Letter by Zheng Regarding Article, "Genome-Wide Polygenic Score and the Risk of Ischemic Stroke in a Prospective Cohort: the Hisayama Study".

To the Editor: I read with great interest the article by Hachiya et al1 published in Stroke recently. Hachiya et al aimed to investigate the relationship between a genome-wide polygenic risk score and the development of ischemic stroke in a population-based prospective cohort study including 3038 Japanese subjects aged ≥40 years. The study showed that high polygenic risk score levels were associated with increased risk of ischemic stroke after adjusting for age and sex (P for trend, 0.03). A similar association was observed after adjusting for environmental risk factors (P for trend, 0.03). The authors concluded that a high polygenic risk score was a significant risk factor for ischemic stroke independent of environmental risk factors. They suggested that polygenic risk score may be useful to identify individuals at a high risk of ischemic stroke. I think that the analyses are inadequate to support the conclusions. Current genome-wide association studies regarding stroke did not exclude subjects concurrent with traditional risk factors. Therefore, the observed associations between stroke and some genetic variants may not be a direct association. For some variants, the observed associations with stroke may be caused or at least partially caused by other traditional factors such as hypertension. The largest genetic study regarding stroke showed that 17 of the 32 stroke-lead variants showed overlap with risk factors such as hypertension.2 In addition, weighted genetic risk scores using the stroke-lead variants were also associated with these factors.2 In the present study, polygenic risk score using large amounts of variants was also associated with several traditional risk factors such as hypertension. Therefore, the use of multivariable analysis is improper because there are inherent relationships (ie, collinearity in statistics) between the polygenic risk score and traditional risk factors. The statement that the association is independent of environmental risk factors is improper. More importantly, the most important question is not whether the polygenic risk score is associated with the development of ischemic stroke but whether the addition of the score to conventional risk factors can improve risk prediction. Two articles recently published in the Journal of the American Medical Association all showed that polygenic risk score was significantly associated with the development of coronary artery disease in middleaged populations.3,4 However, addition of the polygenic risk score to conventional risk factors did not associate with clinically relevant improvement in coronary artery disease risk assessment.3,4 One important reason may be that part of the effect of the current polygenic risk score was already accounted for by conventional risk factors because these conventional risk factors were also partially inheritable. On the other hand, new predictors are less likely to substantially improve model discrimination if the odds ratios of the new predictors are modest (eg, comparable with conventional risk factors) or if the baseline models are well calibrated or optimally defined.3 The study by Hachiya et al showed that the odds ratio of the polygenic risk score is comparable with conventional risk factors. In conclusion, the statement that the association is independent of environmental risk factors is improper. Furthermore, I recommend the authors to perform more analyses (eg, model discrimination, calibration, and net reclassification improvement) to assess whether (and how much) the addition of the polygenic risk score to conventional risk factors can improve risk prediction.