Kernel-based gene–environment interaction tests for rare variants with multiple quantitative phenotypes

Xiaoqin Jin; Gang Shi

doi:10.1371/journal.pone.0275929

Peer Review History

Original SubmissionApril 16, 2022
15 Jun 2022 Decision Letter - Momiao Xiong, Editor PONE-D-22-11234Kernel-based gene–environment interaction tests for rare variants with multiple quantitative phenotypes PLOS ONE Dear Dr. Shi, 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 submit your revised manuscript by Jul 30 2022 11:59PM. 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. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This is a very clear and well-organized paper that discusses four multiphenotype methods for testing GEIs with rare variants, which is a great contribution to the field of GEI pleiotropy where most literature focuses on common variants testing for multiple phenotypes. I have a few comments below: 1. Have you considered comparing your four proposed methods with current existing methods in GEI pleiotropy field via simulations? Also, can you discuss what are the advantages of the proposed models and limitations of the existing methods? 2. In the UK Biobank data application, there are several genes identified by your proposed models to have interactions. Are these genes confirmed in past literature to show correlations with BP phenotypes? Have you tried anyway to validate the results as well as your models? ****** 6. 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Revision 1
6 Jul 2022 Author Response Respond to Editors: We are herein resubmitting our revised manuscript titled “Kernel-Based Gene–Environment Interaction Tests for Rare Variants with Multiple Quantitative Phenotypes” (Manuscript Number: PONE-D-22-11234) to PLoS One. We would like to thank you for giving us the opportunity to revise our manuscript and respond to the comments raised by the reviewer. We also want to thank the reviewer for his detailed comments and constructive suggestions, which help improving the quality of this paper substantially. The manuscript has been revised according to the comments of the reviewer and a point-by-point response to the reviewer’s comments is enclosed. The resubmitted manuscript has been formatted according to the style of PLoS One. We have checked our reference list and added four references in the revised manuscript, the four references were cited in new contents that have added in the revised manuscript according to the reviewer’s comments. ORCID ID has been linked to our Editorial Manager account. Besides, we have added “Author Contributions” in our revised manuscript. Any changes made to our original manuscript have been highlighted in our revised manuscript. The “Funding” statement and “Data Availability Statement” are corrected as follows: Funding This work was supported by the national Thousand Youth Talents Plan to GS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability Statement This research has been conducted using the UK Biobank Resource under Application Number 44080. The genetic and phenotype datasets are available via the UK Biobank data access process. More details are available at http://www.ukbiobank.ac.uk/register-apply/. Respond to Reviewer: 1.Have you considered comparing your four proposed methods with current existing methods in GEI pleiotropy field via simulations? Also, can you discuss what are the advantages of the proposed models and limitations of the existing methods? Response: Thank you for the suggestion! We conducted an extensive literature search and found only one method available for testing GEI with rare variants and multiple phenotypes (Zhang et al. 2019). The method consists of three steps: remove correlation among multiple phenotypes by using principal component analysis or other linear transformations; obtain p value for each transformed phenotype by testing the effects of an optimally weighted combination of gene-environment interactions for rare variants (TOW-GE) (Zhao et al. 2020); employ Fisher’s combination test (FCT) to combine the p values of multiple phenotypes. We denote the method as TOWGE-FCT in this paper. It can be expected that the degree of freedom of TOWGE-FCT would become larger with the increasing number of phenotypes, which might limit statistical power of the test. In the revised manuscript, we have added simulations and compared our proposed four multiphenotype GEI tests with TOWGE-FCT. The results showed that all the five tests have enhanced power as the number of phenotypes associated with interactions increases, our proposed Het-GEI, PPK-GEI and LPK-GEI had larger power than TOWGE-FCT, but Hom-GEI had smaller power than TOWGE-FCT. Moreover, TOWGE-FCT uses a permutation test to estimate p value for each phenotype, which is very time consuming. In comparison, our proposed four tests have asymptotic distributions and p values can be computed analytically. Thus, our proposed tests have much smaller computational cost. We also added discussion on the advantages of our proposed tests and limitations of TOWGE-FCT in the revised manuscript. Zhang J, Sha Q, Hao H, Zhang S, Gao XR, Wang X. Test Gene-Environment Interactions for Multiple Traits in Sequencing Association Studies. Hum Hered. 2019;84(4-5):170-196. https://doi.org/10.1159/000506008 PMID: 32417835 Zhao Z, Zhang J, Sha Q, Hao H. Testing gene-environment interactions for rare and/or common variants in sequencing association studies. PLoS One. 2020;15(3):e0229217. https://doi.org/10.1371/journal.pone.0229217 PMID: 32155162 2.In the UK Biobank data application, there are several genes identified by your proposed models to have interactions. Are these genes confirmed in past literature to show correlations with BP phenotypes? Have you tried anyway to validate the results as well as your models? Response: Thank you for the suggestion! In our work, we identified three genes that have interactions with Hb in BP phenotypes. For NOS3 and MYO1C genes, they have been reported to be correlated with BP phenotypes in (Surendran et al. 2020). For LEUTX gene, in an analysis of 454,787 UK Biobank participants, LEUTX was not associated with the BP phenotypes at the nominal significance level of 0.05 (Backman et al. 2021). While our proposed tests identified LEUTX that shows interaction with Hb in BP phenotypes, the result lacks independent validation. Thus, it should be considered as being preliminary and further experiments are necessary. We acknowledged the limitation of the result in the revised manuscript. Surendran P, Feofanova EV, Lahrouchi N, Ntalla I, Karthikeyan S, Cook J, et al. Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. Nat Genet. 2020;52(12):1314-1332. https://doi.org/10.1038/s41588-020-00713-x PMID: 33230300 Backman JD, Li AH, Marcketta A, Sun D, Mbatchou J, Kessler MD, et al. Exome sequencing and analysis of 454,787 UK Biobank participants. Nature. 2021;599(7886):628-634. https://doi.org/10.1038/s41586-021-04103-z PMID: 34662886 Attachments Attachment Submitted filename: Response to Reviewers.doc https://doi.org/10.1371/journal.pone.0275929.r002
26 Sep 2022 Decision Letter - Mehdi Rahimi, Editor Kernel-based gene–environment interaction tests for rare variants with multiple quantitative phenotypes PONE-D-22-11234R1 Dear Dr. Shi, 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, Mehdi Rahimi, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. 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: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ******** https://doi.org/10.1371/journal.pone.0275929.r003
Formally Accepted
30 Sep 2022 Acceptance Letter - Mehdi Rahimi, Editor PONE-D-22-11234R1 Kernel-based gene–environment interaction tests for rare variants with multiple quantitative phenotypes Dear Dr. Shi: 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 Dr. Mehdi Rahimi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0275929.r004

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