BYU research: Rare gene variants double Alzheimer's risk


BYU researchers have co-authored the publication of 22 new Alzheimer’s disease risk gene studies since 2009. Recently a team of BYU researchers identified gene variations that double a person’s risk of developing Alzheimer’s disease later in life.

Their research, led by Washington University School of Medicine at St. Louis, Mo., was published online Dec. 11, 2013, in the scientific journal Nature. Biology professors John Kauwe and Perry Ridge along with BYU post-baccalaureate Maegan Leary are BYU authors on the study. Co-author Cameron Schmutz is the sole undergraduate author.

“If you had the risky version of every Alzheimer’s gene that we discovered between 2009 and 2011, it would increase your chances for the disease by about 15 percent,” said Dr. Kauwe, who has been involved in the discovery of several common genetic variants linked to Alzheimer’s. “But if you have this single change in your DNA, it doubles your risk.”

Cameron Schmutz works with Dr. John Kauwe and fellow students Josue Gonzalez and Caitlin Munger on Alzheimer's research.
Cameron Schmutz works with Dr. John Kauwe and fellow students Josue Gonzalez and Caitlin Munger on Alzheimer's research. Photo: BYU

Using a clever approach for identifying rare mutations, the investigators focused on families with several members who had Alzheimer’s. The team sequenced genes from several individuals in 14 families, some of which had Alzheimer’s and some who did not.

Comparing DNA from affected people in a family to those in the same family without the disorder, the team eventually identified variations in a gene (PLD3) that showed up in affected family members. Researchers then studied another 11,000 people with and without the disease and found PLD3 gene variants doubled the risk for Alzheimer’s disease.

Although the newly identified gene variations occur rarely, making them difficult for researchers to identify, they represent a substantially increased Alzheimer’s risk for those who carry them.

Alison Goate, a co-author from Washington University, said, “The approach we’ve taken is just as important as the discovery that this gene is involved in Alzheimer’s. By studying gene variants within families, we were able to narrow down the number of variants that might cause disease. If we had been using unrelated individuals, we would not have had the statistical power to find these rare variants.”

Another aspect of this study was the participation of an undergraduate. BYU undergraduates are often co-authors, and even first authors on papers published from the BYU lab. “I feel very lucky that I was able to participate in something that has such a large influence on the scientific community,” said Cameron Schmutz, who plans to attend medical school. “I’m grateful BYU was able to give me the opportunity to have this unique experience.”

To complete the study, researchers used a process called whole exome sequencing to identify mutations in a gene never before linked to Alzheimer’s disease then used other technologies to sequence those variants in additional samples. Much of that additional sequencing took place on BYU’s campus, where he tested and analyzed more than 5,000 DNA samples.

Whole exome sequencing refers to the determination of the actual DNA sequence for all regions of a person’s DNA that are known to code for the production of proteins. This represents about 30 million base pairs of DNA. While still just one percent of all DNA in a human cell, it is substantially more than has been evaluated in the past and allows researchers to examine genetic variants that could not be examined with earlier technologies.

“This progress has been very rapid and bodes well for the future fight against this disease,” said Dr. Kauwe. “While new genes do not immediately mean new cures, they provide the foundation of knowledge upon which effective prevention and cures can be built. Each new gene provides us with new insights into therapeutic approaches that might work. Scientists around the world are excited to see these new discoveries and try to develop better drugs using that information.”

Finding mutations linked to Alzheimer’s disease means it might be possible one day to identify people at risk many years before they develop symptoms. It’s hoped that in the future, patients could be monitored for early signs of Alzheimer’s and possibly get treatments to slow the disease’s progress.

“Despite the incredible advances in technology, it is still the thoughtful and creative insights of individual scientists that drive the real progress,” said Dr. Kauwe. “Our collaborative group is not the biggest or the most powerful, but we have discovered two genes with large effects on Alzheimer’s disease in the last two years. We work hard, respect each other’s ideas and share resources to do innovative and effective science. It is fun to know that is what works and to represent BYU as part of this collaboration.”

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