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Risk Related to Genetic Contributors Can Decline With Age for Some Common Diseases

NEW YORK – Inherited genetic factors linked to some common conditions may have more significant ties to disease risk in younger individuals, while contributing less significantly to disease in those who have managed to reach more advanced ages without developing disease, according to research from the University of Oxford and the Alan Turing Institute.

"Our work was prompted by the growing interest in the use of inherited genetic risk to identify individuals who may go on to develop common diseases ranging from heart disease to cancers," corresponding author Gil McVean, a statistical genetics researcher at the University of Oxford Li Ka Shing Centre for Health Information and Discovery's Big Data Institute, explained in an email.

Following from past research hinting that genetic factors may not confer consistent risk across the human lifespan, the researchers started by using a newly developed computational strategy to analyze genotyping data for almost 409,700 UK Biobank participants of European ancestry, cataloguing the relative risk of disease conferred by variants implicated in two dozen common conditions over time in the large cohort.

After testing their analytical strategy, the team went on to expand those analyses to include studying individuals enrolled in the UK Biobank from other ancestry groups. The findings, published in PLOS Genetics on Thursday, suggested that the relative risk associated with genetic susceptibility for some conditions may wane with age, meaning those who have managed to remain free of such conditions into advanced age may be more likely to stay that way than their younger counterparts carrying similar genetic risk factors.

"[W]e introduce, validate, and apply new statistical methods for investigating the relationship between age and the contributions of genetic risk," the authors explained. "These methods allow us to ask questions such as whether relative risk is constant over time, precisely how relative risk changes over time and whether all genetic risk factors have similar age profiles."

Though the extent of the pattern varied depending on the genetic contributors and disease considered, the investigators noted, the genetic effects tended to dip with age for conditions in which genetic contributions were not consistent with age, including skin cancer, hypertension, atherosclerotic heart disease, and several other common diseases.

"Our results definitely have implications for the use of genetics within the clinic to identify individuals at risk," explained McVean, who is cofounder of the company Genomics PLC, noting that the study "shows that the context of age plays an important role in determining how one should interpret genetic risk."

That, in turn, suggests that there are conditions for which screening, management, or interventions are more beneficial for younger individuals carrying variants implicated in the disease. On the other hand, individuals with the similar disease-related variants who are free from the condition into old age may benefit from additional genetic or lifestyle protection, though additional research is needed to untangle the roots of the diminished genetic risk for certain conditions.

"[F]or many of the most common diseases, age is important," McVean said. "Specifically, among those unfortunate enough to get a disease early in life, their genetic risk was a really important factor. In contrast, for people who get the same disease much later in life, genetics is a much less important part of the explanation."