PONE-D-20-03465

Association of a Genetic Risk Score with BMI along the Life-Cycle: Evidence from several US Cohorts

PLOS ONE

Dear Dr Sanz-de-Galdeano

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.

We would appreciate receiving your revised manuscript by Apr 24 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

David Meyre

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

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

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2) In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

3) In your Methods section, please provide additional information about the participant inclusions method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as: a)  a description of any inclusion/exclusion criteria that were applied to participant inclusion, b) a table of relevant demographic details, c) a statement as to whether your sample can be considered representative of a larger population.

4) We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

5)  Thank you for stating the following in the Acknowledgments/(Title page) Section of your manuscript:

[She acknowledges financial support from PROMETEO/2019/037, and

from the Spanish Ministry of Economy and Competitiveness Grant ECO2017-87069-P]

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

 [The author(s) received no specific funding for this work.]

Please include the updated Funding Statement in your cover letter. We will change the online submission form on your behalf.

[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: Partly

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 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

Reviewer #2: Yes

**********

4. 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

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: This article reports analysis of genetic association with BMI across the life course. The authors ask if genetic associations with BMI are stronger at some ages as compared to others. They use data from two large social surveys that include longitudinal assessments of BMI. The main finding is that genetic associations with BMI are somewhat stronger at older ages up to the 50s/60s, when associations stabilize.

These findings are consistent with previous reports in both the twin and molecular genetic literatures. The authors should note the Belsky et al. 2012 paper, which was the first to report polygenic score associations with BMI development across the first half of the life course. (the Hardy et al. paper cited analyzed only the FTO polymorphism)

The main technical criticism I would make of this analysis is that the authors do not take seriously enough the limitation that much of their data come from self-reports of height and weight. They tell us they did some analysis to evaluate the risk this posed to the inferences they make but don’t show the data. They should.

This is particularly important for interpreting genetic associations with BMI across the transition from adolescence to young adulthood. The adolescent BMI data come from self-reports whereas the young adult data come from anthropometric assessments. If there is less error in measurement in the anthropometry-derived BMIs, this will lead to larger effect-sizes in association analysis.

A second critique is that the authors don’t seem to think much about the biology of BMI change across the life course and how this may affect genetic associations. Two processes are of particular relevance to the analysis reported. First, puberty causes substantial changes in BMI. Pubertal timing varies across individuals. Variation in pubertal timing may therefore result in a kind of measurement error in the BMI phenotype being analyzed in adolescence, biasing genetic effect-sizes toward the null. Second, with advancing age, a range of chronic diseases become more prevalent, leading to wasting (BMI loss). Add Health data on timing of menarche and HRS data on chronic disease morbidity may be helpful in exploring these processes.

Basically, my concern is that the authors are not identifying substantive differences in how genetics affect BMI, but instead are observing variation in the magnitudes of non-genetic causes (or genetic causes not measured in the PGS) across life course stages.

One idea to explore in evaluating this issue is to use some non-genetic measure of risk for obesity. For example, both Add Health and HRS measure parental education, which is associated with BMI across the life course. Do parental education associations with BMI show the same patterns of change with age as genetic associations? If so, is this analysis telling us something about genetics or simply about the sources of systematic variation in BMI? If not, this is a strong piece of evidence that the patterning observed is specifically about the genetics being studied.

MINOR

To my mind, there is a conceptual problem with the article. The authors approach their question within a GxE framework. But the changing association of genetics with BMI as people age is not a GxE. BMI growth is a developmental process, with BMI at later ages strongly influenced by BMI earlier on. Given the authors have repeated measures data on individuals, the question they should be asking is how do BMI genetics influence BMI change across the life course. But this is a matter of taste and differing views of how this problem should be approached ought not to interfere with publication in this journal.

Something else: The polygenic score analyzed by the authors comes from a GWAS that included mainly midlife individuals. For this reason, we might expect the strongest genetic associations in that age range. This might be discussed somewhat more in the introduction and discussion sections of the article.

Reviewer #2: This is an excellent study, well performed and well written, and I recommend its publication.

Statistical methods are explained in detail and results are clear.

There is a typo in the abstract (a duplicated "the").

Congratulations.

**********

6. 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

Reviewer #2: No

[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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-20-03465R1

Association of a Genetic Risk Score with BMI along the Life-Cycle: Evidence from several US Cohorts

PLOS ONE

Dear Dr. Sanz-de-Galdeano,

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.

More specifically, you must add a 'strengths and limitations' section in the discussion section of your manuscript.

Please submit your revised manuscript by Sep 03 2020 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.

Please include the following items when submitting your revised manuscript:

• 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'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

David Meyre

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Please add a 'strengths and limitations' section in the discussion section.

[Note: HTML markup is below. Please do not edit.]

[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.

Association of a Genetic Risk Score with BMI along the Life-Cycle: Evidence from several US Cohorts

PONE-D-20-03465R2

Dear Dr. Sanz-de-Galdeano,

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,

David Meyre

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: