Integrative genomic analyses identify susceptibility genes underlying COVID-19 hospitalization

Abstract

Despite rapid progress in characterizing the role of host genetics in SARS-Cov-2 infection, there is limited understanding of genes and pathways that contribute to COVID-19. Here, we integrate a genome-wide association study of COVID-19 hospitalization (7,885 cases and 961,804 controls from COVID-19 Host Genetics Initiative) with mRNA expression, splicing, and protein levels (n = 18,502). We identify 27 genes related to inflammation and coagulation pathways whose genetically predicted expression was associated with COVID-19 hospitalization. We functionally characterize the 27 genes using phenome- and laboratory-wide association scans in Vanderbilt Biobank (n = 85,460) and identified coagulation-related clinical symptoms, immunologic, and blood-cell-related biomarkers. We replicate these findings across trans-ethnic studies and observed consistent effects in individuals of diverse ancestral backgrounds in Vanderbilt Biobank, pan-UK Biobank, and Biobank Japan. Our study highlights and reconfirms putative causal genes impacting COVID-19 severity and symptomology through the host inflammatory response.

Update on human genetic susceptibility to COVID-19: susceptibility to virus and response

“…[ 66 ] rs115492982—intronic variant of MRPS21 2.5 0.02 Dite et al [ 63 ] rs74956615—3'UTR variant of TYK2 1.6 0.03 Pairo-Castineira et al [ 11 ] rs2034831—intronic variant of ITGA4 1.2 0.05 Dite et al [ 63 ] rs76374459—intronic variant of LZTFL1 1.2 0.05 Dite et al [ 63 ] rs35652899—intronic variant of LZTFL1 1.2 0.05 Dite et al [ 63 ] rs10490770—intronic variant of LZTFL1 2.0 0.06 COVID-19 H.G.I. [ 66 ] rs333—CCR5-Δ32 0.7 0.07 Cuesta-Llavona et al [ 76 ] rs73064425—intronic variant of LZTFL1 2.1 0.08 Pairo-Castineira et al [ 11 ], Ellinghaus et al [ 23 ] rs11385942—intronic variant of LZTFL1 1.8 0.07 Ellinghaus et al [ 23 ] rs1886814—intronic variant of FOXP4 1.3 0.07 COVID-19 H.G.I. [ 66 ] rs76488148—intronic variant of GYG1 1.3 0.07 Dite et al [ …”

“…[ 66 ] rs333—CCR5-Δ32 0.7 0.07 Cuesta-Llavona et al [ 76 ] rs73064425—intronic variant of LZTFL1 2.1 0.08 Pairo-Castineira et al [ 11 ], Ellinghaus et al [ 23 ] rs11385942—intronic variant of LZTFL1 1.8 0.07 Ellinghaus et al [ 23 ] rs1886814—intronic variant of FOXP4 1.3 0.07 COVID-19 H.G.I. [ 66 ] rs76488148—intronic variant of GYG1 1.3 0.07 Dite et al [ 63 ] rs2271616—5'UTR variant of SLC6A20 1.1 0.08 COVID-19 H.G.I. [ 66 ] HLA-DQB1*06:02 N.A 0.08 Novelli et al [ 51 ] rs143334143—intronic variant of CCHCR1 1.9 0.09 Pairo-Castineira et al [ 11 ] HLA-DRB1*15:01 N.A 0.10 Novelli et al [ 51 ] rs12252:G allele of IFITM3 2.2 0.13 Alghamdi et al [ 52 ] rs4801778—intronic variant of PLEKHA4 1.0 0.16 COVID-19 H.G.I.…”

“…[ 66 ] rs76488148—intronic variant of GYG1 1.3 0.07 Dite et al [ 63 ] rs2271616—5'UTR variant of SLC6A20 1.1 0.08 COVID-19 H.G.I. [ 66 ] HLA-DQB1*06:02 N.A 0.08 Novelli et al [ 51 ] rs143334143—intronic variant of CCHCR1 1.9 0.09 Pairo-Castineira et al [ 11 ] HLA-DRB1*15:01 N.A 0.10 Novelli et al [ 51 ] rs12252:G allele of IFITM3 2.2 0.13 Alghamdi et al [ 52 ] rs4801778—intronic variant of PLEKHA4 1.0 0.16 COVID-19 H.G.I. [ 66 ] rs6598045—5'UTR variant of IFITM3 N.A 0.19 Kim et al [ 53 ] rs429358—missense variant of APOE 2.3–2.4 0.20 Kuo et al [ 65 ] rs12610495—intronic variant of DPP9 N.A 0.25 Moon et al [ 41 ] rs12329760—intronic variant of TMPRSS2/MX1 0.9 0.25 Andolfo et al [ 72 ] rs2298661—missense va...…”

“…[ 66 ] rs6598045—5'UTR variant of IFITM3 N.A 0.19 Kim et al [ 53 ] rs429358—missense variant of APOE 2.3–2.4 0.20 Kuo et al [ 65 ] rs12610495—intronic variant of DPP9 N.A 0.25 Moon et al [ 41 ] rs12329760—intronic variant of TMPRSS2/MX1 0.9 0.25 Andolfo et al [ 72 ] rs2298661—missense variant of TMPRSS2/MX1 0.9 0.25 Andolfo et al [ 72 ] rs3787946—intronic variant of TMPRSS2/MX1 0.9 0.28 Andolfo et al [ 72 ] rs9983330—intronic variant of TMPRSS2/MX1 0.9 0.28 Andolfo et al [ 72 ] rs9380142—3'UTR variant of HLA-G 13 0.29 Pairo-Castineira et al [ 11 ] rs2109069—intronic variant of DPP9 1.4 0.33 Pairo-Castineira et al [ 11 ], COVID-19 H.G.I. [ 66 ] rs9985159—intronic variant of TMPRSS2/MX1 0.9 0.33 Andolfo et al [ 72 ] Rs75603675—missense variant of TMPRSS2 N.A 0.36 …”

“…[ 66 ] rs9985159—intronic variant of TMPRSS2/MX1 0.9 0.33 Andolfo et al [ 72 ] Rs75603675—missense variant of TMPRSS2 N.A 0.36 Latini et al [ 71 ] rs1405655—intronic variant of NR1H2 1.1 0.37 COVID-19 H.G.I. [ 66 ] rs12329760—missense variant of TMPRSS2 0.9 0.39 Hou et al [ 73 ] rs657152—intronic variant of ABO 1.3 0.41 Ellinghaus et al [ 23 ] rs677800—intronic variant of ABO N.A 0.55 Moon et al [ 41 ] rs6020298—intronic variant of TMEM189-UBE2V1 1.2 0.58 Wang et al [ 74 ] rs10735079—intronic variant of OAS1/3 1.3 0.64 Pairo-Castineira et al [ 11 ] rs8065800—intronic variant of MAPT 1.7 0.65 COVID-19 H.G.I. [ 66 ] rs10774671—intronic, splicing variant of OAS1 1.1 0.67 COVID-19 H.G.I.…”