| Title: | Whole-Exome Sequencing Analyses Support a Role of Vitamin D Metabolism in Ischemic Stroke |
| Journal: | Stroke |
| Published: | 10 Feb 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36762557/ |
| DOI: | https://doi.org/10.1161/strokeaha.122.040883 |
| URL: | https://doi.org/10.1101/2022.05.31.22275825 |
Publication 11070
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
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.</p>
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.</p>
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).</p>
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.</p>
8 Authors
- Yuhan Xie
- Julián N. Acosta
- Yixuan Ye
- Zachariah S. Demarais
- Carolyn J. Conlon
- Ming Chen
- Hongyu Zhao
- Guido J. Falcone
1 Application
| Application ID | Title |
|---|---|
| 29900 | Defining physical activity phenotypes based on objective measures and dissecting the genetic and phenotypic relationships of physical activity with diseases and health outcomes |
Enabling scientific discoveries that improve human health