Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

Gaziano, Liam; Giambartolomei, Claudia; Pereira, Alexandre C.; Gaulton, Anna; Posner, Daniel; Swanson, Sonja A.; Ho, Yuk‐Lam; Iyengar, Sudha K.; Kosik, Nicole; Vujkovic, Marijana; Gagnon, David; Bento, A. Patrícia; Beltrão, Pedro; Barrio-Hernandez, Iñigo; Rönnblom, Lars; Lundtoft, Christian; Langenberg, Claudia; Pietzner, Maik; Valentine, Dennis; Allara, Elias; Surendran, Praveen; Burgess, Stephen; Zhao, Jing Hua; Peters, James E.; Prins, Bram P.; Danesh, John; Devineni, Poornima; Shi, Yunling; Lynch, Kristine E.; DuVall, Scott L.; Garcon, Helene; Thomann, Lauren O.; Zhou, Jin; Gorman, Bryan R.; Huffman, Jennifer E.; O’Donnell, Christopher J.; Tsao, Philip S.; Beckham, Jean C.; Pyarajan, Saiju; Muralidhar, Sumitra; Huang, Grant D.; Ramoni, Rachel; Hung, Adriana M.; Chang, Kyong–Mi; Sun, Yan V.; Joseph, Jacob; Leach, Andrew R.; Edwards, Todd L.; Cho, Kelly; Gaziano, J. Michael; Butterworth, Adam S.; Casas, Juan P.

doi:10.1101/2020.11.19.20234120

Cited by 28 publications

(49 citation statements)

References 55 publications

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“…Increased expression of IFNAR2 reduced the risk of critical illness, consistent with IFN1 pathways in antiviral defense [16] . These findings were replicated in two further MR studies, with high IFNAR2 expression potentially conferring protection [ 34 , 41 ].…”

Section: Gwas Variants Associated With Covid-19mentioning

confidence: 66%

Host genetic factors determining COVID-19 susceptibility and severity

et al. 2021

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The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic to severe courses of COVID-19 with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI and pre-existing comorbidities. Ethnicity is also relevant to COVID-19 susceptibility and severity. Host genetic predisposition to COVID-19 is now increasingly recognized and whole genome and candidate gene association studies regarding COVID-19 susceptibility have been performed. Several common and rare variants in genes related to inflammation or immune responses have been identified. We summarize research on COVID-19 host genetics and compile genetic variants associated with susceptibility to COVID-19 and disease severity. We discuss candidate genes that should be investigated further to understand such associations and provide insights relevant to pathogenesis, risk classification, therapy response, precision medicine, and drug repurposing.

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Section: Gwas Variants Associated With Covid-19mentioning

confidence: 66%

Host genetic factors determining COVID-19 susceptibility and severity

et al. 2021

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“…13,14,15 Moreover, recent studies exploring potentially important pathways for COVID-19 progression have highlighted TYK2 and its downstream signaling pathway through type 1 interferons as a potential target for treatment. 25 The existing literature can help explain the dual association between reduced risk of autoimmune conditions such as psoriasis and RA and increased risk of severe COVID via TYK2. TYK2, a member of the Janus Kinase (JAK) family of genes, plays a key role in cytokine signal transduction and the inflammatory response, particularly via IL-12, IL-23, and is also important for IL-6 and IL-10 signaling (Fig 3).…”

Section: Discussionmentioning

confidence: 99%

“…14,[27][28][29][30] However, humans with complete TYK2 LOF have clinically significant immunodeficiency with increased susceptibility to mycobacterial and viral infections. 26,31 The balance between immune tolerance and ability to mount a robust early inflammatory response, and viral host defense may in part explain the mixed results of clinical trials using immunosuppressive therapy in COVID-19 to date 25 . Corticosteroid therapy may be beneficial in later stages of COVID-19 infection but detrimental if used early in the disease presumably when an early host defense response is important.…”

Section: Discussionmentioning

confidence: 99%

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

Verma

Tsao

Thomann

et al. 2021

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Background There are certain pre-existing conditions which leads in increased risk of coronavirus disease 2019 (COVID-19) severity and mortality. The objective of this study is to determine shared genetic architecture between COVID-19 severity and other medical conditions using electronic health record (EHR) data from diverse patient populations. Methods and Findings: We conducted Phenome-wide association study (PheWAS) of genetic variants associated with severe COVID-19 in two biobanks with EHR and genomic data: 1) Veteran Affairs (VA) Million Veteran Program (MVP), 2) United Kingdom Biobank (UKBB). Genetic variants associated with critical illness (n=48) or hospitalization (n=39) due to COVID-19 from COVID-19 Host Genetics Initiative genome-wide association studies. Phenotypes defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods; pre-COVID-19 data used to avoid potential confounding. Among 455,683 US Veterans from MVP, variants associated with severe COVID-19 tested for association across 1,559 phenotypes; 353,365 UK Biobank participants, and 1,064 phenotypes tested. Genetic variants at ABO locus (rs550057, rs505922) associated with the largest number of phenotypes (nrs55057= 53 and nrs505922=61); strongest association with venous embolism, odds ratio (OR)rs550057 1.27 (p=5.28 x 10-116), and thrombosis ORrs505922 1.31, p=3.5 x10-183. Among 67 respiratory conditions tested, only idiopathic pulmonary fibrosis, OR rs2277732 1.17, p=1.3410-05, and asthma ORrs143334143 0.94, p=2.31 x10-04, shared variants with severe COVID-19. The RAVER1 locus (rs74956615) associated with reduced risk for autoimmune conditions, e.g. psoriasis OR 0.71, p= 1.53 x10-22, rheumatoid arthritis, OR 0.78, p=1.04 x 10-09; findings replicated in UKBB. A known functional missense variant (rs34536443, TYK2) in the region had the highest linkage disequilibrium with rs74956615, suggesting signal was likely from TYK2. In MVP, PheWAS results stratified by genetic ancestry did not demonstrate significant difference in associations across ancestry. Conclusions Shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes; associations similar across genetic ancestries. Divergent association between inflammatory conditions and severe COVID may be explained by known pathway impairing signaling of inflammatory cytokines, reducing risk for autoimmunity; same pathway reduces type 1 interferon signaling, critical for viral host defense. Caution needed when targeting pathways that may balance immune tolerance and immunodeficiency to treat COVID-19.

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“…In contrast, we identified FAS as contributing specifically to severe COVID-19, but not susceptibility to infection. Gaziano et al 45 identified IFNAR2 and ACE2 as playing causal roles in COVID-19.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies have performed Mendelian randomisation of proteins in COVID-19 44,45 . The MR analysis of Zhou et al identified OAS1 as a causal factor common to COVID-19 susceptibility, hospitalisation and very severe disease 44 .…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

Klarić¹,

Gisby²,

Papadaki³

et al. 2021

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Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.

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Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

Cited by 28 publications

References 55 publications

Host genetic factors determining COVID-19 susceptibility and severity

Host genetic factors determining COVID-19 susceptibility and severity

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

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