Novel genes and sex differences in COVID-19 severity

Abstract

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10−22 and p = 8.1x10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10−8) and ARHGAP33 (p = 1.3x10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Genome-wide screening of sex-biased genetic variants potentially associated with COVID-19 hospitalization

“…We revealed that rs17763742 and rs13071258 are in complete LD ( R 2 = 1; D’ = 1) in European population; the other two SNPs are in weak LD to rs13071258 in European population, with R 2 = 0.08 for rs13071258 vs. rs115679256 and R 2 = 0.43 for rs13071258 vs. rs17763742. We confirmed that most of these published COVID-19 SNPs by Cruz et al ( Cruz et al, 2022 ) are replicable in the current sex-stratified COVID-19 GWASs in either males or females. The lack of replication of sex-biased differential associations for these SNPs in current study may attribute to the relatively small sample sizes of current UK Biobank GWASs.…”

“…We further evaluated previously published COVID-19 risk SNPs showing genome-wide significant association signals in either females/males or both sexes published by Cruz et al (Cruz et al, 2022) in the currently used UK Biobank COVID-19 hospitalization GWASs. We obtained summary statistics of nine genome-wide significant SNPs emerged in sex-unstratified or sex-stratified COVID-19 GWASs from Cruz and colleagues ( Cruz et al, 2022 ).…”

“…We further evaluated previously published COVID-19 risk SNPs showing genome-wide significant association signals in either females/males or both sexes published by Cruz et al (Cruz et al, 2022) in the currently used UK Biobank COVID-19 hospitalization GWASs. We obtained summary statistics of nine genome-wide significant SNPs emerged in sex-unstratified or sex-stratified COVID-19 GWASs from Cruz and colleagues ( Cruz et al, 2022 ). After performing Z-test to determine differential association signals between females and males for these SNPs, we only found three SNPs passed the ΔZ-score p value threshold of p < 0.05 ( Supplementary Figure S1 ) in the data set from Cruz et al ( Cruz et al, 2022 ).…”

“…We obtained summary statistics of nine genome-wide significant SNPs emerged in sex-unstratified or sex-stratified COVID-19 GWASs from Cruz and colleagues ( Cruz et al, 2022 ). After performing Z-test to determine differential association signals between females and males for these SNPs, we only found three SNPs passed the ΔZ-score p value threshold of p < 0.05 ( Supplementary Figure S1 ) in the data set from Cruz et al ( Cruz et al, 2022 ). In the currently used UK Biobank COVID-19 GWASs of females and males, none of these nine SNPs demonstrated differential association between sexes with COVID-19 (all ΔZ-score p > 0.1; Supplementary Figure S1 ).…”

“…Furthermore, previously published COVID-19 GWASs mainly focused on both sexes altogether or considered males and females separately ( Tu et al, 2020 ; Viveiros et al, 2021 ). Recently, several COVID-19 risk SNPs have been reported by sex-stratified GWASs, such as rs17763742, rs4443214, and rs35477280, which are three risk SNPs located in the famous 3p21.31 region and are predominantly associated with COVID-19 in males ( Cruz et al, 2022 ). However, due to the requirement of large sample sizes for both sexes, the determination of the interaction between SNPs and sexes with COVID-19 severity/hospitalization was hindered.…”