Table 1 Seventy-six significant gene–COVID-19 severity associations based on cross-methylome omnibus (CMO) analyses of the COVID-19 Host Genetics Initiative data (version 5; B2 outcome focusing on Europeans).
From: An integrative multiomics analysis identifies putative causal genes for COVID-19 severity
Chr | Gene | Start (build37) | End (build37) | Number of enhancer | Number of CpGs in enhancers | Number of CpGs in gene body regions | CMO P valuea | False discovery rate (FDR) | Known function of the geneb |
|---|---|---|---|---|---|---|---|---|---|
1 | APITD1 | 10490159 | 10512210 | 0 | 0 | 11 | 6.58 × 10−16 | 6.65 × 10−13 | Expressed at very low levels in neuroblastoma tumors; may have a role in a cell death pathway |
1 | TPM3 | 154127784 | 154167124 | 3 | 10 | 16 | 7.52 × 10−6 | 3.80 × 10−3 | Variants result in autosomal dominant nemaline myopathy and other muscle disorders |
2 | PLCD4 | 219472488 | 219501907 | 4 | 11 | 2 | 4.58 × 10−11 | 3.03 × 10−8 | Expression may be a marker for cancer |
3 | SACM1L | 45730548 | 45786916 | 9 | 19 | 2 | 1.90 × 10−9 | 1.21 × 10−6 | Deletion in mouse results in preimplantation lethality; involved in the organization of Golgi membranes and mitotic spindles |
3 | SLC6A20 | 45796942 | 45838027 | 1 | 4 | 4 | 4.86 × 10−29 | 7.59 × 10−26 | Functions as a proline transporter expressed in kidney and small intestine; variants are associated with hyperglycinuria and iminoglycinuria |
3 | LZTFL1 | 45864808 | 45957534 | 2 | 4 | 10 | 1.22 × 10−29 | 3.00 × 10−26 | Nonsense variants cause a form of Bardet–Biedl syndrome; may also function as a tumor suppressor |
3 | CCR9 | 45927996 | 45944667 | 1 | 3 | 4 | 1.82 × 10−29 | 3.91 × 10−26 | A role in directing immune responses to different segments of the gastrointestinal tract; overexpressed in a variety of malignant tumors and is closely associated with tumor proliferation, apoptosis, invasion, migration and drug resistance |
3 | FYCO1 | 45959396 | 46037316 | 8 | 24 | 11 | 2.13 × 10−30 | 6.37 × 10−27 | Variants are associated with inclusion body myositis and autosomal recessive congenital cataracts |
3 | CXCR6 | 45982425 | 45989845 | 6 | 16 | 4 | 2.22 × 10−30 | 6.37 × 10−27 | Controls the localization of resident memory T lymphocytes to different compartments of the lung and maintains airway resident memory T lymphocytes, which are an important first line of defense against respiratory pathogens |
3 | XCR1 | 46058516 | 46069234 | 3 | 11 | 4 | 8.59 × 10−32 | 1.48 × 10−27 | It transduces a signal by increasing the intracellular calcium ions level; the viral macrophage inflammatory protein II is an antagonist of this receptor and blocks signaling |
3 | NRBF2P2 | 46064788 | 46065648 | 0 | 0 | 2 | 3.19 × 10−31 | 2.00 × 10−27 | A pseudogene |
3 | CCR3 | 46205096 | 46308197 | 0 | 0 | 11 | 3.48 × 10−31 | 2.00 × 10−27 | May contribute to the accumulation and activation of eosinophils and other inflammatory cells in the allergic airway; also known to be an entry coreceptor for HIV-1 |
3 | CCR1 | 46243200 | 46249887 | 5 | 14 | 4 | 1.10 × 10−30 | 4.74 × 10−27 | Plays a role in host protection from inflammatory response, and susceptibility to virus and parasite |
