Table 2. Susceptibility Loci Associated with Severe Covid-19 with Respiratory Failure.*.
| Chromosome and Analysis | Meta-analysis | Italian Panel | Spanish Panel | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| P Value | Odds Ratio (95% CI) |
P Value | Odds Ratio (95% CI) |
Allele Frequency | P Value | Odds Ratio (95% CI) |
Allele Frequency | |||
| patient | control | patient | control | |||||||
| 3p21.31† | ||||||||||
| Main analysis | 1.15×10−10 | 1.77 (1.48–2.11) |
1.98×10−7 | 1.74 (1.27–2.38) |
0.14 | 0.09 | 1.32×10−4 | 1.85 (1.50–2.28) |
0.09 | 0.05 |
| Analysis corrected for age and sex | 9.46×10−12 | 2.11 (1.70–2.61) |
7.02×10−8 | 1.95 (1.53–2.48) |
0.14 | 0.09 | 1.17×10−5 | 2.79 (1.76–4.42) |
0.09 | 0.05 |
| 9q34.2‡ | ||||||||||
| Main analysis | 4.95×10−8 | 1.32 (1.20–1.47) |
2.90×10−6 | 1.37 (1.20–1.57) |
0.42 | 0.35 | 3.55×10−3 | 1.26 (1.08–1.48) |
0.42 | 0.35 |
| Analysis corrected for age and sex | 5.35×10−7 | 1.39 (1.22–1.59) |
5.31×10−5 | 1.37 (1.17–1.60) |
0.42 | 0.35 | 2.81×10−3 | 1.45 (1.13–1.84) |
0.42 | 0.35 |
The meta-analysis included 1610 patients and 2205 control participants; the Italian analysis, 835 and 1255, respectively; and the Spanish analysis, 775 and 950, respectively. Allele frequencies of the minor or risk allele (see below) are shown among the patients and the control participants. All the association test statistics were adjusted for the top 10 principal components from the principal-component analysis. Two analyses were performed: a main analysis, which was corrected for 10 principal components, and an analysis that was corrected for age and sex in addition to 10 principal components. In the analyses that were corrected for age and sex, 25 control participants were excluded from the Spanish analysis and the meta-analysis because of missing covariate data. The P values and corresponding odds ratios and 95% confidence intervals (CIs) are shown with respect to the minor allele. Association results for the recessive and heterozygous models for both meta-analyses (main and corrected for age and sex) are shown in Supplementary Appendix 3. Covid-19 denotes coronavirus disease 2019.
For chromosome 3p21.31, the association boundaries for each index single-nucleotide polymorphism (SNP; see the Supplementary Methods section), with the genomic positions retrieved from genome build hg38, were chr3:45800446 through 46135604. The Single Nucleotide Polymorphism database (dbSNP) identifier was rs11385942 (the rs identifier from the National Center for Biotechnology Information, rs11385942, is annotated as chr3:45834968 through 45834969:AAA:AA in dbSNP, version 153, and as chr3:45834967:GA:G in the Trans-Omics for Precision Medicine [TOPMed] imputation reference panel). The SNP rs11385942 was imputed according to TOPMed with high confidence (TOPMed estimated imputation accuracy, R2=0.94 and R2=0.95 for the Italian and Spanish panels, respectively) (Supplementary Appendix 2).The minor or risk allele was GA, and the major allele was G. The key genes (i.e., the candidate genes in the region) were SLC6A20, LZTFL1, FYCO1, CXCR6, XCR1, and CCR9.
For chromosome 9q34.2, the association boundaries for each index SNP, with the genomic positions retrieved from genome build hg38, were chr9:133257521 through 133279871. The SNP rs657152 was genotyped according to the Global Screening Array (GSA) in the Italian and Spanish panels (Supplementary Appendix 2). The minor or risk allele was A, and the major allele was C. The key gene was ABO.