A new gene for Alzheimer’s disease in women has been discovered.
More than 5.8 million people in the United States have Alzheimer’s disease (AD), the most common form of dementia. AD is a progressive neurological condition. Scientists have identified some gene variants that increase the risk of Alzheimer’s. the APOE 4 allele is the best known of these for people over 65 years of age. About 60% of Alzheimer’s patients of European descent carry this genetic variant, compared to only 26% of the general population, suggesting that additional genes may contribute to the genetic basis of the condition. Researchers from Boston University School of Medicine (BUSM) and the University of Chicago have found a new gene called MGMT that increases Alzheimer’s risk in women. The findings of this study were recently published in Alzheimer’s Disease & Dementia: The Journal of the Alzheimer’s Association. Using several techniques, the researchers performed a genome-wide association study (GWAS) for Alzheimer’s disease on two separate datasets. One method focused on dementia in a large extended Hutterite family, a founding group of Central European descent that arrived in the country’s Midwest. Because of their isolated, insular society, the Hutterites have a very small gene pool, making them prime candidates for research into the genetic causes of disease. The Alzheimer’s patients in this study were all women. The second approach looked at genetic data from a nationwide sample of 10,340 women who did not have APOE4. It was based on research showing a link between Alzheimer’s and breast cancer. MGMT was strongly associated with AD onset in both datasets. “This is one of the few and perhaps the strongest associations of a genetic risk factor for Alzheimer’s disease that is specific to women,” said Lindsay Farrer, Ph.D., head of biomedical genetics at BUSM and senior author of the study. “This finding is particularly powerful because it was discovered independently in two different populations using different approaches. While the finding in the large data set was more pronounced in non-APOE ε4 women, the Hutterite sample was too small to assess this pattern with certainty. The researchers then further evaluated MGMT using multiple types of molecular data and other AD-related features derived from human brain tissue. After careful analysis, they found that the epigenetically regulated gene expression (ie, one of the ways cells control gene activity without changing the DNA sequence) of MGMT, which plays a role in repairing DNA damage, is associated significantly with the development of the characteristic AD proteins, amyloid-β and tau, especially in women. “This study highlighted the value of founder populations for genetic mapping studies of diseases such as Alzheimer’s,” said Carole Ober, Ph.D., Chair of Human Genetics at UChicago and senior author of the study. “The relatively uniform environment and reduced genetic variation in the Hutterites increases our power to find associations in smaller sample sizes than are needed for studies in the general population. Validation of our findings in the larger data set used by the Boston University team was extremely gratifying and ultimately led to supportive epigenetic mechanisms linking both sets of GWAS results to the MGMT gene. According to the researchers, this study demonstrates the importance of looking for genetic risk factors for AD that may be sex-specific. Further studies are needed to understand why MGMT affects AD risk to a greater extent in women than in men. Citation: “Genome-wide association and multi-omic studies identify MGMT as a novel risk gene for Alzheimer’s disease in women” by Jaeyoon Chung, Anjali Das, Xinyu Sun, Deborah R. Sobreira, Yuk Yee Leung, Catherine Igartua, Sahar Mozaffari, 2010; Yi-Fan Chou, Sam Thiagalingam, Jesse Mez, Xiaoling Zhang, Gyungah R. Jun, Thor D. Stein, Brian W. Kunkle, Eden R. Martin, Margaret A. Pericak-Vance, Richard Mayeux , Jonathan L. Haines , Gerard D. Schellenberg, Marcelo A. Nobrega, Kathryn L. Lunetta, Jayant M. Pinto, Li-San Wang, Carole Ober, and Lindsay A. Farrer. 10.1002/alz.12719 This study was funded by the National Institutes of Health. The Alzheimer’s Disease Genetics Consortium supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01 AG032984 and RC2 AG036528.