3 | CCR2 | 46395225 | 46402419 | 4 | 11 | 5 | 1.24 × 10−28 | 1.77 × 10−25 | Encodes a protein which is a receptor for monocyte chemoattractant protein-1, which is involved in monocyte infiltration in inflammatory diseases; protein can be a coreceptor with CD4 for HIV-1 infection |
3 | CCR5 | 46411633 | 46417697 | 2 | 4 | 2 | 4.63 × 10−29 | 7.59 × 10−26 | This protein is expressed by T cells and macrophages, and is known to be an important coreceptor for macrophage-tropic virus, including HIV, to enter host cells |
3 | CCRL2 | 46448654 | 46454488 | 6 | 15 | 4 | 4.31 × 10−29 | 7.59 × 10−26 | Expressed at high levels in primary neutrophils and primary monocytes, and is further upregulated on neutrophil activation and during monocyte to macrophage differentiation |
3 | RTP3 | 46538981 | 46542439 | 4 | 16 | 4 | 1.27 × 10−12 | 1.09 × 10−9 | Related pathways include signaling by GPCR and olfactory transduction |
5 | FTH1P10 | 17353804 | 17354733 | 0 | 0 | 2 | 3.17 × 10−5 | 0.01 | A pseudogene |
5 | SLC30A5 | 68389473 | 68426896 | 4 | 10 | 2 | 1.15 × 10−25 | 1.41 × 10−22 | Encodes a member of the SLC30A/ZnT family of zinc transporter proteins; ZnT proteins mediate both cellular zinc efflux and zinc sequestration into membrane-bound organelles |
5 | MARVELD2 | 68710939 | 68740157 | 2 | 14 | 8 | 2.10 × 10−25 | 2.41 × 10−22 | Encoded protein helps establish epithelial barriers such as those in the organ of Corti, where these barriers are required for normal hearing; defects in this gene are a cause of deafness autosomal recessive type 49 |
5 | OCLN | 68788119 | 68853931 | 1 | 6 | 6 | 5.73 × 10−26 | 7.58 × 10−23 | Variants in this gene are thought to be a cause of band-like calcification with simplified gyration and polymicrogyria (BLC-PMG), an autosomal recessive neurologic disorder that is also known as pseudo-TORCH syndrome |
5 | RAPGEF6 | 130759614 | 130970929 | 2 | 3 | 4 | 2.19 × 10−4 | 0.05 | Associated with schizoid personality disorder |
6 | SPDEF | 34505579 | 34524110 | 1 | 6 | 7 | 1.19 × 10−4 | 0.03 | Highly expressed in the prostate epithelial cells, and functions as an androgen-independent transactivator of prostate-specific antigen (PSA) promoter; higher expression of this protein has also been reported in brain, breast, lung, and ovarian tumors, compared to the corresponding normal tissues |
7 | SVOPL | 138279030 | 138386097 | 1 | 2 | 6 | 2.02 × 10−5 | 9.38 × 10−3 | The protein encoded by this gene is thought to be a member of solute carrier family 22, which includes transmembrane proteins that transport toxins and drugs from the body |
9 | DDX31 | 135468384 | 135545788 | 6 | 19 | 2 | 9.78 × 10−5 | 0.03 | Putative RNA helicase likely implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly |
9 | GTF3C4 | 135545422 | 135570342 | 4 | 18 | 1 | 9.22 × 10−5 | 0.02 | Essential for RNA polymerase III to make a number of small nuclear and cytoplasmic RNAs, including 5S RNA, tRNA, and adenovirus-associated (VA) RNA of both cellular and viral origin |
9 | RALGDS | 135973107 | 136039301 | 2 | 13 | 20 | 4.57 × 10−5 | 0.02 | Associated with dystonia 16 and cardiofaciocutaneous syndrome 1 |
