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BACKGROUND: Ischemic stroke (IS) is a highly heritable trait, and genome-wide association studies have identified several commonly occurring susceptibility risk loci for this condition. However, there are limited data on the contribution of rare genetic variation to IS. METHODS: We conducted an exome-wide study using whole-exome sequencing data from 152 058 UK Biobank participants, including 1777 IS cases. We performed single-variant analyses for rare variants and gene-based analyses for loss-of-function and deleterious missense rare variants. We validated these results through (1) gene-based testing using summary statistics from MEGASTROKE—a genome-wide association study of IS that included 67 162 IS cases and 454 450 controls, (2) gene-based testing using individual-level data from 1706 IS survivors, including 142 recurrent IS cases, enrolled in the VISP trial (Vitamin Intervention for Stroke Prevention); and (3) gene-based testing against neuroimaging phenotypes related to cerebrovascular disease using summary-level data from 42 310 UK Biobank participants with available magnetic resonance imaging data. RESULTS: In single-variant association analyses, none of the evaluated variants were associated with IS at genome-wide significance levels ( P <5×10 −8 ). In the gene-based analysis focused on loss-of-function and deleterious missense variants, rare genetic variation at CYP2R1 was significantly associated with IS risk ( P =2.6×10 −6 ), exceeding the Bonferroni-corrected threshold for 16 074 tests ( P <3.1×10 −6 ). Validations analyses indicated that CYP2R1 was associated with IS risk in MEGASTROKE (gene-based test, P =0.003), with IS recurrence in the VISP trial (gene-based test, P =0.001) and with neuroimaging traits (white matter hyperintensity, mean diffusivity, and fractional anisotropy) in the UK Biobank neuroimaging study (all gene-based tests, P <0.05). CONCLUSIONS: Because CYP2R1 plays an important role in vitamin D metabolism and existing observational evidence suggests an association between vitamin D levels and cerebrovascular disease, our results support a role of this pathway in the occurrence of IS.

Background and Objectives:Blood pressure (BP) is often not at goal in stroke survivors, leaving individuals vulnerable to additional vascular events. Given that BP is a highly heritable trait, we hypothesize that a higher polygenic susceptibility to hypertension (PSH) leads to worse BP control in stroke survivors.Methods:We conducted a study within the UK Biobank evaluating persons of European ancestry who survived an ischemic or hemorrhagic stroke. To model the PSH, we created polygenic scores (PRS) for systolic and diastolic BP using 732 genetic variants. We divided the PRSs into quintiles and used linear/logistic regression to test whether higher PSH led to higher observed BP, uncontrolled BP (systolic BP >140 mmHg or diastolic BP >90 mmHg) and resistant BP (uncontrolled BP despite being on >=3 antihypertensive drugs). We conducted an independent replication using data from the Vitamin Intervention for Stroke Prevention (VISP) trial.Results:We analyzed 5,940 stroke survivors. When comparing stroke survivors with very low versus very high PSH, the mean systolic BP was 137 (SD 18) versus 143 (SD 20, p<0.001), the mean diastolic BP was 81 (SD 10) versus 84 (SD 11, p<0001), the prevalence of uncontrolled BP was 42.8% versus 57.2% (p<0.001), and the prevalence of resistant hypertension was 3.9% versus 11% (p<0.001). Results remained significant using multivariable models (p<0.001) and were replicated in the VISP study (all tests with p<0.05).Discussion:A higher PSH is associated with worse BP control in stroke survivors. These findings point to genetic predisposition as an important determinant of poorly controlled BP in this population.

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Background: Self-reported outcomes in stroke survivors remain understudied. Mounting evidence indicate that the burden of stroke is disproportionately high in underrepresented groups. We investigated differences in self-perceived health status in stroke survivors across broadly defined underrepresented minorities. Methods: We analyzed data from stroke survivors enrolled in All of Us. Ischemic and hemorrhagic stroke were defined using validated ICD10 codes. Self-perceived health status was evaluated using 5 domains (quality of life, physical health, mental health, social activities and overall health), each with 5 answers (excellent, very good, good, fair and poor). Each domain was dichotomized as favorable (excellent, very good or good) or unfavorable (fair/poor). We used multivariate logistic regression to model the odds of favorable self-perceived health status in underrepresented groups defined by race/ethnicity, education, income and insurance type. Results: 6,977 stroke survivors were included (mean age 64, female sex 58%), including 1,623 (23.3%) Blacks, 856 (12.3%) Hispanics/Latinos, 654 (9.4%) with less than a high school degree, 2,679 (38.4%) with income <U$S 35k, 3,091 (44.3%) with Medicare/Medicaid and 13 (0.18%) uninsured. A number of underrepresented groups had significantly different self-perceived health status after stroke (Table): low income, limited education and Medicare/Medicaid insurance were associated with self-perceived unfavorable health status in all 5 domains (all results with 95%CI <1). Conclusion: Among stroke survivors, underrepresented groups defined by income, education and health insurance were more likely to perceive their health status as unfavorable. Evaluation of underrepresented groups defined by factors other than race/ethnicity was important to identify these differences. Further research should evaluate whether these differences correlate with objectively measured outcome measures.