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1. Genetic basis of falling risk susceptibility in the UK Biobank Study

Author

Natasja M. van Schoor, David Karasik, Lisette C. P. G. M. de Groot, Lotta J. Seppala, J. Brent Richards, Andre G. Uitterlinden, Katerina Trajanoska, Felix R. Day, Douglas P. Kiel, Carolina Medina-Gomez, Sirui Zhou, John R. B. Perry, Nathalie van der Velde, Fernando Rivadeneira, Yi-Hsiang Hsu, Trajanoska, Katerina [0000-0002-3792-4296], Medina-Gomez, Carolina [0000-0001-7999-5538], de Groot, Lisette C. P. G. M. [0000-0003-2778-2789], Karasik, David [0000-0002-8826-0530], Richards, J. Brent [0000-0002-3746-9086], Kiel, Douglas P. [0000-0001-8474-0310], Uitterlinden, Andre G. [0000-0002-7276-3387], Day, Felix R. [0000-0003-3789-7651], Rivadeneira, Fernando [0000-0001-9435-9441], Apollo - University of Cambridge Repository, de Groot, Lisette CPGM [0000-0003-2778-2789], Richards, J Brent [0000-0002-3746-9086], Kiel, Douglas P [0000-0001-8474-0310], Uitterlinden, Andre G [0000-0002-7276-3387], Day, Felix R [0000-0003-3789-7651], Epidemiology and Data Science, APH - Aging & Later Life, General practice, Internal medicine, APH - Personalized Medicine, Internal Medicine, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, AMS - Amsterdam Movement Sciences, Geriatrics, and AMS - Ageing & Vitality

Subjects
0301 basic medicine, Adult, Male, Multifactorial Inheritance, Quantitative Trait Loci, 45/43, Medicine (miscellaneous), Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Insomnia, medicine, Life Science, SNP, Humans, Genetic Predisposition to Disease, lcsh:QH301-705.5, Genetic association study, VLAG, Genetic association, Aged, Biological Specimen Banks, Falling risk, article, 631/208/205, Heritability, Mendelian Randomization Analysis, Middle Aged, Biobank, Neuroticism, Nutritional Biology, United Kingdom, 030104 developmental biology, lcsh:Biology (General), Case-Control Studies, Accidental Falls, Female, medicine.symptom, General Agricultural and Biological Sciences, 692/499, 030217 neurology & neurosurgery, Demography, Genome-Wide Association Study
Abstract

Both extrinsic and intrinsic factors predispose older people to fall. We performed a genome-wide association analysis to investigate how much of an individual’s fall susceptibility can be attributed to genetics in 89,076 cases and 362,103 controls from the UK Biobank Study. The analysis revealed a small, but significant SNP-based heritability (2.7%) and identified three novel fall-associated loci (Pcombined ≤ 5 × 10−8). Polygenic risk scores in two independent settings showed patterns of polygenic inheritance. Risk of falling had positive genetic correlations with fractures, identifying for the first time a pathway independent of bone mineral density. There were also positive genetic correlations with insomnia, neuroticism, depressive symptoms, and different medications. Negative genetic correlations were identified with muscle strength, intelligence and subjective well-being. Brain, and in particular cerebellum tissue, showed the highest gene expression enrichment for fall-associated variants. Overall, despite the highly heterogenic nature underlying fall risk, a proportion of the susceptibility can be attributed to genetics., Katerina Trajanoska et al. report a genome-wide association study of self-reported falls in UK Biobank participants. They identify three novel fall-associated loci and find that risk of falling shows patterns of polygenic inheritance and a SNP-based heritability of 2.7%.