9 | GBGT1 | 136028340 | 136039332 | 2 | 17 | 6 | 2.91 × 10−5 | 0.01 | Encodes a glycosyltransferase that plays a role in the synthesis of Forssman glycolipid (FG); glycolipids such as FG form attachment sites for the binding of pathogens to cells; expression of this protein may determine host tropism to microorganisms; associated with inflammatory bowel disease 19 and Niemann–Pick disease, type C1 |
9 | OBP2B | 136080664 | 136084630 | 1 | 2 | 1 | 3.32 × 10−6 | 1.78 × 10−3 | Probably binds and transports small hydrophobic volatile molecules |
9 | LCN1P1 | 136100292 | 136103993 | 0 | 0 | 1 | 7.09 × 10−6 | 3.69 × 10−3 | A pseudogene, may bind a variety of ligands including lipids |
9 | SURF1 | 136218610 | 136223552 | 0 | 0 | 3 | 5.42 × 10−5 | 0.02 | Defects are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency |
9 | SURF2 | 136223428 | 136228045 | 0 | 0 | 2 | 2.16 × 10−4 | 0.05 | Associated with hypotonia–cystinuria syndrome |
9 | SURF4 | 136228325 | 136242970 | 0 | 0 | 4 | 1.33 × 10−5 | 6.37 × 10−3 | Associated with colorectal cancer, hereditary nonpolyposis, type 2 and macular degeneration, age-related, 6 |
9 | C9orf96 | 136243117 | 136271220 | 0 | 0 | 2 | 4.51 × 10−5 | 0.02 | Annotates to transferase activity, transferring phosphorus-containing groups and protein tyrosine kinase activity |
9 | SLC2A6 | 136336217 | 136344259 | 2 | 13 | 5 | 2.33 × 10−5 | 0.01 | Probable sugar transporter that acts as a regulator of glycolysis in macrophages; associated with endometrial clear cell adenocarcinoma and testis seminoma |
9 | TMEM8C | 136379708 | 136393734 | 0 | 0 | 2 | 4.80 × 10−5 | 0.02 | Involved in skeletal muscle regeneration in response to injury by mediating the fusion of satellite cells with injured myofibers; also involved in skeletal muscle hypertrophy |
9 | BRD3 | 136895427 | 136933657 | 6 | 21 | 6 | 1.29 × 10−4 | 0.03 | Chromatin reader that recognizes and binds hyperacetylated chromatin and plays a role in the regulation of transcription; regulates transcription by promoting the binding of the transcription factor GATA1 to its targets; associated with foodborne botulism and wound botulism |
10 | NCOA4 | 51565108 | 51590734 | 0 | 0 | 1 | 6.40 × 10−21 | 6.87 × 10−18 | Enhances the androgen receptor transcriptional activity in prostate cancer cells; associated with differentiated thyroid carcinoma and withdrawal disorder |
10 | RHOBTB1 | 62629196 | 62761198 | 3 | 7 | 11 | 1.78 × 10−4 | 0.04 | Associated with ascaridiasis and deafness, autosomal recessive 104 |
12 | OAS3 | 113376157 | 113411054 | 2 | 4 | 4 | 2.76 × 10−8 | 1.63 × 10−5 | Plays a significant role in the inhibition of cellular protein synthesis and viral infection resistance |
12 | OAS2 | 113416200 | 113449528 | 1 | 1 | 2 | 2.04 × 10−6 | 1.13 × 10−3 | Plays a critical role in cellular innate antiviral response |
12 | DTX1 | 113494514 | 113535833 | 2 | 4 | 18 | 9.86 × 10−6 | 4.84 × 10−3 | Involved in neurogenesis, lymphogenesis and myogenesis, and may also be involved in marginal zone B (MZB) cell differentiation. |
12 | CCDC42B | 113587663 | 113597081 | 0 | 0 | 5 | 7.50 × 10−7 | 4.30 × 10−4 | Associated with phosphoglycerate kinase 1 deficiency and Cornelia de Lange syndrome 4 with or without midline brain defects |
12 | SDSL | 113860042 | 113876081 | 4 | 5 | 2 | 3.03 × 10−5 | 0.01 | Has low serine dehydratase and threonine dehydratase activity; associated with subdural empyema and sarcocystosis |
