Modification effect of polygenic risk scores on the risk of the most common multimorbidity associated with aging among Canadian adults: An analysis of the CLSA data

OBJECTIVE: We investigated the modification effects of polygenic risk score (PRS) on the risk of the most common multimorbidity (MCM) in Canadian adults associated with aging. METHODS: We utilized baseline and genomic datasets of 26,622 adults aged 45-85 years from the Canadian Longitudinal Study on Aging. Genome-wide interaction analyses and multivariate logistic regression models were used to identify susceptible markers and examine the PRS-by-age interactions. Susceptible markers with an interaction term p-value <10⁻⁵ were used to compute the PRS for each individual, which was further divided into three PRS groups (high, median, and low) by the PRS terciles. Multivariate logistic regression models were used to examine the PRS-by-age interaction, adjusting for potential confounders and population structure. RESULTS: Multivariate analysis showed that increasing age was significantly associated with a higher risk of MCM, regardless of the PRS group. However, individuals in the top one-third of the PRS tercile (i.e., the high PRS group) were at the highest risk of MCM. For a one-year increase in age, participants in the high PRS group were 1.13 times more likely to have MCM, whereas for a one-year increase in age, it was associated with 1.09- and 1.10-times increased risk of MCM among individuals in the median and low PRS groups, respectively. CONCLUSION: PRS is an important tool for identifying individuals at a higher risk of MCM associated with aging and improves our understanding of the potential biological mechanisms of aging-related diseases.