Title: Genetic evidence causally linking gastroesophageal reflux disease to cholecystitis#A two-
sample Mendelian randomization study
Version: 0 Date: 10 Feb 2024
Reviewer's report:
Some advices/questions as follow:
Abstract Part
Methods:
1. To enable readers to see the population structure of the study at a glance, it is suggested that
the following format be modified  …GWAS for GERD (n=602604)… to …GWAS for GERD
(Ncase= ; Ncontrol= ); cholecystitis as too.
2. As the author mentioned, the GWAS data for this study were obtained from the MR-base
platform, but it is inconsistent with the data extraction platform described in Part 2.1 of the text.
Please check it carefully.
Results:
1. A total of 77 single nucleotide polymorphisms (SNPs) from GWASs...
2. The absence of heterogeneity and pleiotropy in the data suggested that the results were
dependable. Not in your data, it's depending on your sensitivity analysis result. Please check
whether the statement is appropriate.
Introduction Part
1. There is a need for more epidemiological data on the prevalence of GERD and cholecystitis.
2. The structure and background of the introduction part needs further adjustment and
enrichment. For example, the author only outlined the risk factors for cholecystitis, and the
following sentence immediately mentioned the unclear causal relationship between GERD
and cholecystitis.  Why? This kind of background description seems somewhat inappropriate.
Furthermore, later in the text, when the use of MR for analysis is introduced, there is no need to
describe too much about RCTs. It is sufficient to explain the advantages of using MR methods
and the need for this study.
3. Overall, it’s advising to restructuring the Introduction Part.
Materials and Method Part
2.1 Data source and IV selection
1. ...exposure data for GERD(14) was obtained from the most comprehensive and up-to-
date genome-wide association studies (GWAS) comprising 602,604 individuals of European
ancestry...
The GERD GWAS data used in this study is not up to date, and the number of SNPS is only
about 2m. I suggest rephrasing this sentence!
2. proxy SNPs? Where to find those SNPs? Can the author point out which SNP is the proxy
and describe details like table S1?
3. F statistic? or F-Statistics? Please check and keep the terms mentioned in all texts consistent,
just like the mentioned
2.2 MR statistical methods
1. invalid instruments? or invalid IVs?  ...even when up to 50% of the genetic instruments used
are invalid...    genetic instruments? or IVs?
Please check and keep the terms mentioned in all texts consistent
2.3 Sensitivity analysis
1. It is only necessary to describe the method used in the sensitivity analysis. The results need
not be disclosed.
2. The heterogeneity was tested using a funnel plot, and the absence of heterogeneity was
demonstrated by a symmetry plot. ?
Rather than using the funnel/ symmetry plot for a sensitivity analysis, I think it is a way of
presenting the results.
3. Overall, this part of the description is in need of revision
Results Part
3.1 Detail Information of the Included Instrumental variables (IVs)
1. Describing the main information of those Ivs
2. 7 SNPs were found to have significant associations with both GERD and cholecystitis
What is meant by listing the 7 SNPS?
Discussion Part
1. Please shorten the description of the MR methodology
2. Discussing the potential mechanisms underlying GERD and cholecystitis could be further
enriched
Furthermore, it is recommended that the author carefully check all the text for grammatical and
statement errors in the text!
Title: Genetic evidence causally linking gastroesophageal reflux disease to cholecystitis#A two-
sample Mendelian randomization study
Version: 0 Date: 10 Feb 2024
Reviewer's report:
Some advices/questions as follow:
Abstract Part
Methods:
1. To enable readers to see the population structure of the study at a glance, it is suggested that
the following format be modified  …GWAS for GERD (n=602604)… to …GWAS for GERD
(Ncase= ; Ncontrol= ); cholecystitis as too.
2. As the author mentioned, the GWAS data for this study were obtained from the MR-base
platform, but it is inconsistent with the data extraction platform described in Part 2.1 of the text.
Please check it carefully.
Results:
1. A total of 77 single nucleotide polymorphisms (SNPs) from GWASs...
2. The absence of heterogeneity and pleiotropy in the data suggested that the results were
dependable. Not in your data, it's depending on your sensitivity analysis result. Please check
whether the statement is appropriate.
Introduction Part
1. There is a need for more epidemiological data on the prevalence of GERD and cholecystitis.
2. The structure and background of the introduction part needs further adjustment and
enrichment. For example, the author only outlined the risk factors for cholecystitis, and the
following sentence immediately mentioned the unclear causal relationship between GERD
and cholecystitis.  Why? This kind of background description seems somewhat inappropriate.
Furthermore, later in the text, when the use of MR for analysis is introduced, there is no need to
describe too much about RCTs. It is sufficient to explain the advantages of using MR methods
and the need for this study.
3. Overall, it’s advising to restructuring the Introduction Part.
Materials and Method Part
2.1 Data source and IV selection
1. ...exposure data for GERD(14) was obtained from the most comprehensive and up-to-
date genome-wide association studies (GWAS) comprising 602,604 individuals of European
ancestry...
