Genome-wide polygenic risk impact on intracranial aneurysms and acute ischemic stroke

Eun Pyo Hong; Dong Hyuk Youn; Bong Jun Kim; Jae Jun Lee; Doyoung Na; Jun Hyong Ahn; Jeong Jin Park; Jong Kook Rhim; Heung Cheol Kim; Hong Jun Jeon; Gyojun Hwang; Jin Pyeong Jeon; on the behalf of The First Korean Stroke Genetics Association Research

doi:10.1371/journal.pone.0265581

Peer Review History

Original SubmissionOctober 7, 2021
26 Dec 2021 Decision Letter - Giuseppe Novelli, Editor PONE-D-21-32285Genome-wide polygenic risk impact on the intracranial aneurysm and acute ischemic strokePLOS ONE Dear Dr. Pyeong Jeon, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please carefully evaluate what was suggested by the reviewers, especially in terms of size of the sample studied and then provide the necessary elements (statistical and otherwise) to overcome this criticality. Please submit your revised manuscript by February 15 2022. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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We will update your Data Availability statement on your behalf to reflect the information you provide [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? 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Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: In this manuscript the authors aim to shed light on hypothetical shared genetic risk factors for Intracranial Aneurysm (IA) and Acute Ischemic Stroke (AIS), presenting and analysing risk models based on weighted Polygenic Risk Score (wPRS) derived from Genome-Wide Association Studies (GWAS) previously published by the same authors. For what is in my competence, the experimental design sounds carefully conceived and the manuscript is well written. Statistics are described in details and conclusions are reported in a clear and appropriate fashion. However, as the same authors stated in the Discussion section, I must observe that the study has limitations, i.e. small sample size and lack of an investigation on associations between AIS subtypes and IA, which could be of major interest in order to implement the predictive power of the analysis. This study, on his current form, provides a promising starting point and it can have an impact in terms of designing broader and deeper investigations. On the other hand, I think that the discussion addresses relevant topics, such as the importance of the introduction of PRS derived models to improve risk stratification and the lack of generalizability to non-European ancestry population of existing models. A larger investment on the collection of studies from non-European ancestry is definitely needed. Reviewer #2: The Authors claim to determine whether the polygenic risk score developed from intracranial aneurysm patients has a common genetic basis with acute ischemic stroke in a Korean population. To do that they applied a weighted PRS model based on a previous genomewide GWAS study using 250 intracranial aneurysm patients in hospital-based multicenter cohort and a validation study in 222 patients who suffered acute ischemic stroke. The work of the Authors is interesting and points out a different way to approach these conditions, which are known to share several clinical risk factors. However, to the date, due to the small size of the sample and the lack of identification of acute ischemic stroke subtypes the use of PRS in common clinical practice isn't feasible yet. Some typos should be revised. Neverthless Authors' work is worthy of further investigation on a larger cohort which a more accurate clinical subtyping. ****** 6. 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Revision 1
21 Jan 2022 Author Response Manuscript ID: PONE-D-21-32285 “Genome-wide polygenic risk impact on the intracranial aneurysm and acute ischemic stroke” We are submitting a revised version of the above manuscript according to the letter from the Editorial Committee. We have made corrections and clarifications in the manuscript based on reviewers’ comments. In this revision manuscript, we inserted two additional authorships (JJL and DN) because those coauthors contributed to data curation of stroke subtypes and writing to the review process. We highlighted the revised text in gray color in the revised manuscript (filename: Revised Manuscript.docx), the revised manuscript without gray highlighted (filename: Manuscript.docx), and attached the supplementary material (filename: Online_Supplemental_Data.pdf) and the updated figures corrected by PACE (https://pacev2.apexcovantage.com/) (i.e., filenames: Fig1 to Fig4.tif). We described all responses to Reviewer's comments in the file "Revised letter to Reviewer Comments (PDF)" attached by PLOS ONE upload system as well as informed by here (See PDF including detail information such as Supplementary Tables). Comments from the reviewer 1 Comment 1: In this manuscript the authors aim to shed light on hypothetical shared genetic risk factors for Intracranial Aneurysm (IA) and Acute Ischemic Stroke (AIS), presenting and analysing risk models based on weighted Polygenic Risk Score (wPRS) derived from Genome-Wide Association Studies (GWAS) previously published by the same authors. For what is in my competence, the experimental design sounds carefully conceived and the manuscript is well written. Statistics are described in details and conclusions are reported in a clear and appropriate fashion. However, as the same authors stated in the Discussion section, I must observe that the study has limitations, i.e. small sample size and lack of an investigation on associations between AIS subtypes and IA, which could be of major interest in order to implement the predictive power of the analysis. This study, on his current form, provides a promising starting point and it can have an