Detailed stratified GWAS analysis for severe COVID-19 in four European populations

Abstract

Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.

Mental health and COVID-19 in a general population cohort in Spain (COVICAT study)

“…Increased severity of COVID-19 among people with pre-pandemic mental conditions may be therefore better explained by common molecular mechanisms acting at the central level. We have observed that some of the candidate genes of the 17q21.31 inversion locus associated with severity show a strong expression enrichment in the neural system [ 39 ]. For example, protein coding genes including ARL17B , STH , KANSL1 , LRRC37A2 , MAPT , NSF , PLEKHM1 and CRHR1 show high expression in brain tissues and pituitary gland.…”

Genomic architecture and functional effects of potential human inversion supergenes

“…The 17q21.31 inversion stands out for its pleiotropic phenotypic effects and it has been involved in an increasing number of diverse traits [ 12 , 14 , 19 , 20 , 28 , 29 ]. To update and understand better these effects, we have done an exhaustive analysis and manual curation of the GWAS hits ( p < 5 × 10 −8 ) corresponding to all SNPs in high LD ( r 2 > 0.8) with the inversion listed in the GWAS Catalog [ 30 ] (summarized together with their supporting studies in the electronic supplementary material, table S2).…”

“…Moreover, our analysis suggests that H2 selection in Europeans could be more complex than initially thought, involving other traits besides fertility. In particular, there are several phenotypes potentially involved in immune response, a highly selected trait, and it has been recently found that the inversion protects against severe COVID-19 [ 29 ], which could be related to changes in immune cells, lung function or even red blood cell levels. Nevertheless, so far there is little information about the molecular causes behind these phenotypic differences.…”

Poking COVID-19: insights on genomic constraints among immune-related genes between Qatari and Italian populations

“…Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, lead-ing to better targeting of care and vaccination [5][6][7]. In addition, characterizing these host factors may help identifying and development of adapted drugs and vaccines [8][9][10]. The scientific community came together with several efforts to investigate how the genomic variation in the host affects disease susceptibil-ity and progress [11,12].…”