Genetic and clinical determinants of neonatal jaundice and growth patterns in the Qingdao birth cohort: A genome-wide association study

Xu Chen; Peina Du; Shuo Li; Xiaohong Wang; Mengyang Xu; Zhaobin Chu; Yue Zhang; Zhengyang Yao; Xuejie Huan; Yushan Huang; Mingyan Fang; Ya Gao; Guangyi Fan; Xin Jin; Hui Huang; Silin Pan

doi:10.1371/journal.pone.0338567

Peer Review History

Original SubmissionMarch 8, 2025
12 May 2025 Decision Letter - Nejat Mahdieh, Editor Dear Dr. Chen, 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 Jun 26 2025 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. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. 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Please amend the file type to 'Supporting Information'. Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list. 5. Please upload a copy of Supporting Information Table S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, which you refer to in your text on page 6, 7, 8, 9. [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? Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: Comments to the Author Thank you for submitting this paper for review. Please, find my comments below: 1.The wording /English language needs improving throughout. 2.The opening statement, "The health and development of newborns are always a concern," is vague. Please specify the current research status and significance of neonatal jaundice and growth patterns. 3.The Introduction lacks epidemiological or clinical context (e.g., global/Chinese incidence rates, risk factors for neonatal jaundice). Please supplement with relevant data. 4.Exclusion criteria for confounders (e.g., preterm birth, maternal diseases) are not described in the Methods. Please clarify inclusion/exclusion criteria. 5.Seven novel missense mutations (e.g., rs1042597) lack functional predictions (e.g., SIFT/PolyPhen-2 scores) or conservation analyses in the Results. Please provide bioinformatics support. 6.Functional validation (e.g. in vitro studies) or larger cohort replication is recommended if available. 7.Study limitations (e.g., regional bias from Qingdao samples) are not addressed. Please acknowledge generalizability constraints. 8.The Conclusion repeats results but does not highlight core contributions (e.g., "First identification of X novel SNPs in Chinese neonates"). Please succinctly summarize innovations. 9.Please outline future research. Reviewer #2: I appreciate the opportunity to evaluate this timely study on neonatal growth genetics. The authors present a valuable GWAS dataset (n=6,685) with robust quality control, identifying both novel SNPs (e.g., rs148399850) and clinically relevant pathways (e.g., flavonoid glucuronidation). While the rigorous methodology and comprehensive functional enrichment analyses are clear strengths, I recommend clarifying several methodological points and contextualizing findings more deeply to enhance impact. 1.Methods Please: • Clarify if recruitment was random; address potential selection bias. Mention inclusion and exclusion criteria • State if multiple testing correction was applied beyond the GWAS threshold (P =1×10-8). • For SNPs with P =1×10-5add sensitivity analyses to reduce false positives. 2. Results Please: • Resolve the contradiction between "no significant SNPs" and later reporting 109 SNPs (P =1×10-5). • The reported differences in allele frequencies between populations (e.g., Xizang vs. Guangxi) are interesting. A statistical test (e.g., χ²) could further strengthen these observations, though the trends remain biologically plausible. 3. Discussion Please: • Propose functional validation (e.g., in vitro assays for novel SNPs like rs927472313 in TMEM236). • Limitations: o Confounding factors (maternal nutrition, SES) were not adjusted for. o Generalizability to non-East Asian populations is unclear. ****** 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 Reviewer #2: Yes: Farnoosh Emami ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: review-PONE-D-25-10541.docx https://doi.org/10.1371/journal.pone.0338567.r001
Revision 1
10 Nov 2025 Author Response Reply to Reviewer Comments for Manuscript PONE-D-25-10541� “Genetic and Clinical Determinants of Neonatal Jaundice and Growth Patterns in the Qingdao Birth Cohort: A Genome-Wide Association Study” Editor� 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Responses: Thank you for your feedback. We have revised the formatting of our manuscript based on the reference material you provided. 2. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. Responses: We have removed the ethical statement from the Declarations section. 