Overview: Researchers have identified a new gene called MGMT that appears to increase the risk of Alzheimer’s disease in women.
Source: Boston University
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia, affecting more than 5.8 million people in the US. Scientists have discovered some genetic variants that increase the risk of developing Alzheimer’s disease; the most famous of these for those over 65 is the APOE ε4 allele.
About 60 percent of people of European descent with Alzheimer’s carry this genetic variant, compared to just 26 percent of the general population, implying that other genes contribute to the genetic makeup of the disease.
In a new study published this week in Alzheimer’s Disease and Dementia: The Journal of the Alzheimer’s AssociationResearchers from the University of Chicago and Boston University School of Medicine (BUSM) have identified a new gene called MGMT that increases the risk of Alzheimer’s in women.
The researchers conducted a genome-wide association study (GWAS) for Alzheimer’s disease in two independent data sets using different methods.
One approach focused on dementia in a large extended family of Hutterites, a founder population of Central European descent who settled in the Midwest of the country. Hutterites are often examined for genetic determinants of disease because they have a relatively small gene pool due to their isolated, insular culture. In this study, the individuals with Alzheimer’s disease were all women.
The second approach, based on evidence suggesting a link between Alzheimer’s disease and breast cancer, analyzed genetic data from a national sample of 10,340 women who had no APOE ε4. In both datasets MGMT was significantly associated with developing AD.
“This is one of the few, and arguably the strongest, associations of a genetic risk factor for Alzheimer’s disease that is specific to women,” said Lindsay Farrer, PhD, chief of biomedical genetics at BUSM and a senior author of the study.
“This finding is particularly robust because it was discovered independently in two different populations using different approaches. While the finding in the large dataset was most pronounced in women who did not, APOE ε4, the Hutterite sample was too small to evaluate this pattern with any certainty.”
The researchers then further evaluated MGMT using multiple types of molecular data and other AD-related properties derived from human brain tissue. After thorough analysis, they found that those epigenetically regulated gene expression (ie one of the ways cells regulate gene activity without altering the DNA sequence) of MGMTthat plays a role in repairing DNA damage is significantly associated with the development of the signature AD proteins, amyloid-β and tau, especially in women.
“This study emphasized the value of founder populations for genetic mapping studies of diseases such as Alzheimer’s disease,” said Carole Ober, PhD, chair of human genetics at UChicago and a senior author of the study.
“The relatively uniform environment and reduced genetic variation in Hutterites enhances our ability to find associations in smaller sample sizes than required for studies in the general population. The validation of our findings in the larger dataset used by the Boston University group was tremendous.” satisfactory and eventually led to supportive epigenetic mechanisms linking both sets of GWAS results with the MGMT gene.”
According to the researchers, this study demonstrates the importance of looking for genetic risk factors for AD that may be specific to one gender. Further studies are needed to understand why MGMT affects AD risk greater in women than in men.
Financing: Funding for this study was provided by National Institutes of Health grants R01 HD21244, R01 HL085197, RF1 AG057519, R01 AG069453, R01 AG048927, U19 AG068753, U01 AG062602, U01 AG058654, and R01 AG062634. The Alzheimer’s Disease Genetics Consortium supported the collection of samples used in this study through grants from the National Institute on Aging (NIA) U01 AG032984 and RC2 AG036528.
About this news about Alzheimer’s disease and genetics
Original research: Open access.
†Identifying genome-wide association and multi-omics studies MGMT as a new risk gene for Alzheimer’s disease in women” by Lindsay Farrer et al. Alzheimer’s & Dementia
Identifying genome-wide association and multi-omics studies MGMT as a new risk gene for Alzheimer’s disease in women
Variants in the tau gene (MAP) region are associated with breast cancer in women and Alzheimer’s disease (AD) in individuals lacking apolipoprotein E 4 (ε4-).
To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 ε4 women in the Alzheimer’s Disease Genetics Consortium (ADGC) and another among 31 members (22 women). ) from a kinsman Hutterite relative.
We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, p = 4.9 × 10–8) and Hutterite (rs12256016 and rs2803456, OR = 2.0, p = 1.9 × 10-14) data sets. Multi-omics analyzes showed that the most significant and largest number of associations between the single nucleotide polymorphisms (SNPs), DNA-methylated CpGs, MGMT expression and AD-related neuropathological features were observed in females. In addition, Hi-C analyzes for capturing the promoter revealed long-range interactions of the MGMT promoter with MGMT SNPs and CpG sites.
These findings suggest that epigenetically regulated MGMT expression is involved in the pathogenesis of AD, especially in women.