https://orcid.org/0000-0002-8911-3479
Peer Review History
| Original SubmissionMarch 8, 2021 |
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PONE-D-21-07612 Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression PLOS ONE Dear Dr. Martin, 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 07 2021 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:
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MOD, JTRW and IJ have received a collaborative research grant from Takeda Pharmaceuticals. Takeda played no part in the conception, design, implementation, or interpretation of this study. CML is on the Scientific Advisory Board of Myriad Neuroscience. All other authors report no conflicts of interest. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf. Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests
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[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: Yes Reviewer #2: No ********** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ********** 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: No 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: Given the higher prevalence of anxiety and depression in female, the authors took efforts to investigated sex differences of genetic liability in individuals with anxiety or depression using both PRS and CNVs. The two datasets (NCMH and PGC) the authors selected to perform exploration and replicatory analysis were appropriated dataset with sufficient phenotypic information and statistic power. The results were very clear with absence of robust sex effects on PRSs and rare CNV burden. Only weak evidence of higher ADHD PRS in females compared to males were detected, particularly in early onset group. The results provide a better understanding of sex differences of anxiety and depression adults were absent in genetic heterogeneity for both PRS and CNV burden. Introduction. Since the authors has been described the heritability of anxiety and depression using family/ twin study. The sex effects in those equation models have been summarized and also valuable to introduce to the readers, e.g., PMID 26649194, 16212676, 14531579. Methods. PRS calculation: MHC region were excluded only when PRS-SCZ were calculated, why do not keep same protocol for other PRSs calculation? It is suggested to excluded more LD complex region (PMID: 18606306) to avoid PRS result bias. PRSs were calculated for 1315 cases and 157 controls. The authors compared the PRSs only for cases between male and female after PRS standardized in total samples (including controls). As the different prevalence of cases in male compared in female, this standardization procedure may introduce bias for PRS sex comparison, which is suggested to excluded. Multiple testing correction. In Table S2, only PRS-ADHD, PRS-ANX and PRS-MDD showed significant association with case control status. I personally suggest only compare these 3 PRSs in sex groups in following study. Still in Table S2, do PRSs contribute the variance of case-control status differently between male and female? It is good to show the summary statistics separately in male and female group also in table S2. Genetic PCs, please explain the reason that authors select first 5 PCs out of 20 PCs as covariates into the models. Authors compared the sex difference of PRS and CNV burden separately. What if the comparison took both into account (e.g., Add CNV burden as covariates when comparing the PRSs)? Results. Table 2: the sex distribution is clear in total sample (63.2%); however, I could not find the sex distribution of early-onset samples and late-onset samples. Does sex distribution significant different from early-onset samples and late-onset samples? Please indicate this. Discussion. “It is plausible that a family history of psychiatric problems may motivate females to seek clinical help earlier and to be more likely to take part in mental health research, compared to males. Females might also be more aware of and better able to recall the mental health difficulties of their relatives.” This bias could be corrected by parenting report instead of self -report. To support this hypothesis, Chen et al found equal genetic component but larger shared environmental components in female compared with male in self-reporting data; and the equal shared, and nonshared environmental factors for both female and males using parent-report data. “Furthermore, family history of psychiatric disorders captures factors beyond genetic risk, including shared exposures and experiences (e.g., trauma or bereavement). We are unable to differentiate between these possibilities using our study design.” It would be great if authors consider other shared environmental factors given the possibilities of dataset; e.g., Smoking, alcohol comsuption and education attendance. Reviewer #2: While there are a number of strengths to this study, there are a number of problems with the underlying premise and methods. Their premise is that women with depression and anxiety disorders will have greater genetic risk for neurodevelopmental disorders like ADHD and autism. This is surprising given that population and clinical studies have shown that people onsetting with major depression (clinically diagnosed) are less likely to have early cognitive deficits, deficits that are associated with neurodevelopmental disorders. In fact, boys/men have higher rates of ADHD, autism and other neurodevelopmental disorders. So, this reader is not sure from where their hypothesis emanated. Further, sex differences in depression emerge just post-puberty with young women onsetting at a greater rate than young men (and this holds across the lifespan as women have higher rates of depression than men). Finally, childhood onset depression does not show sex differences in incidence. (The age of <26 years as “early onset” does not reflect early onset.) Perhaps the previous studies on this topic from which they drew their hypotheses are reflecting the fact that across all psychiatric disorders, women experience higher levels of depressive and anxiety symptoms, just like women in general in the population. This may be one reason why depressive/anxiety symptomatology is associated with many psychiatric disorders and by sex. However, this is not telling us about major depression as a clinical diagnosis. It seems that the NCMH sample is more a reflection of symptomatology experienced rather than frank diagnoses. This is not a minor point - misclassification of disorder (based on self reports) can have different effects on findings than clinical diagnoses. The PGC data are a better reflection of the latter. In addition, the men in their sample were significantly different clinicially - greater severity, higher rate of neurodevelopmental disorders, greater substance use disorders - characteristics we know reflect men with MDD. Again, not sure then from where the original hypothesis is emanating if men in the sample themselves have higher rates of neurodevelopmental diagnoses. Are the authors suggesting that there may be higher genetic risk for neurodevelopmental disorders in women with depression that then are expressed as depression in women and not expressed in childhood as neurodevelopmental disorders? This seems convoluted. Additional point to address in the Introduction that stated no one had tested for sex differences in SNPS across disorders: Comorbidity of psychiatric disorders is pervasive and sex differences in shared SNPs were addressed for depression, bipolar disorder and schizophrenia in a large genome wide study in a recent paper in Biological Psychiatry by Blokland et al. ********** 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: Yes: Bochao Danae Lin 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.] 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. |
| Revision 1 |
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PONE-D-21-07612R1 Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression PLOS ONE Dear Dr. Martin, 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. ============================== ACADEMIC EDITOR: There's a minor comment that needs attention. ============================== Please submit your revised manuscript by Aug 01 2021 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:
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. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Sinan Guloksuz, M.D., Ph.D. Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] 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 Reviewer #2: (No Response) ********** 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 Reviewer #2: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 Reviewer #2: 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 Reviewer #2: 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: Although the authors mentioned that "the population ancestry variation captured by PCs beyond the top 5 PCs is minimal, reflecting the relatively small and ancestrally homogeneous nature of that sample.", the fraction of variance explained by top 5 PCs still not given in the manuscript, it is recommended to report. Thanks for the responses of the rest are clear. Reviewer #2: Authors primarliy responded adequately to concerns. One comment with respect to the diagnostic question of depression - The use of "self report of depressive symptomatology" as distinct from a clinical diagnosis of depression is not only a "minimally phenotyped definition" but may have genetic risk finding implications given that the latter is more likely to demonstrate genetic risk than the former. In fact, that may be one reason why the findings differ across samples. A comment as such is warranted or perhaps should be discussed with regard to implications for their findings. One additional minor note - In the introduction, the comment about “no SNPS showing genome-wide sex differences” gives the impression of a complete lack of sex differences in autosomal SNPs when this is not the complete story with regard to schizophrenia and major depression in the recent literature. ********** 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: Yes: Bochao Danae Lin 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.] 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. |
| Revision 2 |
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Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression PONE-D-21-07612R2 Dear Dr. Martin, 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, Sinan Guloksuz, M.D., Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: |
| Formally Accepted |
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PONE-D-21-07612R2 Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression Dear Dr. Martin: 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. Sinan Guloksuz Academic Editor PLOS ONE |
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