Dissecting Polygenic Etiology of Ischemic Stroke in the Era of Precision Medicine
Abstract
:1. Polygenic Nature of Ischemic Stroke
1.1. Pioneer Studies on Monogenetic Disease
1.2. Genome-Wide Association Studies (GWAS)
1.3. Polygenic Risk Score (PRS) Construction
1.4. Low-Frequency Variants Explain More Phenotypic Variation
2. Polygenic Risk for Cardiovascular Disease May Also Contribute to the Risk for Sporadic IS
2.1. Candidate Gene Approach
2.2. Genetic Correlation between Cardiometabolic Risk Factors and IS
2.3. Mendelian Randomization for Causal Inference
3. Polygenic Risk Scores (PRSs) Augment IS Subtyping
4. Genetic Basis of Cardioembolic Stroke
5. Genetic Basis of Sporadic Cerebral Small Vessel Disease (CSVD)
5.1. Heritability of CSVD
5.2. Genetic Variants from Extracellular Matrix (ECM) Genes May Contribute to the Risk for Sporadic CSVD
5.3. Genes Associated with Blood–Brain Barrier (BBB) Integrity May Contribute to the Risk for CSVD
5.4. Genetic Basis of Sporadic Cerebral Amyloid Angiopathy
6. Pathway-Specific PRS Analysis for IS
6.1. Pathway-Specific PRS Construction
6.2. A Modified Paradigm of IS Risk Stratification beyond TOAST Subtyping
7. Pathway-Specific PRS Analysis of Post-IS Mortality
7.1. Pathway-Specific PRSs Augment Etiologic Subtyping of IS and Outcome Prediction
7.2. Improved Predictability of Pathway-Specific PRS for Post-IS Mortality Using an Integrated Cox Proportional Hazards Model
7.3. Validation of Exiting Etiologies and Drug-Targeting Pathways
8. Future Perspectives
8.1. The Utility of PRS in Mixed or Underrepresented Populations
8.2. The Challenges of Integrating PRS into Clinical Decision Support Systems and Risk Stratification Procedures
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Available Statement
Conflicts of Interest
Abbreviations
References
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SNP | Locus | Gene | Phenotype | p-Value | Reference |
---|---|---|---|---|---|
rs2230500 | 14q22-q23 | PRKCH | Lacunar infarct | 5.1 × 10−7 | [67] |
rs2230500 | 14q22-q23 | PRKCH | ICH | 5.4 × 10−3 | [68] |
rs4646994 | 17q23 | ACE | WMH | NA | [69] |
rs1055129 | 17q25 | TRIM47 | WMH | 4.1 × 10−8 | [70] |
rs3744028 | 17q25 | TRIM65 | WMH | 4.0 × 10−9 | |
rs4646994 | 17q23 | ACE | Lacunar infarct | 6.0 × 10−3 | [36] |
rs2984613 | 1q22 | PMF1 SLC25A44 | Non-lobar ICH | 1.6 × 10−8 | [71] |
rs72848980 | 17q25.1 | NEURL1 | WMH | 2.7 × 10−19 | [72] |
rs7894407 | 10q24.33 | PDCD11 | WMH | 2.7 × 10−19 | |
rs12357919, rs7909791 | 10q24 | SH3PXD2A | WMH | 1.6 × 10−9 | |
rs78857879 | 2p16.1 | EFEMP1 | WMH | 1.5 × 10−8 | [72] |
rs11679640 | 2p21 | HAAO | WMH | 4.4 × 10−8 | |
rs72934505 | 2q33.2 | NBEAL1 | WMH | 2.2 × 10−8 | [73] |
rs941898 | 14q32.2 | EVL | WMH | 4.0 × 10−8 | |
rs962888 | 17q21.31 | C1QL1 | WMH | 1.1 × 10−8 | |
rs9515201 | 13q34 | COL4A2 | WMH | 6.9 × 10−9 | |
rs10744777 | 12 | ALDH2 | Small artery stroke | 2.92 × 10−9 | [74] |
rs12204590 | 6p25 | FOXF2 | WMH | 2.17 × 10−6 | [17] |
rs12445022 | 16q24 | ZCCHC14 | WMH | 5.3 × 10−5 | [75] |
rs13164785, rs67827860 | 5q14.3 | VCAN | MD, FA | 3.7 × 10−18 1.3 × 10−14 | [76] |
rs275350 | 6q25.1 | PLEKHG1 | WMH | 1.6 × 10−8 | [77] |
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Li, J.; Abedi, V.; Zand, R. Dissecting Polygenic Etiology of Ischemic Stroke in the Era of Precision Medicine. J. Clin. Med. 2022, 11, 5980. https://doi.org/10.3390/jcm11205980
Li J, Abedi V, Zand R. Dissecting Polygenic Etiology of Ischemic Stroke in the Era of Precision Medicine. Journal of Clinical Medicine. 2022; 11(20):5980. https://doi.org/10.3390/jcm11205980
Chicago/Turabian StyleLi, Jiang, Vida Abedi, and Ramin Zand. 2022. "Dissecting Polygenic Etiology of Ischemic Stroke in the Era of Precision Medicine" Journal of Clinical Medicine 11, no. 20: 5980. https://doi.org/10.3390/jcm11205980