Published
2020
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2. Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: A Mendelian randomization study

Author

Luke Devey, Lon R. Cardon, Sirui Zhou, Dawn Waterworth, Cong Guo, George Davey Smith, Robert A. Scott, Claudia Langenberg, Lauren E. Mokry, J. Brent Richards, Philippe Sanseau, Nicholas J. Wareham, Richards, J. Brent [0000-0002-3746-9086], Apollo - University of Cambridge Repository, and Richards, J Brent [0000-0002-3746-9086]

Subjects
0301 basic medicine, Oncology, Epidemiology, 45/43, lcsh:Medicine, Type 2 diabetes, Severity of Illness Index, Inflammatory bowel disease, law.invention, 631/208, 0302 clinical medicine, Randomized controlled trial, law, Odds Ratio, 692/308/174, lcsh:Science, Enterocolitis, Receptors, Interleukin-18, Multidisciplinary, Drug discovery, Anti-Inflammatory Agents, Non-Steroidal, Confounding, Interleukin-18, article, 3. Good health, Drug repositioning, Treatment Outcome, 692/4020/1503/257, medicine.symptom, medicine.medical_specialty, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Genetic Predisposition to Disease, Alleles, business.industry, lcsh:R, Drug Repositioning, 631/154, Mendelian Randomization Analysis, Inflammatory Bowel Diseases, medicine.disease, 030104 developmental biology, lcsh:Q, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11–1.34, P-value = 6 × 10−5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05–1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials.

Published
2019
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3. Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative

