Summary: According to researchers, men with the highest fraction of blood cells without the Y chromosome were more likely to be diagnosed with Alzheimer’s disease.
Source: Cell Press.
The loss of the Y chromosome in batches of blood cells over time continues to develop as one biological explanation for why men, on average, live shorter lives than women.
Researchers reporting May 23, 2016 in the American Journal of Human Genetics found that men with blood samples showing loss of chromosome Y developed Alzheimer’s as often as people born with genes that put them at the most risk for the disease. The work will be presented at the annual conference of the European Society of Human Genetics.
“Most genetic research today is focused on inherited gene variants — mutations that are inherited by the offspring, but what we’re looking at are postzygotic mutations that are acquired during life,” says senior author Lars Forsberg, a researcher in the Department of Immunology, Genetics, and Pathology at Uppsala University in Sweden. “Using new tools to analyze genetic variations that accumulate with age, we can help explain how sporadic diseases like cancer or Alzheimer’s manifest,” says first author Jan Dumanski.
One such postzygotic mutation found in the cells of biological males is the loss of the Y chromosomein a degree of blood cells. Loss of Y occurs in up to 17 percent of men and is more likely to be found in older men and men who smoke. This study expands on the idea that loss of Y, already a known risk factor for cancer (10.1038/ng.2966), could be a predictive biomarker for a wider range of poor health outcomes, specifically Alzheimer’s. Why loss of Y can be linked to an increased risk for disease remains unclear, but the authors speculate it has to do with reduced immune system performance.
The researchers looked at over 3,000 men to ascertain whether there was any predictive association between loss of Y in blood cells and Alzheimer’s disease. The participants came from three long-term studies that could provide regular blood samples: the European Alzheimer’s Disease Initiative, the Uppsala Longitudinal Study of Adult Men, and the Prospective Investigation of the Vasculature in Uppsala Seniors. Across the datasets, those with the highest fraction of blood cells without a Y chromosome were consistently more likely to be diagnosed with Alzheimer’s.
“Having loss of Y is not 100 percent predictive that you will have either cancer or Alzheimer’s,” Forsberg says, adding that there were men in the study who had the mutation and lived with no symptoms well into their 90s. “But in the future, loss of Y in blood cells can become a new biomarker for disease risk and perhCell Press evaluation can make a difference in detecting and treating problems early.”
Forsberg, Dumanski, and colleagues will next investigate the effect of loss of Y in larger cohorts and explore in greater detail how it confers risk for specific types of cancers and disease. They also plan to look at the cellular changes caused by loss of Y and how it affects different types of blood cells.
Funding: The study was primarily funded by the Olle Enqvist Byggmästare Foundation, the European Research Council, the Swedish Cancer Society, the Swedish Research Council, the Swedish Heart-Lung Foundation, and Sci-Life-Lab-Uppsala
Source: Joseph Caputo – Cell Press
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease” by Jan P. Dumanski, Jean-Charles Lambert, Chiara Rasi, Vilmantas Giedraitis, Hanna Davies, Benjamin Grenier-Boley, Cecilia M. Lindgren, Dominique Campion, Carole Dufouil, The European Alzheimer’s Disease Initiative Investigators, Florence Pasquier, Philippe Amouyel, Lars Lannfelt, Martin Ingelsson, Lena Kilander, Lars Lind, and Lars A. Forsberg in American Journal of Human Genetics. Published online May 20 2016 doi:10.1016/j.ajhg.2016.05.014
Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease
Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16–21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females.
“Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease” by Jan P. Dumanski, Jean-Charles Lambert, Chiara Rasi, Vilmantas Giedraitis, Hanna Davies, Benjamin Grenier-Boley, Cecilia M. Lindgren, Dominique Campion, Carole Dufouil, The European Alzheimer’s Disease Initiative Investigators, Florence Pasquier, Philippe Amouyel, Lars Lannfelt, Martin Ingelsson, Lena Kilander, Lars Lind, and Lars A. Forsberg in American Journal of Human Genetics. Published online May 20 2016 doi:10.1016/j.ajhg.2016.05.014