impact in terms of designing broader and deeper investigations. On the other hand, I think that the discussion addresses relevant topics, such as the importance of the introduction of PRS derived models to improve risk stratification and the lack of generalizability to non-European ancestry population of existing models. A larger investment on the collection of studies from non-European ancestry is definitely needed. Answer: Thank you very much for the positive comments on our study. However, as you mentioned, the main limitations are that the sample size in this study was underpowered and the wPRS assessments according to the ischemic stroke subtype based on a large number of patients is an ongoing project. Due to the nature of bioinformatics, if the sample size of the main data in a GWAS is insufficient, the study outcome will be underpowered. Realistically, a way to address this issue is to reduce the false positives associated with diseases by adding a fine-mapping analysis. However, fine-mapping analysis is an alternative approach to discover candidate variants associated with complex traits based on GWAS summary statistics (Reference 1 below). Thus, the best solution would be to increase the number of patients with IA in a future study. Regarding the second limitation, we performed a subsequent analysis of wPRS assessments in the subtypes of acute ischemic stroke (AIS) including cardioembolism (CE, n= 50), large artery atherosclerosis (LAA, n = 72), small-vessel occlusion (SVO, n = 75), and undetermined (UD, n = 25) (Supplemental Table S2 below). Overall, IA-predicting wPRSs increased the risk of all subtypes of AIS with predictabilities between 0.794 and 0.836. Nevertheless, the sample size in each type of stroke was also small. Thus, additional analysis of a large number of AIS patients is necessary. We included these limitations in the Discussion section (page 10 and lines 203-214). Reference 1. Schaid DJ, Chen W, Larson NB. From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat Rev Genet. 2018;19(8):491-504. http://doi.org/10.1038/s41576-018-0016-z PMID: 2984461 S2 Table. Application of weighted polygenic risk scores according to subtypes of acute ischemic stroke (AIS) (See detail in PDF) Comments from the reviewer 2 Comment 1: The Authors claim to determine whether the polygenic risk score developed from intracranial aneurysm patients has a common genetic basis with acute ischemic stroke in a Korean population. To do that they applied a weighted PRS model based on a previous genome wide GWAS study using 250 intracranial aneurysm patients in hospital-based multicenter cohort and a validation study in 222 patients who suffered acute ischemic stroke. The work of the Authors is interesting and points out a different way to approach these conditions, which are known to share several clinical risk factors. However, to the date, due to the small size of the sample and the lack of identification of acute ischemic stroke subtypes the use of PRS in common clinical practice isn't feasible yet. Some typos should be revised. Nevertheless, Authors' work is worthy of further investigation on a larger cohort which a more accurate clinical subtyping. Answer: Per your comments, the relatively small sample size in the study and the absence of an analysis of the acute ischemic stroke (AIS) subtypes by PRS were acknowledged as the main limitations of the study. Due to the nature of bioinformatics, if the sample size of the main data in a GWAS is insufficient, the study outcomes will be underpowered. Realistically, a way to address this issue is to reduce the false positives associated with diseases by adding a fine-mapping analysis. Nevertheless, fine-mapping analysis is an alternative approach to discover candidate variants associated with complex traits based on GWAS summary statistics (Reference 1 below). Thus, the best solution would be to increase the number of patients with IA in a future study. Regarding the second limitation, we performed a subsequent analysis further of wPRS assessments in the subtypes of acute ischemic stroke (AIS) including cardioembolism (CE, n= 50), large artery atherosclerosis (LAA, n = 72), small-vessel occlusion (SVO, n = 75), and undetermined (UD, n = 25) (Supplemental Table S2, below). Overall, IA-predicting wPRSs increased the risk of all subtypes of AIS with predictabilities between 0.794 and 0.836. Nevertheless, the sample size in each stroke subtypes was also small. Thus, additional analysis of a larger number of AIS patients is necessary. We included these limitations in the Discussion section (page 10 and lines 203-214). Furthermore, English grammar and typographical errors were checked again by English proofreading performed by the native speakers and scientific expertise. . Reference 1. Schaid DJ, Chen W, Larson NB. From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat Rev Genet. 2018;19(8):491-504. http://doi.org/10.1038/s41576-018-0016-z PMID: 2984461 Attachments Attachment Submitted filename: Revision letter to Reviewer Comments.pdf https://doi.org/10.1371/journal.pone.0265581.r002
7 Mar 2022 Decision Letter - Giuseppe Novelli, Editor Genome-wide polygenic risk impact on intracranial aneurysms and acute ischemic stroke PONE-D-21-32285R1 Dear Dr.Jin Pyeong Jeon, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Giuseppe Novelli Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0265581.r003
Formally Accepted
30 Mar 2022 Acceptance Letter - Giuseppe Novelli, Editor PONE-D-21-32285R1 Genome-wide polygenic risk impact on intracranial aneurysms and acute ischemic stroke Dear Dr. Jeon: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Giuseppe Novelli Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0265581.r004

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