3. We note that Figure 4 in your submission contain [map/satellite] images which may be copyrighted. All PLOS content is published under the Creative Commons Attribution License (CC BY 4.0), which means that the manuscript, images, and Supporting Information files will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. For these reasons, we cannot publish previously copyrighted maps or satellite images created using proprietary data, such as Google software (Google Maps, Street View, and Earth). For more information, see our copyright guidelines: http://journals.plos.org/plosone/s/licenses-and-copyright. We require you to either (1) present written permission from the copyright holder to publish these figures specifically under the CC BY 4.0 license, or (2) remove the figures from your submission: a. You may seek permission from the original copyright holder of Figure 4 to publish the content specifically under the CC BY 4.0 license. We recommend that you contact the original copyright holder with the Content Permission Form (http://journals.plos.org/plosone/s/file?id=7c09/content-permission-form.pdf) and the following text: “I request permission for the open-access journal PLOS ONE to publish XXX under the Creative Commons Attribution License (CCAL) CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/). Please be aware that this license allows unrestricted use and distribution, even commercially, by third parties. Please reply and provide explicit written permission to publish XXX under a CC BY license and complete the attached form.” Please upload the completed Content Permission Form or other proof of granted permissions as an "Other" file with your submission. In the figure caption of the copyrighted figure, please include the following text: “Reprinted from [ref] under a CC BY license, with permission from [name of publisher], original copyright [original copyright year].” b. If you are unable to obtain permission from the original copyright holder to publish these figures under the CC BY 4.0 license or if the copyright holder’s requirements are incompatible with the CC BY 4.0 license, please either i) remove the figure or ii) supply a replacement figure that complies with the CC BY 4.0 license. Please check copyright information on all replacement figures and update the figure caption with source information. If applicable, please specify in the figure caption text when a figure is similar but not identical to the original image and is therefore for illustrative purposes only. The following resources for replacing copyrighted map figures may be helpful: USGS National Map Viewer (public domain): http://viewer.nationalmap.gov/viewer/ The Gateway to Astronaut Photography of Earth (public domain): http://eol.jsc.nasa.gov/sseop/clickmap/ Maps at the CIA (public domain): https://www.cia.gov/library/publications/the-world-factbook/index.html and https://www.cia.gov/library/publications/cia-maps-publications/index.html NASA Earth Observatory (public domain): http://earthobservatory.nasa.gov/ Landsat: http://landsat.visibleearth.nasa.gov/ USGS EROS (Earth Resources Observatory and Science (EROS) Center) (public domain): http://eros.usgs.gov/# Natural Earth (public domain): http://www.naturalearthdata.com/ Responses: We have removed the map and replaced it with a new figure to present the same analysis results. 4. We notice that your supplementary figures are uploaded with the file type 'Figure'. Please amend the file type to 'Supporting Information'. Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list. Responses: We have added legends for the supplementary figures and supplementary tables after the references. 5. Please upload a copy of Supporting Information Table S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, which you refer to in your text on page 6, 7, 8, 9. Responses: We have uploaded the supplementary table. Reviewer #1: Thank you for submitting this paper for review. Please, find my comments below: 1. The wording /English language needs improving throughout. Responses: Thank you for your feedback. We have thoroughly revised the manuscript to improve its linguistic fluency throughout. 2. The opening statement, "The health and development of newborns are always a concern," is vague. Please specify the current research status and significance of neonatal jaundice and growth patterns. Responses: Thank you for your feedback. We revised the Background sentence in the abstract to more clearly reflect the clinical relevance and current research context. 3. The Introduction lacks epidemiological or clinical context (e.g., global/Chinese incidence rates, risk factors for neonatal jaundice). Please supplement with relevant data. Responses: Thank you for your feedback. We added a brief epidemiological and clinical context to the Introduction to clarify the frequency, clinical relevance, and major risk factors of neonatal jaundice. 4. Exclusion criteria for confounders (e.g., preterm birth, maternal diseases) are not described in the Methods. Please clarify inclusion/exclusion criteria. Responses: Thank you for your feedback. We have now clarified the exclusion of preterm cases. Other maternal complications could not be systematically excluded due to incomplete records. These potential confounding factors need to be considered and controlled for in subsequent studies. 5. Seven novel missense mutations (e.g., rs1042597) lack functional predictions (e.g., SIFT/PolyPhen-2 scores) or conservation analyses in the Results. Please provide bioinformatics support. Responses: Thank you for your feedback. We have added functional annotation results for the seven novel missense variants based on SIFT and PolyPhen-2 predictions in the Results section and included the full data in a supplementary table (Table S14). 6. Functional validation (e.g. in vitro studies) or larger cohort replication is recommended if available. Responses: Thank you for the suggestion. We agree that functional validation and replication in additional cohorts would strengthen the findings. We have now added a description reflecting this point in the Discussion section. 