The GERD GWAS data used in this study is not up to date, and the number of SNPS is only
about 2m. I suggest rephrasing this sentence!
2. proxy SNPs? Where to find those SNPs? Can the author point out which SNP is the proxy
and describe details like table S1?
3. F statistic? or F-Statistics? Please check and keep the terms mentioned in all texts consistent,
just like the mentioned
2.2 MR statistical methods
1. invalid instruments? or invalid IVs?  ...even when up to 50% of the genetic instruments used
are invalid...    genetic instruments? or IVs?
Please check and keep the terms mentioned in all texts consistent
2.3 Sensitivity analysis
1. It is only necessary to describe the method used in the sensitivity analysis. The results need
not be disclosed.
2. The heterogeneity was tested using a funnel plot, and the absence of heterogeneity was
demonstrated by a symmetry plot. ?
Rather than using the funnel/ symmetry plot for a sensitivity analysis, I think it is a way of
presenting the results.
3. Overall, this part of the description is in need of revision
Results Part
3.1 Detail Information of the Included Instrumental variables (IVs)
1. Describing the main information of those Ivs
2. 7 SNPs were found to have significant associations with both GERD and cholecystitis
What is meant by listing the 7 SNPS?
Discussion Part
1. Please shorten the description of the MR methodology
2. Discussing the potential mechanisms underlying GERD and cholecystitis could be further
enriched
Furthermore, it is recommended that the author carefully check all the text for grammatical and
statement errors in the text!
Please review this paper.
user
Title: Genetic evidence causally linking gastroesophageal reflux disease to cholecystitis#A two-
sample Mendelian randomization study
Version: 0 Date: 10 Feb 2024
Reviewer's report:
Some advices/questions as follow:
Abstract Part
Methods:
1. To enable readers to see the population structure of the study at a glance, it is suggested that
the following format be modified  …GWAS for GERD (n=602604)… to …GWAS for GERD
(Ncase= ; Ncontrol= ); cholecystitis as too.
2. As the author mentioned, the GWAS data for this study were obtained from the MR-base
platform, but it is inconsistent with the data extraction platform described in Part 2.1 of the text.
Please check it carefully.
Results:
1. A total of 77 single nucleotide polymorphisms (SNPs) from GWASs...
2. The absence of heterogeneity and pleiotropy in the data suggested that the results were
dependable. Not in your data, it's depending on your sensitivity analysis result. Please check
whether the statement is appropriate.
Introduction Part
1. There is a need for more epidemiological data on the prevalence of GERD and cholecystitis.
2. The structure and background of the introduction part needs further adjustment and
enrichment. For example, the author only outlined the risk factors for cholecystitis, and the
following sentence immediately mentioned the unclear causal relationship between GERD
and cholecystitis.  Why? This kind of background description seems somewhat inappropriate.
Furthermore, later in the text, when the use of MR for analysis is introduced, there is no need to
describe too much about RCTs. It is sufficient to explain the advantages of using MR methods
and the need for this study.
3. Overall, it’s advising to restructuring the Introduction Part.
Materials and Method Part
2.1 Data source and IV selection
1. ...exposure data for GERD(14) was obtained from the most comprehensive and up-to-
date genome-wide association studies (GWAS) comprising 602,604 individuals of European
ancestry...
The GERD GWAS data used in this study is not up to date, and the number of SNPS is only
about 2m. I suggest rephrasing this sentence!
2. proxy SNPs? Where to find those SNPs? Can the author point out which SNP is the proxy
and describe details like table S1?
3. F statistic? or F-Statistics? Please check and keep the terms mentioned in all texts consistent,
just like the mentioned
2.2 MR statistical methods
1. invalid instruments? or invalid IVs?  ...even when up to 50% of the genetic instruments used
are invalid...    genetic instruments? or IVs?
Please check and keep the terms mentioned in all texts consistent
2.3 Sensitivity analysis
1. It is only necessary to describe the method used in the sensitivity analysis. The results need
not be disclosed.
2. The heterogeneity was tested using a funnel plot, and the absence of heterogeneity was
demonstrated by a symmetry plot. ?
Rather than using the funnel/ symmetry plot for a sensitivity analysis, I think it is a way of
presenting the results.
3. Overall, this part of the description is in need of revision
Results Part
3.1 Detail Information of the Included Instrumental variables (IVs)
1. Describing the main information of those Ivs
2. 7 SNPs were found to have significant associations with both GERD and cholecystitis
What is meant by listing the 7 SNPS?
Discussion Part
1. Please shorten the description of the MR methodology
2. Discussing the potential mechanisms underlying GERD and cholecystitis could be further
enriched
Furthermore, it is recommended that the author carefully check all the text for grammatical and
statement errors in the text!
assistant