26 May 2016

The runt of the chromosome litter may have more to its bite than simply determining male sex. According to a study published June 2 in The American Journal of Human Genetics, loss of the Y chromosome in a fraction of blood cells drove up men’s risk of Alzheimer’s disease nearly sevenfold. If confirmed, the finding would make mosaic loss of Y (LOY)—a phenomenon that occurs in about 15 percent of men by age 70—a stronger risk factor for AD than having a single copy of ApoE4. Led by Jan Dumanski and Lars Forsberg at Uppsala University in Sweden, the researchers proposed that the dysfunction of Y-less immune cells could underpin the elevated AD risk. They also hinted that Y’s age-related ouster, which is linked to cancer as well as AD, could be the culprit behind a shorter male lifespan.

“This study is incredibly well-performed,” commented Terrence Town of the University of Southern California in Los Angeles, who favors the dysfunctional immune cell hypothesis. “Support for the idea that peripheral immune cells play a role in AD has come from a rather surprising place.” Other commentators stressed the importance of replicating the association in other cohorts before jumping to conclusions.

Researchers first observed frequent expulsion of the Y chromosome in the blood of aging men more than 50 years ago. However, only recently have studies suggested that losing the diminutive chromosome—long considered a genetic wasteland—in a subset of cells could have real consequences. Dumanski and colleagues linked LOY in blood cells to shorter lifespan and to non-hematopoietic cancers (see Forsberg et al., 2014). Another report ranked LOY above age as a predictor of colorectal and prostate cancer (see Noveski et al., 2016). However, a study led by Stephen Chanock at the National Institutes of Health in Bethesda, Maryland, reported little to no association between LOY and some cancers (see Zhou et al., 2016). Why LOY happens is unknown, but researchers suspect a combination of health and environmental factors are to blame. Dumanski’s group recently reported an association between smoking and LOY (see Dumanski et al., 2015).

Given its link with cancer, Dumanski and colleagues wondered whether LOY in white blood cells, which are predominantly immune cells, influences other aging disorders thought to have an immune component, such as AD. The researchers looked for an association in three cohorts: the European Alzheimer’s Disease Initiative (EADI1), a sampling of seniors from three French cities that began in 1999; the Uppsala Longitudinal Study of Adult Men (ULSAM), which started tracking 50-year-old men in the early 1970s; and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), which began enrolling 70-year-old people in 2001. Altogether, the researchers analyzed blood samples from more than 3,200 participants. They used single-nucleotide polymorphism (SNP) arrays to calculate the level of Y chromosome loss, and validated these findings with whole-genome sequencing in a subset of samples.

They detected Y chromosome loss from blood in 17 percent of all participants. The incidence of LOY and fraction of cells with LOY increased with age. The incidence of LOY among men with AD was nearly three times that in their age-matched healthy peers, and it occurred in a larger fraction of blood cells. Because two of the cohorts (ULSAM and PIVAS) included prospective analyses, the researchers were able to determine whether LOY predicted subsequent AD. In this analysis, LOY carried a 6.8-fold higher risk of AD over an average of about eight years follow-up, even after controlling for confounding variables such as age at sampling, ApoE4 status, smoking, and body-mass index.

AD risk was also correlated with the fraction of blood cells with LOY: men with LOY in 35 percent of their blood cells had a higher AD risk than men with 10 percent LOY. The researchers found that even when considering only men within a narrow age window, LOY still strongly associated with AD. Thus, LOY is not a mere marker of aging, but influences the risk of AD independently, they concluded.

How might LOY lead to AD? Dumanski speculated that loss of genes on the Y chromosome could render immune cells dysfunctional, which would then hinder processes involved in staving off AD, such as the efficient clearance of misfolded proteins or of unhealthy cells in the brain. His lab will investigate which immune cell types are most vulnerable to LOY, and also hunt for potentially relevant immune-related genes on the Y chromosome. None of the published genome-wide association studies tested the sex chromosomes.

