PONE-D-24-22709"Identifying Key Genes in COPD Risk via Multiple Population Data Integration and Gene Prioritization"PLOS ONE

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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: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: In this study, GWAS data from Japanese and European populations were utilized to investigate the association between lung function and genetic variants. Post-GWAS analyses were performed independently for each population cohort. Gene prioritization techniques were employed to identify genes of potential relevance, and independent SNPs that exhibited significant associations were identified. Furthermore, functional analyses were conducted to determine the functional associations between these identified genes and the lung function phenotype. The results revealed significant novel SNPs and genes that have not been reported by standard meta-analysis approach. These findings provided valuable insights into the multi-population GWAS, enhancing the understanding of the genetic landscape across divergent population.

Comment 1: In this study, three types of mapping approaches have been used to identify and prioritize the genes, with one of them as chromatin interaction mapping. In line 175, the authors stated that no genes were mapped as a result of chromatin interaction mapping in Japanese population, while two genes have been identified in European population. The authors should discuss the potential reasons for not identifying the genes in Japanese population. In Fig. 1, the results of chromatin interaction mapping in Japanese population should also be illustrated.

Comment 2: In Table 1, the Japanese population (N=14061) exhibits a significantly lower number of genomic risk loci, lead SNPs, independent SNPs, and candidate SNPs compared to the European population (N=79055). This discrepancy raises the question of whether the disparity is mainly due to differences in sample size or if other factors also contribute. The authors should discuss it comprehensively.

Comment 3: In line 234-236, the authors stated that they performed pathway analysis regarding 28 genes common to both populations. In Fig. 3, the results showed that the number of genes enriched for each pathway was around 2-3. The interactions among these genes were not illustrated thoroughly. Since the 28 genes are all protein-coding genes, protein-protein interaction network analysis should also be performed to better understand the functional relationships of genes in shared biological processes.

Comment 4: In line 244, the authors stated that the enrichment analysis was solely based on KEGG pathway. In general, the results of GO terms should also be provided. In addition, Supplementary Fig4 (line 245) was mistakenly cited as “the plot illustrating the top KEGG pathways associated with these genes”. The authors should correct it.

Comment 5: For Figure S1 and S2, the authors should provide detailed descriptions and explanations in the figure legends.

Comment 6:

Line 227: “The analysis showed that populations show” should be “The analysis showed that the populations exhibited”

Line 238: “Hydrolysis” should be “hydrolysis”

Line 245: “Genes were found” should be “The genes were found”

Line 246: “which indicates” should be “, indicating”;

“affect” should be “effects”;

“thus” should be “and”.

Line 252: “SNP” should be “SNPs”

Line 257-259: Should be changed into “There are several ways to perform post-GWAS. In this study, we performed cross-population post-GWAS to identify and prioritize significant genes and SNPs in each population, as well as to identify new independent significant SNPs and important phenotype-associated pathways and genes."

Line 263: “many” should be “both”

Line 280: "the regulatory enzyme" should be “the regulatory enzymes”, "which synthesize NO" should be "which synthesizes NO"

Line 287: “There's” should be “There has”

Line 334: “SNPs” should be “SNP”

Line 335-337: “We discovered…the European population GWAS.” should be “We discovered that a novel independent significant SNP, rs137893789, was mapped with TNXB with a CADD score of 15.21 in the European population GWAS using an LD-based specific population approach.”

Line 358-359: “Our study…mechanisms.” should be: “In this study, we utilized GWAS data, which is a commonly used method to identify risk-associated variants that play a crucial role in understanding complex genetic mechanisms.”

Line 368: “same” should be “the same”

Line 370: “underlaying” should be “underlying”

Line 385: “Lead” should be “lead”

Reviewer #2: This manuscript investigated the genetic variants associated with COPD risk, particularly focusing on the different ancestral genetic compositions across multiple datasets. The author first identified genes harboring variants associated with lung function decline within each GWAS cohort and then employed a “Multi-Population gene prioritization approach” to integrate results across studies. The authors reported 28 prioritized genes associated with the disease common across the populations and demonstrated the advantage of comparing the prioritized genes (in contrast to generating meta-analysis statistics) in identifying disease-associated biology when utilizing samples with diverse genetic backgrounds. The methods used in the paper were reasonable, and the paper was generally well written, and the method was described in detail.

Major comments

- The resolution of figures is low and it is hard to read the plot text. This is particularly true for Figure 1

- L56: “have been proven to be….”

- Please include a description of the model used for GWAS in each cohort, and whether they are directly comparable

- L120: is there a reason to choose a specific threshold of “CADD > 12.37”?

- L129: is only the lung data used?

- Several prioritized genes encode the MHC Class II molecules and are among the most polymorphic regions of the human genome. There have been GWAS studies that simply removed the MHC region. I believe this won’t affect the author’s results too much, but I wonder whether the author can comment on this, particularly how transethnic comparison may be affected by the MHC.

- L227-228: “The analysis showed that populations show genetic diversity, as different SNPs were 228 identified for the same gene in different populations” I think this is a very interesting observation. Is there previous work that makes similar findings? Does this attribute to the genetic background different, or potentially suggest different pathogenesis between populations?

- L277: This paragraph (and the later few as well) should belong to the discussion

- Code availability

Minor comments:

- While interchangeable, I believe “SNP” is more often used for GWAS, while SNV is usually used for somatic variants in the cancer studies

- Please make sure to use a consistent format for “trans-ethnic” or “transethnic”

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Reviewer #1: No

Reviewer #2: No

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Identifying key genes in COPD risk via multiple population data integration and gene prioritization

PONE-D-24-22709R1

Dear Dr. Zainab,

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,

Yonglan Zheng, Ph.D.

Academic Editor

PLOS ONE