Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Butler‐Laporte, Guillaume; Povysil, Gundula; Kosmicki, Jack A.; Cirulli, Elizabeth T.; Drivas, Theodore G.; Furini, Simone; Saad, Chadi; Schmidt, Axel; Olszewski, Pawel; Quinodoz, Mathieu; Çelik, Elifnaz; Kundu, Kousik; Walter, Klaudia; Jung, Junghyung; Stockwell, Amy; Sloofman, Laura; Charney, Alexander; Jordan, Daniel M.; Beckmann, Noam D.; Przychodzen, Bartlomiej; Chang, T. S.; Pottinger, Tess D.; Shang, Ning; Brand, Fabian; Fava, Francesca; Mari, Francesca; Chwiałkowska, Karolina; Niemira, Magdalena; Korotko, Urszula; Pula, Szymon; Baillie, J Kenneth; Stuckey, A.; Ganna, Andrea; Karczewski, Konrad J.; Veerapen, Kumar; Bourgey, Mathieu; Bourque, Guillaume; Eveleigh, Robert; Forgetta, Vincenzo; Morrison, David R.; Langlais, David; Lathrop, Mark; Mooser, Vincent; Nakanishi, Teruyuki; Frithiof, Robert; Hultström, Michael; Lipcsey, Miklós; Marincevic-Zuniga, Yanara; Nordlund, Jessica; Barrett, Kelly; Bolze, Alexandre; White, Simon; Riffle, Stephen; Tanudjaja, Francisco; Sandoval, Efren; Neveux, Iva; Dabe, Shaun; Casadei, Nicolas; Motameny, Susanne; Alaamery, Manal; Massadeh, Salam; Aljawini, Nora; Almutairi, Mansour S; Arab, Yaseen M; Alqahtan, Saleh A; Harthi, Fawz S. Al; Almutairi, Amal; Alqubaishi, Fatima; Alotaibi, Sarah; Binowayn, Albandari; Alsolm, Ebtehal A.; Bardisy, Hadeel El; Fawzy, Mohammad; Geschwind, Daniel H.; Arteaga, Stephanie; Stephens, Alexis; Butte, Manish J.; Boutros, Paul C.; Yamaguchi, Takafumi; Shu, Tao; Eng, Stefan; Sanders, Timothy; Tung, Paul; Broudy, Michael E.; Pan, Yu; González, Alfredo; Chavan, Nikhil; Johnson, Ruth; Paşaniuc, Bogdan; Yaspan, Brian L.; Smieszek, Sandra P.; Rivolta, Carlo; Bibert, Stéphanie; Bochud, Pierre‐Yves; Dąbrowski, Maciej; Zawadzki, Paweł; Sypniewski, Mateusz; Kaja, Elżbieta; Chariyavilaskul, Pajaree; Nilaratanakul, Voraphoj; Hirankarn, Nattiya; Shotelersuk, Vorasuk; Pongpanich, Monnat; Phokaew, Chureerat; Chetruengchai, Wanna; Kawai, Yosuke; Hasegawa, Takanori; Naito, Tatsuhiko; Namkoong, Ho; Edahiro, Ryuya; Kimura, Akinori; Ogawa, Seishi; Kanai, Takanori; Fukunaga, Koichi; Okada, Yukinori; Imoto, Seiya; Miyano, Satoru; Mangul, Serghei; Abedalthagafi, Malak; Zeberg, Hugo; Grzymski, Joseph J.; Washington, Nicole; Ossowski, Stephan; Ludwig, Kerstin U.; Schulte, Eva C.; Rieß, Olaf; Moniuszko, Marcin; Kwaśniewski, Mirosław; Mbarek, Hamdi; Ismail, Said I.; Verma, Anurag; Goldstein, David; Kiryluk, Krzysztof; Renieri, Alessandra; Ferreira, Manuel A. R.; Richards, J. Brent

doi:10.1101/2022.03.28.22273040

Cited by 6 publications

(10 citation statements)

References 65 publications

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“…Using an unbiased X-wide gene burden test, we also identified X-linked recessive (XR) TLR7 deficiency in 17 male patients aged 7-71 years with critical COVID-19 pneumonia, accounting for ∼1% of cases in men (Figure 1) [28]. Moreover, six of the 11 TLR7 variants previously reported in patients from other studies were deleterious (carried by nine of 16 patients) [29–34], whereas the TLR7 variants in other studies were not disclosed [20,21]. TLR3 senses viral dsRNA in respiratory epithelial cells, whereas TLR7 senses ssRNA in plasmacytoid dendritic cells [1].…”

Section: Introductionmentioning

confidence: 96%

“…Other children with AR IFNAR1, IFNAR2, TBK1, or STAT2 deficiency were subsequently reported, as well as children with AR TYK2 deficiency [15–19] (Figure 1). Some other groups were unable to replicate these findings, but the variants were not tested biochemically and it is unclear whether recessive defects were considered [11,20–22]. There may also be other reasons for their findings [1,23], the most important being the age distribution of the case cohorts.…”

Section: Introductionmentioning

confidence: 99%

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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Matuozzo