Alternatively, LOY in peripheral immune cells could simply reflect genomic instability occurring elsewhere in the body, including the brain, Dumanski said. In that case, it could at least serve as a biomarker. These ideas are not mutually exclusive, as a dysfunctional immune system would exacerbate any ill effects of genomic instability in the brain, he added. Indeed, researchers have reported genomic rearrangements and duplications in neurons of people with AD (see Jul 2015 news). 

Replication of this association in other prospective cohorts is critical, commented Chanock. “This study is an important first step, but further work is needed to confirm it, determine its actual strength, and investigate its basis,” he said.

Sometimes the strength of an association can wane as more data emerges—this so-called “winner’s curse” dogged the AD risk factor TREM2, which lost some luster as more studies were published (see Oct 2013 news). However, Carlos Cruchaga of Washington University in St. Louis said the study was well-performed, and that the ultimate strength of the association was not the most important factor. “As long as the association is real, it will help us understand the biology of the disease.”

Where do women fit into this picture? Town speculated that perhaps women have a higher incidence of AD than men because they lack a protective factor on the Y chromosome. In turn, “loss of the Y chromosome makes a man more like a woman (genetically speaking), and this could raise AD risk in men,” he said.

The findings, at the very least, will stimulate researchers to take a second glance at the pesky Y chromosome.—Jessica Shugart

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References

News Citations

1. Could Genetic Mosaicism in Adult Neurons Precipitate Disease? 15 Jul 2015
2. Fall Flurry of Letters Kicks Up Dust Around TREM2 18 Oct 2013

Paper Citations

1. Forsberg LA, Rasi C, Malmqvist N, Davies H, Pasupulati S, Pakalapati G, Sandgren J, Diaz de Ståhl T, Zaghlool A, Giedraitis V, Lannfelt L, Score J, Cross NC, Absher D, Janson ET, Lindgren CM, Morris AP, Ingelsson E, Lind L, Dumanski JP. Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat Genet. 2014 Jun;46(6):624-8. Epub 2014 Apr 28 PubMed.
2. Noveski P, Madjunkova S, Sukarova Stefanovska E, Matevska Geshkovska N, Kuzmanovska M, Dimovski A, Plaseska-Karanfilska D. Loss of Y Chromosome in Peripheral Blood of Colorectal and Prostate Cancer Patients. PLoS One. 2016;11(1):e0146264. Epub 2016 Jan 8 PubMed.
3. Zhou W, Machiela MJ, Freedman ND, Rothman N, Malats N, Dagnall C, Caporaso N, Teras LT, Gaudet MM, Gapstur SM, Stevens VL, Jacobs KB, Sampson J, Albanes D, Weinstein S, Virtamo J, Berndt S, Hoover RN, Black A, Silverman D, Figueroa J, Garcia-Closas M, Real FX, Earl J, Marenne G, Rodriguez-Santiago B, Karagas M, Johnson A, Schwenn M, Wu X, Gu J, Ye Y, Hutchinson A, Tucker M, Perez-Jurado LA, Dean M, Yeager M, Chanock SJ. Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nat Genet. 2016 May;48(5):563-8. Epub 2016 Apr 11 PubMed.
4. Dumanski JP, Rasi C, Lönn M, Davies H, Ingelsson M, Giedraitis V, Lannfelt L, Magnusson PK, Lindgren CM, Morris AP, Cesarini D, Johannesson M, Tiensuu Janson E, Lind L, Pedersen NL, Ingelsson E, Forsberg LA. Mutagenesis. Smoking is associated with mosaic loss of chromosome Y. Science. 2015 Jan 2;347(6217):81-3. Epub 2014 Dec 4 PubMed.

Further Reading

Papers

1. Forsberg LA, Absher D, Dumanski JP. Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime. J Med Genet. 2013 Jan;50(1):1-10. Epub 2012 Nov 21 PubMed.