Clinical OMICS

SEP-OCT 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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www.clinicalomics.com September/October 2018 Clinical OMICs 31 a major risk factor for stroke and heart failure, AF contrib- utes to roughly 130,000 deaths every year in the U.S. and represents an increasingly significant healthcare burden as the global population ages. "More than a quarter of people over the age of 80 years suffer from atrial fibrillation, but treatments are limited, and we don't really understand the biological or genetic basis of the condition," Willer acknowl- edged. Current treatments for AF include drugs that can either help to control the heart's rhythm, or that reduce the risk of stroke. In some cases surgical procedures can block the abnormal electrical signals that cause the upper cham- bers of the heart to beat irregularly. "Atrial fibrillation is a complex disorder, and there isn't a single causative genetic fac- tor," Willer continued. "While the risk of AF in any one individual may be increased by environmental factors such as heart surgery, it's generally believed that there could be hundreds or even thousands of genetic variants that impact on AF risk." And although each of these may only have a very small stand- alone effect on risk, "… carrying many of these variants in combination has an additive effect that can increase your overall risk of AF significantly." Developing an AF Risk Score Large biobanks containing tissue samples and data on the health, lifestyle, and demographics of many thousands of healthy people and individuals with different diseases have made it possible to study how genetic variation across our genomes impacts on health and disease. "Being able to tap into these large biobanks means that we can now study sample sizes that are big enough to identify genetic risk fac- tors for complex disorders such as AF," Willer commented. "GWAS is a very powerful approach for finding common variants that exert very small individual effects on disease risk. But when we started this study two years ago there had been relatively few GWAS focused on AF." For their study, the UM team and colleagues in the U.S., Denmark, Norway, Iceland, Spain, and Japan drew on data from six different large-scale biobanks in the U.K, U.S., and Scandinavia: UM's Michigan Genomics Initiative (MGI), UK Biobank, Norway's HUNT study, DiscovEHR, Iceland's deCODE Genetics, and AFGen Consortium. They tested 34,740,186 individual genetic variants for an association with AF, by comparing the prevalence of each variant in 60,620 individuals with AF and 970,216 healthy controls. Analyzing the results identified 142 independent genetic risk variants sited within 111 different regions of the genome—80 of which had not previously been associated with AF—and linked 151 functional genes directly with an increased risk for AF. The researchers then applied mathematical tools to con- struct a polygenic risk score that could predict an indi- vidual's risk of AF, dependent upon which of the genetic variants they carried. "The risk score takes into account an aggregation of all the genetic variants," Willer told Clinical OMICs. "The higher the score, the greater the predicted risk of AF." When the research- ers tested the score on the UK Biobank data, they found that it was highly predictive, but also very specific for AF. Interest- ingly, the results showed that individuals who developed AF at a younger age were more likely to have a greater number of the genetic variants than those who developed AF later in life. AF Variants Implicated in Other Heart Conditions Many of the identified protein-coding genes were likely involved in cardiac muscle structure and function, ion channel function and calcium signalling, and hormone sig- nalling. "This is what we expected," Willer commented. Other genetic risk variants were also close to genes in which mutations are already known to cause serious heart problems in humans. More unexpectedly, a number of the genetic variants are related to genes that are involved in fetal heart devel- opment, but which are normally switched off in the adult heart. "For example, there was a strong associ- ation between AF and the gene for fetal myosin heavy chain," Willer said. Myosin heavy chain is (continued on next page) "GWAS is a very powerful approach for finding common variants that exert very small individual effects on disease risk." —Cristen Willer, Ph.D., University of Michigan seksan Mongkhonkhamsao / Getty Images

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