GWAS-based polygenic risk scoring for predicting cerebral artery dissection in the Chinese population.

Publisher: BioMed Central Country of Publication: England NLM ID: 100968555 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2377 (Electronic) Linking ISSN: 14712377 NLM ISO Abbreviation: BMC Neurol Subsets: MEDLINE

Original Publication: London : BioMed Central, [2001-

Genome-Wide Association Study*/methods ; Multifactorial Inheritance*/genetics ; Genetic Predisposition to Disease*/genetics ; Polymorphism, Single Nucleotide*/genetics ; Asian People*/genetics; Humans ; Male ; Female ; Middle Aged ; Adult ; China/epidemiology ; Intracranial Aneurysm/genetics ; Intracranial Aneurysm/epidemiology ; Aortic Dissection/genetics ; Aortic Dissection/epidemiology ; Aortic Dissection/diagnosis ; Case-Control Studies ; Risk Assessment/methods ; East Asian People

Objective: Cerebral artery dissection (CeAD) is a rare but serious disease. Genetic risk assessment for CeAD is lacking in Chinese population. We performed genome-wide association study (GWAS) and computed polygenic risk score (PRS) to explore genetic susceptibility factors and prediction model of CeAD based on patients in Huashan Hospital.
Methods: A total of 210 CeAD patients and 280 controls were enrolled from June 2017 to September 2022 in Department of Neurology, Huashan Hospital, Fudan University. We performed GWAS to identify genetic variants associated with CeAD in 140 CeAD patients and 210 control individuals according to a case and control 1:1.5 design rule in the training dataset, while the other 70 patients with CeAD and 70 controls were used as validation. Then Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were utilized to identify the significant pathways. We constructed a PRS by capturing all independent GWAS SNPs in the analysis and explored the predictivity of PRS, age, and sex for CeAD.
Results: Through GWAS analysis of the 140 cases and 210 controls in the training dataset, we identified 13 leading SNPs associated with CeAD at a genome-wide significance level of P < 5 × 10 ^- 8 . Among them, 10 SNPs were annotated in or near (in the upstream and downstream regions of ± 500Kb) 10 functional genes. rs34508376 (OR2L13) played a suggestive role in CeAD pathophysiology which was in line with previous observations in aortic aneurysms. The other nine genes were first-time associations in CeAD cases. GO enrichment analyses showed that these 10 genes have known roles in 20 important GO terms clustered into two groups: (1) cellular biological processes (BP); (2) molecular function (MF). We used genome-wide association data to compute PRS including 32 independent SNPs and constructed predictive model for CeAD by using age, sex and PRS as predictors both in training and validation test. The area under curve (AUC) of PRS predictive model for CeAD reached 99% and 95% in the training test and validation test respectively, which were significantly larger than the age and sex models of 83% and 86%.
Conclusions: Our study showed that ten risk loci were associated with CeAD susceptibility, and annotated functional genes had roles in 20 important GO terms clustered into biological process and molecular function. The PRS derived from risk variants was associated with CeAD incidence after adjusting for age and sex both in training test and validation.
(© 2024. The Author(s).)

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No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; No. 8227052180 National Natural Science Foundation of China; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan university.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; none The Cerebrovascular Disease Management Project of Sailing Foundation of China Stroke Association.; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation; NO. HIGHER2022107 Heart and Brain Health Public Welfare Project of Buchang Zhiyuan Foundation

Keywords: Cerebral artery dissection; Genetic risk; Polygenic risk score; Predictive model

Date Created: 20240725 Date Completed: 20240726 Latest Revision: 20240728

20240728

PMC11271197

10.1186/s12883-024-03759-0

39054468