Novel risk loci for COVID-19 hospitalization among admixed American populations

Reviewer #1 (Public Review):

Summary:
This paper conducted a GWAS meta-analysis for COVID-19 hospitalization among admixed American populations. The authors identified four genome-wide significant associations, including two novel loci (BAZ2B and DDIAS), and an additional risk locus near CREBBP using cross-ancestry meta-analysis. They utilized multiple strategies to prioritize risk variants and target genes. Finally, they constructed and assessed a polygenic risk score model with 49 variants associated with critical COVID-19 conditions.

Strengths:
Given that most of the previous studies were done in European ancestries, this study provides unique findings about the genetics of COVID-19 in admixed American populations. The GWAS data would be a valuable resource for the community. The authors conducted comprehensive analyses using multiple different strategies, including Bayesian fine mapping, colocalization, TWAS, etc., to prioritize risk variants and target genes. The polygenic risk score (PGS) result demonstrated the ability of the cross-population PGS model for COVID-19 risk stratification.

Weaknesses:
1. One of the major limitations of this study is that the GWAS sample size is relatively small, which limits its power.

2. The fine mapping section is unclear and there is a lack of information. The authors assumed one causal signal per locus, and only provided credible sets, but did not provide posterior inclusion probabilities (PIP) for the variants to be causal.

3. Colocalization and TWAS used eQTL data from GTEx data, which are mainly from European ancestries. It is unclear how much impact the ancestry mismatch would have on the result. The readers should be cautious when interpreting the results and designing follow-up studies.

Reviewer #2 (Public Review):

This is a genome-wide association study of COVID-19 in individuals of admixed American ancestry (AMR) recruited from Brazil, Colombia, Ecuador, Mexico, Paraguay, and Spain. After quality control and admixture analysis, a total of 3,512 individuals were interrogated for 10,671,028 genetic variants (genotyped + imputed). The genetic association results for these cohorts were meta-analyzed with the results from The Host Genetics Initiative (HGI), involving 3,077 cases and 66,686 controls. The authors found two novel genetic loci associated with COVID-19 at 2q24.2 (rs13003835) and 11q14.1 (rs77599934), and other two independent signals at 3p21.31 (rs35731912) and 6p21.1 (rs2477820) already reported as associated with COVID-19 in previous GWASs. Additional meta-analysis with other HGI studies also suggested risk variants near CREBBP, ZBTB7A, and CASC20 genes.

Strengths:
These findings rely on state-of-the-art methods in the field of Statistical Genomics and help to address the issue of a low number of GWASs in non-European populations, ultimately contributing to reducing health inequalities across the globe.

Weaknesses:
There is no replication cohort, as acknowledged by the authors (page 29, line 587), and no experimental validation to assess the biological effect of putative causal variants/genes. Thus, the study provides good evidence of association, rather than causation, between the genetic variants and COVID-19. Lastly, I consider it crucial to report the results for the SCOURGE Latin American GWAS, in addition to its meta-analysis with HGI results, since HGI data has a different phenotype scheme (Hospitalized COVID vs Population) compared to SCOURGE (Hospitalized COVID vs Non-hospitalized COVID).

Reviewer #3 (Public Review):

Summary:
In the context of the SCOURGE consortium's research, the authors conduct a GWAS meta-analysis on 4,702 hospitalized individuals of admixed American descent suffering from COVID-19. This study identified four significant genetic associations, including two loci initially discovered in Latin American cohorts. Furthermore, a trans-ethnic meta-analysis highlighted an additional novel risk locus in the CREBBP gene, underscoring the critical role of genetic diversity in understanding the pathogenesis of COVID-19.

Strengths:
1. The study identified two novel severe COVID-19 loci (BAZ2B and DDIAS) by the largest GWAS meta-analysis for COVID-19 hospitalization in admixed Americans.

2. With a trans-ethnic meta-analysis, an additional risk locus near CREBBP was identified.

Weaknesses:
1. The GWAS power is limited due to the relatively small number of cases.

2. There is no replication study for the novel severe COVID-19 loci, which may lead to false positive findings.

3. Significant differences exist in the ages between cases and controls, which could potentially introduce biased confounders. I'm curious about how the authors treated age as a covariate. For instance, did they use ten-year intervals? This needs clarification for reproducibility.

4."Those in the top PGS decile exhibited a 5.90-fold (95% CI=3.29-10.60, p=2.79x10-9) greater risk compared to individuals in the lowest decile". I would recommend comparing with the 40-60% PGS decile rather than the lowest decile, as the lowest PGS decile does not represent 'normal controls'.

5. In the field of PGS, it's common to require an independent dataset for training and testing the PGS model. Here, there seems to be an overfitting issue due to using the same subjects for both training and testing the variants.

6. The variants selected for the PGS appear arbitrary and may not leverage the GWAS findings without an independent training dataset.

7. The TWAS models were predominantly trained on European samples, and there is no replication study for the findings as well.