Author

Butler-Laporte, Guillaume, Povysil, Gundula, Kosmicki, Jack A, Cirulli, Elizabeth T, Drivas, Theodore, Furini, Simone, Saad, Chadi, Schmidt, Axel, Olszewski, Pawel, Korotko, Urszula, Quinodoz, Mathieu, Çelik, Elifnaz, Kundu, Kousik, Walter, Klaudia, Jung, Junghyun, Stockwell, Amy D, Sloofman, Laura G, Jordan, Daniel M, Thompson, Ryan C, Del Valle, Diane, Simons, Nicole, Cheng, Esther, Sebra, Robert, Schadt, Eric E, Kim-Schulze, Seunghee, Gnjatic, Sacha, Merad, Miriam, Buxbaum, Joseph D, Beckmann, Noam D, Charney, Alexander W, Przychodzen, Bartlomiej, Chang, Timothy, Pottinger, Tess D, Shang, Ning, Brand, Fabian, Fava, Francesca, Mari, Francesca, Chwialkowska, Karolina, Niemira, Magdalena, Pula, Szymon, Baillie, J Kenneth, Stuckey, Alex, 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 Jm, 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 M, 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 A, Al Harthi, Fawz S, Almutairi, Amal, Alqubaishi, Fatima, Alotaibi, Sarah, Binowayn, Albandari, Alsolm, Ebtehal A, El Bardisy, Hadeel, Fawzy, Mohammad, Cai, Fang, Soranzo, Nicole, Butterworth, Adam, COVID-19 Host Genetics Initiative, DeCOI Host Genetics Group, GEN-COVID Multicenter Study (Italy), Mount Sinai Clinical Intelligence Center, GEN-COVID Consortium (Spain), GenOMICC Consortium, Japan COVID-19 Task Force, Regeneron Genetics Center, Geschwind, Daniel H, Arteaga, Stephanie, Stephens, Alexis, Butte, Manish J, Boutros, Paul C, Yamaguchi, Takafumi N, Tao, Shu, Eng, Stefan, Sanders, Timothy, Tung, Paul J, Broudy, Michael E, 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, 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 S, Zeberg, Hugo, Grzymski, Joseph J, Washington, Nicole L, Ossowski, Stephan, Ludwig, Kerstin U, Schulte, Eva C, Riess, Olaf, Moniuszko, Marcin, Kwasniewski, Miroslaw, Mbarek, Hamdi, Ismail, Said I, Verma, Anurag, Goldstein, David B, Kiryluk, Krzysztof, Renieri, Alessandra, Ferreira, Manuel AR, Richards, J Brent, Butler-Laporte, Guillaume [0000-0001-5388-0396], Povysil, Gundula [0000-0003-4625-5909], Kosmicki, Jack A [0000-0003-1252-6192], Cirulli, Elizabeth T [0000-0001-7808-2809], Drivas, Theodore [0000-0002-8717-0111], Saad, Chadi [0000-0001-6963-9126], Olszewski, Pawel [0000-0003-1010-8843], Korotko, Urszula [0000-0002-1779-8368], Quinodoz, Mathieu [0000-0002-9841-4433], Çelik, Elifnaz [0000-0002-0324-5228], Kundu, Kousik [0000-0002-1019-8351], Walter, Klaudia [0000-0003-4448-0301], Sloofman, Laura G [0000-0001-7628-4378], Jordan, Daniel M [0000-0002-5318-8225], Thompson, Ryan C [0000-0002-0450-8181], Del Valle, Diane [0000-0001-6983-5362], Simons, Nicole [0000-0002-3952-1458], Chang, Timothy [0000-0002-9225-9874], Brand, Fabian [0000-0003-1885-7021], Chwialkowska, Karolina [0000-0001-8053-8959], Niemira, Magdalena [0000-0002-0701-4961], Pula, Szymon [0000-0002-5684-5358], Stuckey, Alex [0000-0001-8636-737X], Bello, Xabier [0000-0002-4990-8496], Karczewski, Konrad J [0000-0003-2878-4671], Bourgey, Mathieu [0000-0002-8432-834X], Bourque, Guillaume [0000-0002-3933-9656], Eveleigh, Robert Jm [0000-0002-4147-382X], Morrison, David [0000-0001-8380-3615], Langlais, David [0000-0003-4429-0110], Mooser, Vincent [0000-0002-8632-0448], Nakanishi, Tomoko [0000-0001-9510-5646], Frithiof, Robert [0000-0003-2278-7951], Hultström, Michael [0000-0003-4675-1099], Lipcsey, Miklos [0000-0002-1976-4129], Nordlund, Jessica [0000-0001-8699-9959], Schiabor Barrett, Kelly M [0000-0001-6194-787X], Bolze, Alexandre [0000-0001-7399-2766], White, Simon [0000-0001-6375-2363], Dabe, Shaun [0000-0002-2494-962X], Casadei, Nicolas [0000-0003-2209-0580], Motameny, Susanne [0000-0003-1186-1108], Massadeh, Salam [0000-0001-9193-0008], Almutairi, Mansour S [0000-0003-2736-8991], Arabi, Yaseen M [0000-0001-5735-6241], Fawzy, Mohammad [0000-0002-1318-9979], Arteaga, Stephanie [0000-0003-1441-8849], Stephens, Alexis [0000-0002-5979-6838], Yamaguchi, Takafumi N [0000-0003-1082-3871], Eng, Stefan [0000-0002-5245-6507], Gonzalez, Alfredo [0000-0001-8963-3135], Johnson, Ruth [0000-0002-1929-0998], Yaspan, Brian [0000-0002-3787-2510], Smieszek, Sandra [0000-0002-8006-0454], Rivolta, Carlo [0000-0002-0733-9950], Bochud, Pierre-Yves [0000-0002-2208-4757], Dabrowski, Maciej [0000-0003-4150-3985], Zawadzki, Pawel [0000-0002-9032-2315], Kaja, Elżbieta [0000-0003-1277-6140], Chariyavilaskul, Pajaree [0000-0003-1096-6020], Nilaratanakul, Voraphoj [0000-0002-3964-5477], Hirankarn, Nattiya [0000-0003-2224-6856], Shotelersuk, Vorasuk [0000-0002-1856-0589], Pongpanich, Monnat [0000-0003-3228-3351], Phokaew, Chureerat [0000-0002-4246-2604], Chetruengchai, Wanna [0000-0003-2495-6595], Sugiyama, Masaya [0000-0002-9084-7197], Kawai, Yosuke [0000-0003-0666-1224], Hasegawa, Takanori [0000-0001-7251-9950], Namkoong, Ho [0000-0001-6181-4284], Miyano, Satoru [0000-0002-1753-6616], Mangul, Serghei [0000-0003-4770-3443], Zeberg, Hugo [0000-0001-7118-1249], Grzymski, Joseph J [0000-0003-2646-8958], Ossowski, Stephan [0000-0002-7416-9568], Ludwig, Kerstin U [0000-0002-8541-2519], Schulte, Eva C [0000-0003-3105-5672], Verma, Anurag [0000-0002-5063-9107], Goldstein, David B [0000-0001-7627-0259], Kiryluk, Krzysztof [0000-0002-5047-6715], Renieri, Alessandra [0000-0002-0846-9220], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository

