Whole-exome sequencing analyses in a Saudi Ischemic Stroke Cohort reveal association signals, and shows polygenic risk scores are related to Modified Rankin Scale Risk.

Autor: Alkhamis FA; Department of Neurology, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia., Alabdali MM; Department of Neurology, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia., Alsulaiman AA; Department of Neurology, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia., Alamri AS; Department of Neurology, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia., Alali R; Department of Internal Medicine, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia., Akhtar MS; Department of Clinical Biochemistry, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia., Alsalman SA; Department of Neurology, King Fahd Hospital, Alhafof, Saudi Arabia., Cyrus C; Department of Clinical Biochemistry, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia., Albakr AI; Department of Neurology, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia., Alduhalan AS; Department of Neurology, King Fahd Hospital of The University, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia., Gandla D; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, 19104, USA., Al-Romaih K; Centre for Genomic Medicine, KFSH&RC, Riyadh, 11211, Saudi Arabia., Abouelhoda M; Centre for Genomic Medicine, KFSH&RC, Riyadh, 11211, Saudi Arabia., Loza BL; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, 19104, USA., Keating B; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA, 19104, USA., Al-Ali AK; Department of Clinical Biochemistry, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, 31441, Saudi Arabia. aalali@iau.edu.sa.
Jazyk: angličtina
Zdroj: Functional & integrative genomics [Funct Integr Genomics] 2023 Mar 27; Vol. 23 (2), pp. 102. Date of Electronic Publication: 2023 Mar 27.
DOI: 10.1007/s10142-023-01039-7
Abstrakt: Ischemic stroke represents a significant societal burden across the globe. Rare high penetrant monogenic variants and less pathogenic common single nucleotide polymorphisms (SNPs) have been described as being associated with risk of diseases. Genetic studies in Saudi Arabian patients offer a greater opportunity to detect rare high penetrant mutations enriched in these consanguineous populations. We performed whole exome sequencing on 387 ischemic stroke subjects from Saudi Arabian hospital networks with up to 20,230 controls from the Saudi Human Genome Project and performed gene burden analyses of variants in 177 a priori loci derived from knowledge-driven curation of monogenic and genome-wide association studies of stroke. Using gene-burden analyses, we observed significant associations in numerous loci under autosomal dominant and/or recessive modelling. Stroke subjects with modified Rankin Scale (mRSs) above 3 were found to carry greater cumulative polygenic risk score (PRS) from rare variants in stroke genes (standardized PRS mean > 0) compared to the population average (standardized PRS mean = 0). However, patients with mRS of 3 or lower had lower cumulative genetic risk from rare variants in stroke genes (OR (95%CI) = 1.79 (1.29-2.49), p = 0.0005), with the means of standardized PRS at or lower than 0. In conclusion, gene burden testing in Saudi stroke populations reveals a number of statistically significant signals under different disease inheritance models. However, interestingly, stroke subjects with mRS of 3 or lower had lower cumulative genetic risk from rare variants in stroke genes and therefore, determining the potential mRS cutoffs to use for clinical significance may allow risk stratification of this population.
(© 2023. The Author(s).)
Databáze: MEDLINE
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