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Butler-Laporte, Guillaume, Povysil, Gundula, Kosmicki, Jack, Cirulli, Elizabeth, Drivas, Theodore, Furini, Simone, Saad, Chadi, Schmidt, Axel, Olszewski, Pawel, Korotko, Urszula, Quinodoz, Mathieu, Çelik, Elifnaz, Kundu, Kousik, Walter, Klaudia, Jung, Junghyung, Stockwell, Amy, Sloofman, Laura, Charney, Alexander, Jordan, Daniel, Beckmann, Noam, Przychodzen, Bartlomiej, Chang, Timothy, Pottinger, Tess, Shang, Ning, Brand, Fabian, Fava, Francesca, Mari, Francesca, Chwialkowska, Karolina, Niemira, Magdalena, Pula, Szymon, Baillie, Kenneth, Stuckey, Alex, Ganna, Andrea, Karczewski, Konrad, Veerapen, Kumar, Bourgey, Mathieu, Bourque, Guillaume, Eveleigh, Robert J. M.; Forgetta, Vincenzo, Morrison, David, Langlais, David, Lathrop, Mark, Mooser, Vincent, Nakanishi, Tomoko, Frithiof, Robert, Hultström, Michael, Lipcsey, Miklos, Marincevic-Zuniga, Yanara, Nordlund, Jessica, Schiabor Barrett, Kelly, 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, Arabi, Yaseen, Alqahtan, Saleh, Al Harthi, Fawz, Almutairi, Amal, Alqubaishi, Fatima, Alotaibi, Sarah, Binowayn, Albandari, Alsolm, Ebtehal, Bardisy, Hadeel El, Fawzy, Mohammad, Geschwind, Daniel, Arteaga, Stephanie, Stephens, Alexis, Butte, Manish, Boutros, Paul, Yamaguchi, Takafumi, Tao, Shu, Eng, Stefan, Sanders, Timothy, Tung, Paul, Broudy, Michael, Pan, Yu, Gonzalez, Alfredo, Chavan, Nikhil, Johnson, Ruth, Pasaniuc, Bogdan, Yaspan, Brian, Smieszek, Sandra, Rivolta, Carlo, Bibert, Stephanie, Bochud, Pierre-Yves, Dabrowski, Maciej, Zawadzki, Pawel, 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, Washington, Nicole, Ossowski, Stephan, Ludwig, Kerstin, Schulte, Eva, Riess, Olaf, Moniuszko, Marcin, Kwasniewski, Miroslaw, Mbarek, Hamdi, Ismail, Said, Verma, Anurag, Goldstein, David, Kiryluk, Krzysztof, Renieri, Alessandra, Ferreira, Manuel, Richards, Brent, Initiative, Covid- Host Genetics, De, C. O. I. Host Genetics Group, Study, Gen-Covid Multicenter, Gen, Omicc Consortium, Japan, Covid-Task Force, Regeneron Genetics, Center.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332108

ABSTRACT

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,048 severe disease cases and 571,009 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41×10 -7 ). These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

2.
Nat Genet ; 54(2): 125-127, 2022 02.
Article in English | MEDLINE | ID: covidwho-1625297

ABSTRACT

The OAS1/2/3 cluster has been identified as a risk locus for severe COVID-19 among individuals of European ancestry, with a protective haplotype of approximately 75 kilobases (kb) derived from Neanderthals in the chromosomal region 12q24.13. This haplotype contains a splice variant of OAS1, which occurs in people of African ancestry independently of gene flow from Neanderthals. Using trans-ancestry fine-mapping approaches in 20,779 hospitalized cases, we demonstrate that this splice variant is likely to be the SNP responsible for the association at this locus, thus strongly implicating OAS1 as an effector gene influencing COVID-19 severity.


Subject(s)
2',5'-Oligoadenylate Synthetase/genetics , COVID-19/genetics , COVID-19/pathology , Genetic Predisposition to Disease , Physical Chromosome Mapping , RNA Splicing/genetics , Severity of Illness Index , /genetics , COVID-19/enzymology , Humans , Linkage Disequilibrium/genetics , Risk Factors , /genetics
3.
Kidney Int Rep ; 6(12): 2979-2992, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1549766

ABSTRACT

INTRODUCTION: Loss of kidney function is a common feature of COVID-19 infection, but serum creatinine (SCr) is not a sensitive or specific marker of kidney injury. We tested whether molecular biomarkers of tubular injury measured at hospital admission were associated with acute kidney injury (AKI) in those with COVID-19 infection. METHODS: This is a prospective cohort observational study consisting of 444 consecutive patients with SARS-CoV-2 enrolled in the Columbia University emergency department (ED) at the peak of the pandemic in New York (March 2020-April 2020). Urine and blood were collected simultaneously at hospital admission (median time: day 0, interquartile range: 0-2 days), and urine biomarkers were analyzed by enzyme-linked immunosorbent assay (ELISA) and a novel dipstick. Kidney biopsies were probed for biomarker RNA and for histopathologic acute tubular injury (ATI) scores. RESULTS: Admission urinary neutrophil gelatinase-associated lipocalin (uNGAL) level was associated with AKI diagnosis (267 ± 301 vs. 96 ± 139 ng/ml, P < 0.0001) and staging; uNGAL levels >150 ng/ml had 80% specificity and 75% sensitivity to diagnose AKI stages 2 to 3. Admission uNGAL level quantitatively associated with prolonged AKI, dialysis, shock, prolonged hospitalization, and in-hospital death, even when admission SCr level was not elevated. The risk of dialysis increased almost 4-fold per SD of uNGAL independently of baseline SCr, comorbidities, and proteinuria (odds ratio [OR] [95% CI]: 3.59 [1.83-7.45], P < 0.001). In the kidneys of those with COVID-19, NGAL mRNA expression broadened in parallel with severe histopathologic injury (ATI). Conversely, low uNGAL levels at admission ruled out stages 2 to 3 AKI (negative predictive value: 0.95, 95% CI: 0.92-0.97) and the need for dialysis (negative predictive value: 0.98, 95% CI: 0.96-0.99). Although proteinuria and urinary (u)KIM-1 were implicated in tubular injury, neither was diagnostic of AKI stages. CONCLUSION: In the patients with COVID-19, uNGAL level was quantitatively associated with histopathologic injury (ATI), loss of kidney function (AKI), and severity of patient outcomes.

