamamoto, Megan L. Grove, Adam Naj, Maria Vronskaya, Jose L. Salazar, Anita L. DeStefano, Jennifer A. Brody, Albert V. Smith, Najaf Amin, Rebecca Sims, Carla A. Ibrahim-Verbaas, Seung-Hoan Choi, Claudia L. Satizabal, Oscar L. Lopez, Alexa Beiser, M. Arfan Ikram, Melissa E. Garcia, Caroline Hayward, Tibor V. Varga, Samuli Ripatti, Paul W. Franks, Göran Hallmans, Olov Rolandsson, Jan-Håkon Jansson, David J. Porteous, Veikko Salomaa, Gudny Eiriksdottir, Kenneth M. Rice, Hugo J. Bellen, Daniel Levy, Andre G. Uitterlinden, Valur Emilsson, Jerome I. Rotter, Thor Aspelund, Cohorts for Heart and Aging Research in Genomic Epidemiology consortium , Alzheimer’s Disease Genetic Consortium , Genetic and Environmental Risk in Alzheimer’s Disease consortium , Christopher J. O’Donnell, Annette L. Fitzpatrick, Lenore J. Launer, Albert Hofman, Li-San Wang, Julie Williams, Gerard D. Schellenberg, Eric Boerwinkle, Bruce M. Psaty, Sudha Seshadri, Joshua M. Shulman, Vilmundur Gudnason, and Cornelia M. van Duijn in PLOS Genetics. Published online October 20 2016 doi:10.1371/journal.pgen.1006327
Abstract
Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer’s Disease
We performed an exome-wide association analysis in 1393 late-onset Alzheimer’s disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5–15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L,
establishing it as a functionally damaging allele.
Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade. "Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease” by Johanna Jakobsdottir, Sven J. van der Lee, Joshua C. Bis, Vincent Chouraki, David Li-Kroeger, Shinya Yamamoto, Megan L. Grove, Adam Naj, Maria Vronskaya, Jose L. Salazar, Anita L. DeStefano, Jennifer A. Brody, Albert V. Smith, Najaf Amin, Rebecca Sims, Carla A. Ibrahim-Verbaas, Seung-Hoan Choi, Claudia L. Satizabal, Oscar L. Lopez, Alexa Beiser, M. Arfan Ikram, Melissa E. Garcia, Caroline Hayward, Tibor V. Varga, Samuli Ripatti, Paul W. Franks, Göran Hallmans, Olov Rolandsson, Jan-Håkon Jansson, David J. Porteous, Veikko Salomaa, Gudny Eiriksdottir, Kenneth M. Rice, Hugo J. Bellen, Daniel Levy, Andre G. Uitterlinden, Valur Emilsson, Jerome I. Rotter, Thor Aspelund, Cohorts for Heart and Aging Research in Genomic Epidemiology consortium , Alzheimer’s Disease Genetic Consortium , Genetic and Environmental Risk in Alzheimer’s Disease consortium , Christopher J. O’Donnell, Annette L. Fitzpatrick, Lenore J. Launer, Albert Hofman, Li-San Wang, Julie Williams, Gerard D. Schellenberg, Eric Boerwinkle, Bruce M. Psaty, Sudha Seshadri, Joshua M. Shulman, Vilmundur Gudnason, and Cornelia M. van Duijn in PLOS Genetics. Published online October 20 2016 doi:10.1371/journal.pgen.1006327
http://neurosciencenews.com/genetics-icelanders-alzheimers-5324/
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