13 | TSC22D1 | 45007655 | 45151283 | 5 | 6 | 3 | 1.82 × 10−8 | 1.12 × 10−5 | The encoded protein may play a critical role in tumor suppression |
17 | NSF | 44668035 | 44834830 | 0 | 0 | 2 | 8.06 × 10−5 | 0.02 | Associated with tetanus and type 1 diabetes mellitus 13 |
17 | WNT3 | 44839872 | 44910520 | 3 | 10 | 14 | 2.90 × 10−5 | 0.01 | May play a key role in some cases of human breast, rectal, lung, and gastric cancer |
19 | ZNF266 | 9523272 | 9546254 | 18 | 67 | 4 | 8.63 × 10−5 | 0.02 | May be involved in transcriptional regulation |
19 | ZNF121 | 9671029 | 9695209 | 16 | 65 | 2 | 8.20 × 10−5 | 0.02 | May be involved in transcriptional regulation |
19 | ZNF561 | 9715356 | 9732075 | 19 | 70 | 1 | 6.86 × 10−5 | 0.02 | Related to pathways of gene expression and herpes simplex virus 1 infection |
19 | ZNF846 | 9862669 | 9903856 | 11 | 37 | 1 | 7.19 × 10−5 | 0.02 | Associated with monkeypox; related to pathways of herpes simplex virus 1 infection |
19 | FBXL12 | 9920943 | 9938492 | 22 | 77 | 1 | 7.54 × 10−5 | 0.02 | Mediates the polyubiquitination and proteasomal degradation of CAMK1 leading to disruption of cyclin D1/CDK4 complex assembly which results in G1 cell cycle arrest in lung epithelia; related to pathways of innate immune system and class I MHC mediated antigen processing and presentation |
19 | PPAN | 10216965 | 10225414 | 23 | 78 | 11 | 8.34 × 10−5 | 0.02 | May have a role in cell growth; associated with narcolepsy |
19 | EIF3G | 10225693 | 10230596 | 16 | 63 | 4 | 7.18 × 10−5 | 0.02 | Associated with narcolepsy |
19 | DNMT1 | 10244021 | 10341962 | 17 | 46 | 8 | 9.42 × 10−5 | 0.02 | Variation is associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE |
19 | S1PR2 | 10334520 | 10341948 | 3 | 17 | 1 | 6.32 × 10−5 | 0.02 | Defects have been associated with congenital profound deafness |
19 | ICAM1 | 10381511 | 10397291 | 4 | 13 | 8 | 5.63 × 10−5 | 0.02 | Encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system; binds to integrins of type CD11a/CD18, or CD11b/CD18 and is also exploited by rhinovirus as a receptor; associated with malaria and hepatocellular carcinoma |
19 | ICAM4 | 10397643 | 10399198 | 3 | 16 | 7 | 4.75 × 10−5 | 0.02 | Associated with blood group system, Landsteiner–Wiener and anemia, congenital dyserythropoietic, type Iv; related to pathways of innate immune system and actin dynamics signaling pathway |
19 | ICAM5 | 10400657 | 10407454 | 3 | 16 | 12 | 5.93 × 10−5 | 0.02 | May be a critical component in neuron–microglial cell interactions in the course of normal development or as part of neurodegenerative diseases; associated with acute hemorrhagic conjunctivitis and holoprosencephaly; related to pathways of innate immune system and degradation of the extracellular matrix |
19 | ZGLP1 | 10415479 | 10420556 | 1 | 2 | 2 | 3.76 × 10−5 | 0.02 | Associated with hermaphroditism |
19 | FDX1L | 10416103 | 10426691 | 0 | 0 | 5 | 9.96 × 10−5 | 0.03 | Associated with mitochondrial myopathy, episodic, with or without optic atrophy and reversible leukoencephalopathy and mitochondrial myopathy; related to pathways of HIV life cycle and diseases of metabolism |
19 | ICAM3 | 10444452 | 10450499 | 2 | 6 | 7 | 5.45 × 10−5 | 0.02 | May be the most important ligand for LFA-1 in the initiation of the immune response; contributes to apoptotic neutrophil phagocytosis by macrophages |