4.
J Clin Invest ; 131(23)2021 12 01.
Article in English | MEDLINE | ID: covidwho-1546628

ABSTRACT

BackgroundThere is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition.MethodsWe combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank.ResultsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6-2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2-2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2-2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8-3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2-1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.ConclusionsThe major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.


Subject(s)
Alleles , COVID-19 , Chromosomes, Human, Pair 3/genetics , Gene Frequency , Genetic Loci , Polymorphism, Genetic , SARS-CoV-2 , Age Factors , Aged , Aged, 80 and over , COVID-19/genetics , COVID-19/mortality , Female , Humans , Male , Middle Aged , Patient Acuity , Risk Factors
5.
Nat Med ; 27(6): 1012-1024, 2021 06.
Article in English | MEDLINE | ID: covidwho-1472229

ABSTRACT

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.


Subject(s)
Aging/genetics , Communicable Diseases/genetics , Pneumonia/genetics , Sepsis/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Aging/pathology , Biological Specimen Banks , Chromosome Aberrations , Communicable Diseases/complications , Communicable Diseases/microbiology , Digestive System Diseases/epidemiology , Digestive System Diseases/genetics , Digestive System Diseases/microbiology , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Hematologic Neoplasms/complications , Hematologic Neoplasms/genetics , Hematologic Neoplasms/microbiology , Humans , Male , Middle Aged , Mosaicism , Pneumonia/epidemiology , Pneumonia/microbiology , Risk Factors , Sepsis/epidemiology , Sepsis/microbiology , Urogenital Abnormalities/epidemiology , Urogenital Abnormalities/genetics , Urogenital Abnormalities/microbiology , Young Adult
6.
Journal of Clinical Investigation ; 131(15):1-1,1A, 2021.
Article in English | ProQuest Central | ID: covidwho-1338047

ABSTRACT

[...]the power computation shown in their Figure 1 is based on an incorrect hypothesis about the odds ratio, which would be expected to be lower when using general population controls (as they did) than when using paucisymptomatic and asymptomatic infected individuals (as we did). (iv) The ethnic origin of the patients differs between the 2 studies: 58% of our 659 patients (and 8 of our 9 pLOF carriers) were European, versus only 10% of their 713 patients with severe disease (and the pLOF carrier was East Asian). (v) Age is a key factor neglected in their comparison: our sample was much younger (mean age, 51.8 years) than theirs (mean, 65.9 years), and 7 of our 9 pLOF carriers were younger than 60 years. Because the rates of pLOFs vary considerably across populations, adjustment for only 3 principal components of ancestry in rare-variant association tests of multiethnic cohorts does not provide adequate control for population structure. [...]none of the associations showed even marginal significance. [...]consistent with our study, these findings do not support substantial contributions of inborn errors in type I IFN immunity to COVID-19 severity.

8.
Transpl Int ; 34(6): 1019-1031, 2021 06.
Article in English | MEDLINE | ID: covidwho-1140311

ABSTRACT

The increasing global prevalence of SARS-CoV-2 and the resulting COVID-19 disease pandemic pose significant concerns for clinical management of solid organ transplant recipients (SOTR). Wearable devices that can measure physiologic changes in biometrics including heart rate, heart rate variability, body temperature, respiratory, activity (such as steps taken per day) and sleep patterns, and blood oxygen saturation show utility for the early detection of infection before clinical presentation of symptoms. Recent algorithms developed using preliminary wearable datasets show that SARS-CoV-2 is detectable before clinical symptoms in >80% of adults. Early detection of SARS-CoV-2, influenza, and other pathogens in SOTR, and their household members, could facilitate early interventions such as self-isolation and early clinical management of relevant infection(s). Ongoing studies testing the utility of wearable devices such as smartwatches for early detection of SARS-CoV-2 and other infections in the general population are reviewed here, along with the practical challenges to implementing these processes at scale in pediatric and adult SOTR, and their household members. The resources and logistics, including transplant-specific analyses pipelines to account for confounders such as polypharmacy and comorbidities, required in studies of pediatric and adult SOTR for the robust early detection of SARS-CoV-2, and other infections are also reviewed.


Subject(s)
COVID-19 , Organ Transplantation , Wearable Electronic Devices , Adult , Child , Humans , Pandemics , SARS-CoV-2
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