Older men missing Y chromosome in blood more likely to develop Alzheimer’s

Researchers tracking older men have found an association between the loss of the male-only Y chromosome in blood cells and higher likelihood of Alzheimer’s diagnosis. Previously the same group demonstrated that loss of the Y chromosome, a common occurrence among aging men, was associated with a higher risk of cancer. Publishing in the American Journal of Human Genetics, the researchers suggest loss of the Y chromosome could be a predictive biomarker for cancer and Alzheimer’s, and could help explain why men on average live shorter than women.

 

Dr. Chris Lau, Professor, Department of Medicine, University of California, San Francisco (webpage):

Expertise: Y chromosome genes in health and disease, molecular causes of sex determination and differentiation, roles of sex chromosomes in human cancers

“Although informative, the study is preliminary in nature and only highlights the fact that the Y chromosome could serve important functions beyond male sex determination and sperm production. What exactly on the Y chromosome that increases the risk of Alzheimer’s disease is the key issue. The Y chromosome contains numerous genes, some shared with women and others that are unique to men. So, it depends on what is lost to determine what is important for Alzheimer’s disease. Without such information, the loss of Y (LOY) is just an observation.

“Recent complete sequencing of the Y chromosome has demonstrated that there are 17 functional genes on the male-specific region, a manageable number for functional or patient-oriented analyses. The logical next step is to find out how these genes function during both prenatal and postnatal development and to study their changes in aging populations and during disease initiation, progression, and treatment.

“These male-specific genes could contribute to sex-dependent differences in conditions like hypertension, autism, Hirschsprung disease, and liver cancer, which each have significant male-biases among their respective patient populations. In contrast to the loss of Y in this report, the presence of the Y chromosome in males actually increases the risks for these respective diseases. It is conceivable that genes on the Y chromosome could predispose boys to autism or Hirschsprung early in development, but also protect older men from Alzheimer’s disease later in life.

“The Y chromosome could be important for many quantitative traits, in addition to male sex determination and sperm production. There are reports of both Y-located cancer-causing genes and tumor suppressors. However, it is doubtful that loss of Y alone can be used as a predictive biomarker for Alzheimer’s disease and cancer. Having the Y chromosome with an activated cancer-causing gene will be more likely to contribute to cancer than losing it. So, loss of Y alone cannot explain why men live shorter lives than women, other genetic and environmental factors need to be considered.

“Geneticists observed the occasional loss of Y in human cancer cells under the microscope in the 70s and 80s, but never developed it into any consistent diagnostic routine for cancers. The present study represents a similar observation, but with results from large populations and using modern biostatistics. However, without knowing the specific genes involved, the conclusions and usefulness are similarly limited.”

 

Dr. Thomas Wingo, Assistant Professor, Departments of Neurology and Human Genetics, Emory University School of Medicine (website)

Expertise: Genetics of young- and late-onset Alzheimer’s, protein aggregation in neurodegenerative diseases

“The hypothesis is intriguing but I am left with a number of unanswered questions. Any single test is probably not going to be a realistic biomarker for a complex disease like Alzheimer’s.

“In their analysis, the measure of the loss of the Y chromosome appears to vary with the size of the group studied, and this is not fully explained by age since the Uppsala PIVUS cohort, with the highest % loss of Y, appears to all be 70. This calls into question the reliability of their measure, and makes me wonder how the statistical models might be influenced when using the merged data. Autosomal (non-X/Y chromosomes) should have also been examined, since this would potentially hint at a mechanism.

“Another puzzling aspect of this study is their finding that loss of Y chromosome increases the risk of cancer and Alzheimer’s disease. Generally, either no association or the inverse has been described in other cohorts. A more comprehensive treatment of quality control would have been helpful, too, since it was not clear how they removed mixed samples or ensured phenotypic-genetic sex agreement, but that’s a minor concern.”

 

Declared interests (see GENeS register of interests policy):

No interests declared.

 

Reference:

Mosaic loss of chromosome Y in blood is associated with Alzheimer’s disease‘ by Dumanski et al., published in the American Journal of Human Genetics on Monday, May 23, 2016

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