Talouarn

Marchal

et al. 2022

Preprint

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BackgroundWe previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants wasTLR7, with an OR of 27.68 (95%CI:1.5-528.7,P=1.1×10−4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2],P=2.1×10−4). Adding the recently reportedTYK2COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4];P=3.4×10−3). When these 14 loci andTLR7were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0],P=4.7×10−7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9],P=0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years;P=1.68×10−5).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Matuozzo

Talouarn

Marchal

et al. 2022

Preprint

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“…In comparison, even the most robustly associated and replicated common variants are predicted to modestly increase an individual's risk for severe COVID-19 by a maximum odds ratio (OR) of about 2 [32], as opposed to an estimated OR of 50 for rare variants that cause IEI [48]. Three studies have so far performed large-scale genome-or exome-wide studies that studied associations between rare variants and disease susceptibility in non-hospitalized patients with confirmed SARS-CoV-2 infection compared to population controls [41,49,50]. Only one rare variant upstream of ACE2 was found that reached exome-wide significance, correlating with decreased expression of the SARS-CoV-2 receptor [41].…”

Section: Genetic Associations With Susceptibility To Severe or Critic...mentioning

confidence: 99%

“…Although a relationship between rare variants in these type I IFN genes and critical COVID-19 is plausible given the importance of intact type I IFN signalling in the anti-SARS-CoV-2 host immune response and the corroboration by some additional cases, four larger, independent studies failed to replicate the enrichment of variants in the TLR3 and IRF7-pathway in patients with critical COVID-19 [35,49,50,55]. This discrepancy could be in part explained by differences in cohort characteristics, including age distribution, definition of disease severity and possibly also clinical baseline parameters such as pre-existent comorbidities or history of infections, and the use of a-or pauci-symptomatic versus population controls.…”

Section: Inborn Errors Of Type I Interferon Signalling In Patients Wi...mentioning

confidence: 99%

Clinical implications of host genetic variation and susceptibility to severe or critical COVID-19

et al. 2022

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Since the start of the coronavirus disease 2019 (COVID-19) pandemic, important insights have been gained into virus biology and the host factors that modulate the human immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 displays a highly variable clinical picture that ranges from asymptomatic disease to lethal pneumonia. Apart from well-established general risk factors such as advanced age, male sex and chronic comorbidities, differences in host genetics have been shown to influence the individual predisposition to develop severe manifestations of COVID-19. These differences range from common susceptibility loci to rare genetic variants with strongly predisposing effects, or proven pathogenic variants that lead to known or novel inborn errors of immunity (IEI), which constitute a growing group of heterogeneous Mendelian disorders with increased susceptibility to infectious disease, auto-inflammation, auto-immunity, allergy or malignancies. The current genetic findings point towards a convergence of common and rare genetic variants that impact the interferon signalling pathways in patients with severe or critical COVID-19. Monogenic risk factors that impact IFN-I signalling have an expected prevalence between 1 and 5% in young, previously healthy individuals (<60 years of age) with critical COVID-19. The identification of these IEI such as X-linked TLR7 deficiency indicates a possibility for targeted genetic screening and personalized clinical management. This review aims to provide an overview of our current understanding of the host genetic factors that predispose to severe manifestations of COVID-19 and focuses on rare variants in IFN-I signalling genes and their potential clinical implications.

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“…In addition to GWAS and the associated data, TLR7 located in the X chromosome was considered a potential monogenic cause that predisposed young male patients without comorbidities to severe COVID-19 [ 13 , 14 ]. The most recent research from 21 cohorts across 12 countries also reported that rare, deleterious TLR7 variants are risk factors that predisposed the severity of COVID-19 (13.1-fold increase) [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Host Genetic Risk Factors Associated with COVID-19 Susceptibility and Severity in Vietnamese

Nhung

Ton

Ngọc

et al. 2022

Genes

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Since the emergence and rapid transmission of SARS-CoV-2, numerous scientific reports have searched for the association of host genetic variants with COVID-19, but the data are mostly acquired from Europe. In the current work, we explored the link between host genes (SARS-CoV-2 entry and immune system related to COVID-19 sensitivity/severity) and ABO blood types with COVID-19 from whole-exome data of 200 COVID-19 patients and 100 controls in Vietnam. The O blood type was found to be a protective factor that weakens the worst outcomes of infected individuals. For SARS-CoV-2 susceptibility, rs2229207 (TC genotype, allele C) and rs17860118 (allele T) of IFNAR2 increased the risk of infection, but rs139940581 (CT genotype, allele T) of SLC6A20 reduced virus sensitivity. For COVID-19 progress, the frequencies of rs4622692 (TG genotype) and rs1048610 (TC genotype) of ADAM17 were significantly higher in the moderate group than in the severe/fatal group. The variant rs12329760 (AA genotype) of TMPRSS2 was significantly associated with asymptomatic/mild symptoms. Additionally, rs2304255 (CT genotype, allele T) of TYK2 and rs2277735 (AG genotype) of DPP9 were associated with severe/fatal outcomes. Studies on different populations will give better insights into the pathogenesis, which is ethnic-dependent, and thus decipher the genetic factor’s contribution to mechanisms that predispose people to being more vulnerable to COVID-19.

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Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Cited by 6 publications

References 65 publications

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Clinical implications of host genetic variation and susceptibility to severe or critical COVID-19

Host Genetic Risk Factors Associated with COVID-19 Susceptibility and Severity in Vietnamese

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