PONE-D-21-21985Effects of gene–lifestyle interactions on obesity based on a multi-locus risk score: cross-sectional analysisPLOS ONE

Dear Dr. Nakamura,

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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: No

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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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

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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: No

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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 manuscript by Nakamura et al reports on a cross-sectional study assessing the gene environment interaction between a number of dietary and physical activity. This comprehensive reasonably large study includes many useful predictors to assess the impact on BMI.

This reviewer has the following suggestions to improve the manuscript.

Methods:

Study population: It will be helpful if the authors mention that the population was from Japan.

“local population” is obvious for the authors, but not necessarily for a reader outside of Japan. One needs to infer this. They could use: “participants were residents of Japan who participated…..”

How many patients were assessed from the first visit to the cancer hospital. Individuals coming in for cancer visits may or may not be normal. Might these provide confounding for the results. Will it be useful to undertake analysis without these patients to see if there is an impact of these individuals on the results. If there is no impact of these, the authors may include all cases, but it will be useful to report this, as these patients are likely to be different. It is also possible that these patients are already excluded in the outlier removal undertaken in the methods.

Lines 160-164: The physical activity classification using METs is not clear from the explanation provided here. This reviewer tried to read reference # 25, a prior publication of the same cohort, where the levels seem to be different from 5 described here and not straight forward.

Statistical analysis:

Clear and detailed enough to understand the methods. This reviewer is curious to know whether subgroup analysis was performed by sex only. This is frequent in a cohort of this nature, and it will be useful to report even if the results were not informative in such an analysis.

Lines 150-151: Is this the GRS range identified in the cohort? What does the theoretical range mean? If this is indeed the range for the cohort, this should belong to the results section.

Lines 195-196: It is not clear what do the authors mean by candidate approach? Does it mean “univariate” v/s multivariable for the final model? The S4 table suggests use of a multivariable model with selection of predictors. It appears to be subgroup analysis by GRS quartiles. What is the goal of this analysis?

Results:

In general, if the 95% CI is provided in addition to the coefficient, standard error is not required in the table. 95% CI is more informative, and it is suggested that the authors stick with this, rather than SD.

Lines 208-209: This result can be better reported as: “The increase in BMI for every unit increase in the GRS was 2.45 (95% CI xxx-xxx, p <.001).” When one is using weighted GRS, is the unit of increase per risk allele, or per unit increase in GRS?

Table 1: While the table is provided as upper and lower half of GRS, the way to make these subgroups is not clear. Are the 2 subgroups divided at 0? This would be clear if they provided the results of the GRS obtained for the cohort, and clarified that it was divided into 2 groups

It will be useful to provide an overview summary of the results in the tables in 1 or 2 sentences, e.g. there was no difference in the age, sex distribution or the captured environmental variables when compared by the two subgroups of the GRS (Table 1).

Lines 216- onwards for Gene-lifestyle interaction analysis: This section should also include some better language description of the results connecting them with the methods.

e.g. Using the stepwise regression with backward selection, xxx predictors of relevance were selected for the final model.

Line 266: From Table 2, the p-value for the interaction, GRS* saturated fats is 0.016, different from the one in text. Can the authors please verify.

Do the authors have any plausible explanation for the interaction between GRS and age?

In the high GRS group, every year increase in age decreases the BMI by 0.11 (decrease in 1.1/decade)? While this manuscript is focused on the gene-environment effect, this interaction cannot be completely ignored, and needs at least a comment.

Discussion:

This is a cross-sectional study. Hence, the results of the LMM models suggest association. Association is not causation, and it is not appropriate to use the results of the regression models to suggest this.

It is understandable that the results are contrary to the hypothesis for saturated fatty acids. As the authors suggest, it is possible that the negative association may reflect that the recruited patients may be already involved in health counseling. However, it is not appropriate to suggest that this association means that individuals with higher GRS would not benefit from counseling for intake of saturated fatty acids. The analysis from this cross-sectional study will not be able to address such a question. They need to incorporate the results in the context of prior literature.

The authors have selectively addressed the results of the saturated fats interaction with little attention to other results. It is not clear why this was done. There are other lifestyle factors that were statistically significant in the results that need further attention, literature review and better context in discussion.

For wider applicability of results, it may be useful to compare the results of this study with similar studies in different race/ethnic groups.

Reviewer #2: Good job researching on a complex phenomenon of measuring multi-locus risk score for obesity, considering its relevance in the field of personalized genomics. This topic for the manuscript was very well thought out. It is important to look at the combined effect of gene-lifestyle on BMI and its impact on obesity, as it contributes towards realizing the goals of applying an individual’s personalized gene profile to analyze complex phenotypes. The study provides evidence for an interaction effect between genetic risk score on both nutritional intake and physical activi

It is always a good idea to explore through a national multi-institutional cross-sectional data to test for new hypothesis, as this utilizes data that has had effort and time put in to generate it, thereby decreasing the amount of time and work necessary to generate new data. This is also a great step in moving forward to analyze multiple parameters that may have not been tested earlier. Your overall aim is very interesting as it stems from a logical thought process to generate multi-locus risk score considering the polygenic nature of the genetic interactions. However, the hypothesis if there are any or whether it is a hypothesis free research is not clear in the manuscript.

The manuscript is good for consideration for publication, once the suggestions are incorporated.

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Reviewer #1: No

Reviewer #2: No

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Effects of gene–lifestyle interactions on obesity based on a multi-locus risk score: a cross-sectional analysis

PONE-D-21-21985R1

Dear Dr. Nakamura,

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.

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Kind regards,

Tomoyoshi Komiyama, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Authors,

Thank you for submitting your revised manuscript.

Your study analyzed how genetic risk and lifestyle factors (such as nutritional intake and physical activity) are linked to BMI, based on cross-sectional data from the Japan Multi- Institutional Collaborative Cohort Study.

I see you corrected the highlighted sections according to the reviewer’s suggestions.

Also, I found your updated version much clearer than the original.

Therefore, I have no further comments as all of my previous concerns were adequately addressed.

I believe this manuscript will satiate the reader's interest.

Tomoyoshi Komiyama

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 #2: All comments have been addressed

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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 #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

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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 #2: Yes

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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 #2: Yes

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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 #2: Appreciate the authors for incorporating all of the suggested changes. It would be good to review the article for copy-edits and formatting as required by the Journal.

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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 #2: No

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