19 | PDE4A | 10527449 | 10580305 | 4 | 17 | 21 | 5.93 × 10−5 | 0.02 | Associated with asthma and pulmonary eosinophilia |
19 | CDKN2D | 10677138 | 10679735 | 6 | 22 | 3 | 6.12 × 10−5 | 0.02 | The negative regulation of the cell cycle involved in this protein was shown to participate in repressing neuronal proliferation, as well as spermatogenesis; associated with adult central nervous system primitive neuroectodermal neoplasm and parathyroid adenoma; related to pathways of immune response IL-23 signaling pathway and mitotic G1-G1/S phases |
19 | AP1M2 | 10683347 | 10697991 | 2 | 8 | 12 | 1.86 × 10−4 | 0.04 | Associated with Pettigrew syndrome and chromophobe renal cell carcinoma; related to pathways of vesicle-mediated transport and HIV life cycle |
19 | SLC44A2 | 10713133 | 10755235 | 7 | 27 | 16 | 2.06 × 10−4 | 0.05 | Associated with femoral vein thrombophlebitis and deafness, autosomal recessive 68; related to pathways of transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds and innate immune system |
19 | C19orf38 | 10947251 | 10980466 | 4 | 15 | 3 | 7.72 × 10−5 | 0.02 | Unknown |
19 | DOCK6 | 11309971 | 11373157 | 4 | 20 | 17 | 8.02 × 10−5 | 0.02 | Associated with Adams–Oliver syndrome 2 and Adams–Oliver syndrome |
19 | NAPSA | 50861734 | 50869087 | 0 | 0 | 8 | 1.60 × 10−4 | 0.04 | The encoded protease may play a role in the proteolytic processing of pulmonary surfactant protein B in the lung and may function in protein catabolism in the renal proximal tubules |
21 | OLIG2 | 34398153 | 34401504 | 3 | 5 | 16 | 3.83 × 10−12 | 2.86 × 10−9 | Required for oligodendrocyte and motor neuron specification in the spinal cord, as well as for the development of somatic motor neurons in the hindbrain |
21 | OLIG1 | 34442450 | 34444726 | 0 | 0 | 10 | 2.78 × 10−12 | 2.27 × 10−9 | Associated with oligodendroglioma and anaplastic astrocytoma; related to pathways of neural crest differentiation and neural stem cell differentiation pathways and lineage-specific markers |
21 | IFNAR2 | 34602206 | 34637980 | 5 | 17 | 7 | 3.89 × 10−15 | 3.52 × 10−12 | Associated with immunodeficiency 45 and primary immunodeficiency with post–measles–mumps–rubella vaccine viral infection; related to pathways of measles and innate immune system |
21 | IL10RB | 34638663 | 34669539 | 2 | 6 | 2 | 2.59 × 10−15 | 2.47 × 10−12 | Associated with inflammatory bowel disease 25, autosomal recessive and hepatitis B; related to pathways of immune response IL-23 signaling pathway and innate immune system |
21 | IFNAR1 | 34696734 | 34732168 | 1 | 2 | 3 | 2.98 × 10−12 | 2.32 × 10−9 | Functions as an antiviral factor; associated with hepatitis C and yellow fever; related to pathways of measles and innate immune system |
21 | IFNGR2 | 34775202 | 34851655 | 1 | 9 | 7 | 1.29 × 10−11 | 9.21 × 10−9 | Associated with immunodeficiency 28 and autosomal dominant Mendelian susceptibility to mycobacterial diseases due to partial IFNgammaR2 deficiency; related to pathways of innate immune system and PEDF induced signaling |
21 | DNAJC28 | 34860497 | 34864027 | 2 | 10 | 1 | 1.77 × 10−11 | 1.22 × 10−8 | Associated with Mullegama–Klein–Martinez syndrome and microphthalmia, syndromic 10 |
