PONE-D-22-30912Investigating effect modification between childhood maltreatment and genetic risk for cardiovascular disease in the UK BiobankPLOS ONE

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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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 is a great paper though there was no finding on significant interaction between childhood maltreatment and PGS influencing CVD.

1. There may be no interaction indeed, however, a true association may have not been revealed due to low statistical power using the 1 df test of the interaction effect alone. The 2 df test is more powerful when PGS is weak, and the interaction effect is moderate than either the 1df test of the PGS or the 1df test of the interaction alone. Using the 2df joint test under the H0: Beta(PGS) = Beta(PGX x childhood maltreatment), you may be able to identify associations that were not discovered using the 1df test.

2. Have you considered including age squared as one of the covariates? In case including age only in the model would not be sufficient to control for the effect of age.

3. A minor suggestion is that I found some typos or grammatical errors in the context. For example, in the method for effect modification, I was wondering whether you meant multivariable “logistic” regression for binary traits, not “linear” regression.

Reviewer #2: - Statistical significance of the interaction (p-value) should be mentioned in the abstract.

- Table 2 presented the variable distributions in the analytical sample versus the whole UKB to show that the distributions of various factors were not substantially different. This information is better placed into supplementary materials, since the information of the whole UKB was not directly related to this study and is very likely available from other studies that used the full cohort. Instead, showing the sample characteristics by the childhood maltreatment score or by sex would be more informative.

- While it makes sense to analyze the continuous traits as per SD difference, the results would be more interpretable if the SD can be converted to the actual units (e.g., how much is per SD of BMI in this analytical sample?)

- Childhood maltreatment score was used as a continuous variable in all analyses. The underlying hypothesis is that different types of maltreatment have the same equal effect on cardiovascular traits, which may not be true. The authors did not examine potential heterogeneity in the associations by maltreatment types although the data are available (e.g., sexual abuse is often considered the more severe form of childhood maltreatment).

- The study only found a significant interaction between childhood maltreatment and genetic susceptibility to BMI. A recent study reported that BMI was the most important factor that mediated the association between childhood abuse and metabolic profiles in midlife (PMID: 35471987). Incorporating this study in the discussion may potentially increase the significance of the findings from the current study.

- Discussion: it should be acknowledged that the assessment of childhood maltreatment was also crude that did not capture frequency, duration, severity or timing for each type of maltreatment. For example, childhood maltreatment that occurs earlier in childhood may result in stronger gene-environment interaction effect. Also, the definition of ‘child’ in the assessment question is vague. Someone could consider an “adolescent” as a child while others may not. The maltreatment during adolescence may not have the same biological effect as the one during early childhood <5 years old.

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Reviewer #1: No

Reviewer #2: No

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Investigating effect modification between childhood maltreatment and genetic risk for cardiovascular disease in the UK Biobank

PONE-D-22-30912R1

Dear Dr. Urquijo,

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.

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Kind regards,

Heming Wang, PhD

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

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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 #1: Yes

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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

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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 #1: 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 #1: Thank you for clarifying and providing the details with sufficient evidence. I agree with all author's comments.

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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 #1: No

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