7. Study limitations (e.g., regional bias from Qingdao samples) are not addressed. Please acknowledge generalizability constraints. Responses: Thank you for your feedback. We have now acknowledged the limitation of the regional source of the cohort and noted that caution is required when generalizing the findings to other populations. 8. The Conclusion repeats results but does not highlight core contributions (e.g., "First identification of X novel SNPs in Chinese neonates"). Please succinctly summarize innovations. Responses: We have revised the Conclusion to reduce repetition of detailed results and to more clearly highlight the main contributions of this study. 9. Please outline future research. Responses: We have outlined the directions for future research in the discussion, including the need for functional validation, replication in additional cohorts, and longitudinal follow-up to assess long-term outcomes. Reviewer #2: I appreciate the opportunity to evaluate this timely study on neonatal growth genetics. The authors present a valuable GWAS dataset (n=6,685) with robust quality control, identifying both novel SNPs (e.g., rs148399850) and clinically relevant pathways (e.g., flavonoid glucuronidation). While the rigorous methodology and comprehensive functional enrichment analyses are clear strengths, I recommend clarifying several methodological points and contextualizing findings more deeply to enhance impact. 1.Methods Please: • Clarify if recruitment was random; address potential selection bias. Mention inclusion and exclusion criteria Responses: Thank you for the comment. We have clarified in the Methods that newborns were randomly recruited; preterm infants and those who had recent blood transfusions were excluded. • State if multiple testing correction was applied beyond the GWAS threshold (P =1×10-8). Responses: Thank you for the comment. Only the standard GWAS significance threshold (P < 5×10⁻⁸) was applied in this study, which is widely accepted to control the family-wise error rate (FWER). Because of the limited sample size, loci with P < 1×10⁻⁵ were also explored for functional relevance. Additional corrections such as FDR or Bonferroni can be added if required. • For SNPs with P =1×10-5add sensitivity analyses to reduce false positives. Responses: Thank you for your helpful suggestion. We have conducted the leave-one-out sensitivity analysis (Fig S5), and added the description and statement in the revised manuscript. 2. Results Please: • Resolve the contradiction between "no significant SNPs" and later reporting 109 SNPs (P =1×10-5). Responses: Thank you for pointing this out. We have revised the results to distinguish significant loci from suggestive associations, clarifying the statistical thresholds and removing ambiguity. • The reported differences in allele frequencies between populations (e.g., Xizang vs. Guangxi) are interesting. A statistical test (e.g., χ²) could further strengthen these observations, though the trends remain biologically plausible. Responses: Thank you for your helpful suggestion. We have now performed χ² tests to assess allele-frequency differences among populations. The corresponding results have been added as Table S8, and a brief description was included in the results section . 3. Discussion Please: • Propose functional validation (e.g., in vitro assays for novel SNPs like rs927472313 in TMEM236). Responses: Thank you for your helpful suggestion. We will conduct functional verification in our future research, and the corresponding paragraphs have been added to the Discussion section of the manuscript . • Limitations: o Confounding factors (maternal nutrition, SES) were not adjusted for. o Generalizability to non-East Asian populations is unclear. Responses: Thank you for your insightful comments. Due to the limitations of our sampling design, we could not comprehensively control for all potential confounding factors. The confounders that were excluded have now been specified in the revised manuscript . We also acknowledge the regional limitation of our cohort, which should be addressed in future studies. Corresponding statements regarding confounding factors and regional generalizability have been added to the discussion section. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0338567.r002
25 Nov 2025 Decision Letter - Nejat Mahdieh, Editor <p>Genetic and Clinical Determinants of Neonatal Jaundice and Growth Patterns in the Qingdao Birth Cohort: A Genome-Wide Association Study PONE-D-25-10541R1 Dear Dr. Chen, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . 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, Nejat Mahdieh Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #2: Yes ****** Reviewer #2: The authors have carefully responded to all reviewer comments. the revised version demonstrates significant improvement in both structure and content. ****** 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 #2: No ******** https://doi.org/10.1371/journal.pone.0338567.r003
Formally Accepted
Acceptance Letter - Nejat Mahdieh, Editor PONE-D-25-10541R1 PLOS One Dear Dr. Chen, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps. Lastly, 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. If we can help with anything else, please email us at customercare@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. Nejat Mahdieh Academic Editor PLOS One https://doi.org/10.1371/journal.pone.0338567.r004

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