A Family and a Genome-Wide Polygenic Risk Score Are Independently Associated With Stroke in a Population-Based Study

Abstract

BACKGROUND: Positive family history and genetic risk scores have been shown to independently capture those individuals with high risk for stroke. The aim of our study was to evaluate the amount of shared information between family history and genetic risk and to investigate their combined effect on the association with prevalent and incident stroke cases. METHODS: We obtained a family risk score (FamRS), weighted for disease onset and family size as well as genome-wide polygenic risk score (PGS) including over 3.2 million single-nucleotide polymorphisms in the population-based prospective KORA F3 (Cooperative Health Research in the Region of Augsburg) study (n=3071) from Southern Germany. FamRS and PGS were evaluated separately and combined. The measures were once treated as continuous variables but also divided in the highest 20%, 10%, 5%, and 1% percentiles. Odds ratios via logistic regression and hazard ratios via Cox regression were estimated. A stroke event was defined as a hospitalization for stroke that was self-reported in a standardized interview by certified and supervised personnel. RESULTS: The FamRS outperformed other simplified family measures such as affected parents or number of affected family members. FamRS and PGS were not correlated, and no individuals were observed with both very high FamRS and very high PGS (top 1% percentile). In a combined model, both FamRS and PGS were independently from each other associated with risk of stroke, also independent of other traditional risk factors (p [FamRS]=0.02, p [PGS]=0.005). Individuals in the top 1% of either FamRS or PGS were found to have >5-fold risk for stroke (odds ratios, 5.82 [95% CI, 2.08–14]; P =0.0002). The results for incident stroke events showed the same trend but were not significant. CONCLUSIONS: Our study shows that a family risk score and PGS capture different information concerning individual stroke risk. Combining the risk measures FamRS and PGS increases predictive power, as demonstrated in a population-based study.

Clinical Course, Therapy, and Long-Term Outcomes of Children With Moyamoya Disease and Posterior Cerebral Artery Involvement

“…Patients with a family history of MMD tend to have more severe conditions and faster progression, 29,30 and it was a predictor associated with delayed-onset PCAi herein. Thus, genetic factors play an essential role in PCAi.…”

Family history of stroke – a useful clue for the primary care physician and stroke neurologist: a narrative review

“…Recently, Hammerle et al . [ 144 ] introduced a “family risk score”, which is based on information about family history of stroke weighted for disease onset and number of relatives. They demonstrated that it outperformed simple measures and was associated with increased risk of stroke independently from other risk factors or risk scores based on single-nucleotide polymorphisms (so-called “polygenic risk scores” [ 145 , 146 ]).…”

Association of Family History and Polygenic Risk Score With Longitudinal Prognosis in Parkinson Disease

“…As shown in our study, the clinical usability of family history and PRS are independent of each other, and this pattern has been reported in other diseases, such as diabetes and stroke. 45 , 46 Thus, further development of a combined model to account for both family history and PRS could be useful in explaining the clinical heterogeneity of PD. 47 …”