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; Korotko, Urszula; Quinodoz, Mathieu; Çelik, Elifnaz; Kundu, Kousik; Walter, Klaudia; Jung, Junghyun; Stockwell, Amy; Sloofman, Laura; Jordan, Daniel M.; Thompson, Ryan; Valle, Diane Del; Simons, Nicole W.; Cheng, Esther; Sebra, Robert; Schadt, Eric E.; Kim‐Schulze, Seunghee; Gnjatic, Sacha; Mérad, Miriam; Buxbaum, Joseph D.; Beckmann, Noam D.; Charney, Alexander; Przychodzen, Bartlomiej; Chang, Timothy S.; Pottinger, Tess D.; Shang, Ning; Brand, Fabian; Fava, Francesca; Mari, Francesca; Chwiałkowska, Karolina; Niemira, Magdalena; Pula, Szymon; Baillie, J Kenneth; Stuckey, Alexander; Salas, Antonio; Bello, Xabier; Pardo-Seco, Jacobo; Gómez-Carballa, Alberto; Rivero‐Calle, Irene; Martinón‐Torres, Federico; 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 M Schiabor; Lee, William; 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; Arabi, Yaseen M.; Alqahtani, Saleh; Harthi, Fawz S. Al; Almutairi, Amal; Alqubaishi, Fatima; Alotaibi, Sarah; Binowayn, Albandari; Alsolm, Ebtehal A.; Bardisy, Hadeel El; Fawzy, Mohammad; Cai, Fang; Soranzo, Nicole; Butterworth, Adam S.; Geschwind, Daniel H.; Arteaga, Stephanie; Stephens, Alexis; Butte, Manish J.; Boutros, Paul C.; Yamaguchi, Takafumi N.; 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; Tokunaga, Katsushi; Sugiyama, Masaya; 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:10.1371/journal.pgen.1010367

Cited by 26 publications

(27 citation statements)

References 60 publications

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“…We used simulations to determine the power of our sample to detect an association at the 2.5 × 10 −6 exome-wide significance threshold (Additional file 1 : Fig S3); our sample had a power of more than 80% for detecting alleles with a carrier frequency of 5 × 10 −3 in the general population and a relative risk of critical COVID-19 of at least 6. These results are consistent with those of two previous large exome-wide studies including more than 1000 critical cases and thousands of population-based controls that found no statistically significant autosomal gene burden associations at stringent significance thresholds accounting for the number of phenotypes and variant sets analyzed [ 11 , 21 ]. However, under a recessive model, the strongest association—albeit not statistically significant at GW level—was obtained with the X-linked TLR7 gene, for which association has consistently been reported across studies [ 21 , 22 , 30 , 32 ], reaching the less conservative exome-wide significance threshold of 2.5 × 10 −6 in some of these previous studies [ 21 , 22 ].…”

Section: Discussionsupporting

confidence: 91%

“…1 ) [ 30 ]. Moreover, six of the 11 TLR7 variants previously reported in patients from other studies were deleterious (carried by nine of 16 patients) [ 31 – 36 ], whereas the TLR7 variants in other studies were not disclosed [ 21 , 22 ]. TLR3 senses viral dsRNA in respiratory epithelial cells, whereas TLR7 senses ssRNA in plasmacytoid dendritic cells [ 25 , 28 ].…”

Section: Introductionmentioning

confidence: 96%

“…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 , 21 – 23 ]. There may also be other reasons for their findings [ 1 , 24 ], 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

Talouarn²,

Marchal³

et al. 2023

Genome Med

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Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for 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). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/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). Conclusions Rare 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: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 96%

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

Matuozzo

Talouarn²,

Marchal³

et al. 2023

Genome Med

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show abstract

“…Previous studies have reported additional genes in this pathway: TLR7 (ref. 10,11 ) and DOCK2 (ref. 12 ).…”

Section: Main Textmentioning

confidence: 99%

A second update on mapping the human genetic architecture of COVID-19

Ganna

2022

Preprint

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Investigating the role of host genetic factors in COVID-19 severity and susceptibility can inform our understanding of the underlying biological mechanisms that influence adverse outcomes and drug development. Here we present a second updated genome-wide association study (GWAS) on COVID-19 severity and infection susceptibility to SARS-CoV-2 from the COVID-19 Host Genetic Initiative (data release 7). We performed a meta-analysis of up to 219,692 cases and over 3 million controls, identifying 51 distinct genome-wide significant loci—adding 28 loci from the previous data release. The increased number of candidate genes at the identified loci helped to map three major biological pathways involved in susceptibility and severity: viral entry, airway defense in mucus, and type I interferon.

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“…were disrupted across the burn initiation, progression and outcome. TLR7 was down expressed in burn murine model whose genetic mutation was observed in severe COVID-19 patients (Butler-Laporte, Povysil, Kosmicki, Cirulli, Drivas, Furini, Saad, Schmidt, Olszewski and Korotko et al 2022; Wen, Mobli, Radhakrishnan and Radhakrishnan 2022).…”

Section: Discussionmentioning

confidence: 99%

A burns and COVID-19 shared stress responding gene network deciphers CD1C-CD141-DCs as the key cellular components in septic prognosis

Qiao¹,

Wang²,

Xu³

et al. 2023

Preprint

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Differential body responses to various stresses, infectious or noninfectious, govern clinical outcomes ranging from asymptoma to death. However, the common molecular and cellular nature of the stress responsome across different stimuli is not described. In this study, we compared the expression behaviors between burns and COVID-19 infection by choosing the transcriptome of peripheral blood from related patients as the analytic target since the blood cells reflect the systemic landscape of immune homeostasis. We identified an immune co-stimulator (CD86)-centered network, named stress-response core (SRC), which coordinated multiple immune processes and was robust in membership and highly related to the clinical traits in both burns and COVID-19. An independent whole blood single-cell RNA sequencing of COVID-19 patients demonstrated that the monocyte-dendritic cell (Mono-DC) wing was the major cellular source of the SRC, among which the higher expression of the SRC in the monocyte was associated with the asymptomatic COVID-19 patients, while the quantity-restricted and function-defected CD1C-CD141- DCs were recognized as the key signature which linked to bad consequences in COVID-19. Specifically, the proportion of the CD1C-CD141- DCs and their SRC expression levels were step-wise reduced along with worse clinic conditions while the sub-cluster of CD1C-CD141- DCs of the critical COVID-19 patients was characterized of IFN signaling quiescence, high mitochondrial metabolism and immune-communication inactivation. Thus, our study identified an expression-synchronized and function-focused gene network which was decreased under burns and COVID-19 stress and argued the CD1C-CD141- DC as the prognosis-related cell population which might serve as a new target of diagnosis and therapy.

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

Cited by 26 publications

References 60 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

A second update on mapping the human genetic architecture of COVID-19

A burns and COVID-19 shared stress responding gene network deciphers CD1C-CD141-DCs as the key cellular components in septic prognosis

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