Subjects
Medicine and health sciences, Research and analysis methods, Physical sciences, Toll-Like Receptor 7, Biology and life sciences, SARS-CoV-2, FOS: Physical sciences, Humans, COVID-19, Exome, Genetic Predisposition to Disease, Genome-Wide Association Study, Research Article
Abstract

Acknowledgements: We thank the patients who volunteered to all participating cohorts, and the researchers and clinicians who enrolled them into the respective studies. A full list of acknowledgments can be found in S1 and S2 Tables., Funder: Lady Davis Institute of the Jewish General Hospital, Funder: Canadian Foundation for Innovation, Funder: NIH Foundation, Funder: Fonds de Recherche Québec Santé (FRQS), Funder: McGill Interdisciplinary Initiative in Infection and Immunity (MI4), Funder: Jewish General Hospital Foundation, Funder: Génome Québec; funder-id: http://dx.doi.org/10.13039/100013062, Funder: Public Health Agency of Canada, Funder: McGill University; funder-id: http://dx.doi.org/10.13039/100008582, Funder: Calcul Québec and Compute Canada, Funder: Compute Canada; funder-id: http://dx.doi.org/10.13039/100013020, Funder: Stiftung Universitätsmedizin Essen; funder-id: http://dx.doi.org/10.13039/501100010380, Funder: State of Saarland, Funder: Dr. Rolf M. Schwiete Foundation, Funder: Munich Clinician Scientist Programm, Funder: Netzwerk-Universitaetsmedizin-COVIM; Grant(s): NaFoUniMedCovid19, FKZ: 01KX2021, Funder: Federal Ministry of Education and Research, Funder: Leenaards Foundation, Funder: Santos-Suarez Foundation, Funder: Carigest, Funder: Istituto Buddista Italiano Soka Gakkai; Grant(s): 2020-2016_RIC_3 via project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19”, Funder: e-ASIA Joint Research Program (National Science and Technology Development Agency), 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 5,085 severe disease cases and 571,737 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 = 5.41x10-7). This association was consistent across sexes. 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.

Published
2022

4. The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals

Author

Butler-Laporte, Guillaume, Gonzalez-Kozlova, Edgar, Su, Chen-Yang, Zhou, Sirui, Nakanishi, Tomoko, Brunet-Ratnasingham, Elsa, Morrison, David, Laurent, Laetitia, Afilalo, Jonathan, Afilalo, Marc, Henry, Danielle, Chen, Yiheng, Carrasco-Zanini, Julia, Farjoun, Yossi, Pietzner, Maik, Kimchi, Nofar, Afrasiabi, Zaman, Rezk, Nardin, Bouab, Meriem, Petitjean, Louis, Guzman, Charlotte, Xue, Xiaoqing, Tselios, Chris, Vulesevic, Branka, Adeleye, Olumide, Abdullah, Tala, Almamlouk, Noor, Moussa, Yara, DeLuca, Chantal, Duggan, Naomi, Schurr, Erwin, Brassard, Nathalie, Durand, Madeleine, Del Valle, Diane Marie, Thompson, Ryan, Cedillo, Mario A, Schadt, Eric, Nie, Kai, Simons, Nicole W, Mouskas, Konstantinos, Zaki, Nicolas, Patel, Manishkumar, Xie, Hui, Harris, Jocelyn, Marvin, Robert, Cheng, Esther, Tuballes, Kevin, Argueta, Kimberly, Scott, Ieisha, Mount Sinai COVID-19 Biobank Team, Greenwood, Celia MT, Paterson, Clare, Hinterberg, Michael, Langenberg, Claudia, Forgetta, Vincenzo, Mooser, Vincent, Marron, Thomas, Beckmann, Noam, Kenigsberg, Ephraim, Charney, Alexander W, Kim-Schulze, Seunghee, Merad, Miriam, Kaufmann, Daniel E, Gnjatic, Sacha, Richards, J Brent, Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository

Subjects
Proteomics, Research, Immunity, COVID-19, SOMAscan
Abstract

Funder: Public health agency of Canada, Funder: Canadian institute for health research, Funder: Génome Québec; doi: http://dx.doi.org/10.13039/100013062, Funder: Fonds de Recherche du Québec - Santé; doi: http://dx.doi.org/10.13039/501100000156, INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 × 10-4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

Published
2022

5. ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19

Author

Maik Pietzner, Robert Lorenz Chua, Eleanor Wheeler, Katharina Jechow, Julian D. S. Willett, Helena Radbruch, Saskia Trump, Bettina Heidecker, Hugo Zeberg, Frank L. Heppner, Roland Eils, Marcus A. Mall, J. Brent Richards, Leif-Erik Sander, Irina Lehmann, Sören Lukassen, Nicholas J. Wareham, Christian Conrad, Claudia Langenberg, Pietzner, Maik [0000-0003-3437-9963], Wheeler, Eleanor [0000-0002-8616-6444], Radbruch, Helena [0000-0001-6941-3397], Zeberg, Hugo [0000-0001-7118-1249], Heppner, Frank L [0000-0001-9816-8917], Mall, Marcus A [0000-0002-4057-2199], Richards, J Brent [0000-0002-3746-9086], Sander, Leif-Erik [0000-0002-0476-9947], Lukassen, Sören [0000-0001-7045-6327], Wareham, Nicholas J [0000-0003-1422-2993], Conrad, Christian [0000-0001-7036-342X], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Respiratory System, 45/43, General Physics and Astronomy, genetics [DNA-Binding Proteins], Peptidyl-Dipeptidase A, General Biochemistry, Genetics and Molecular Biology, 82/80, 692/699/255/2514, ELF5 protein, human, Humans, genetics [COVID-19], metabolism [Peptidyl-Dipeptidase A], metabolism [Epithelial Cells], 49/91, genetics [Angiotensin-Converting Enzyme 2], Multidisciplinary, SARS-CoV-2, article, COVID-19, Epithelial Cells, General Chemistry, 631/208/205, genetics [Transcription Factors], 692/4017, DNA-Binding Proteins, ddc:500, Angiotensin-Converting Enzyme 2, 692/499, Transcription Factors
Abstract

Funder: Wellcome Trust, Funder: National Institute for Health Research (NIHR), Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 × 10-6) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.

Published
2022
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6. The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals

Author

Butler-Laporte, Guillaume, Gonzalez-Kozlova, Edgar, Su, Chen-Yang, Zhou, Sirui, Nakanishi, Tomoko, Brunet-Ratnasingham, Elsa, Morrison, David, Laurent, Laetitia, Afilalo, Jonathan, Afilalo, Marc, Henry, Danielle, Chen, Yiheng, Carrasco-Zanini, Julia, Farjoun, Yossi, Pietzner, Maik, Kimchi, Nofar, Afrasiabi, Zaman, Rezk, Nardin, Bouab, Meriem, Petitjean, Louis, Guzman, Charlotte, Xue, Xiaoqing, Tselios, Chris, Vulesevic, Branka, Adeleye, Olumide, Abdullah, Tala, Almamlouk, Noor, Moussa, Yara, DeLuca, Chantal, Duggan, Naomi, Schurr, Erwin, Brassard, Nathalie, Durand, Madeleine, Del Valle, Diane Marie, Thompson, Ryan, Cedillo, Mario A, Schadt, Eric, Nie, Kai, Simons, Nicole W, Mouskas, Konstantinos, Zaki, Nicolas, Patel, Manishkumar, Xie, Hui, Harris, Jocelyn, Marvin, Robert, Cheng, Esther, Tuballes, Kevin, Argueta, Kimberly, Scott, Ieisha, Greenwood, Celia M T, Paterson, Clare, Hinterberg, Michael, Langenberg, Claudia, Forgetta, Vincenzo, Mooser, Vincent, Marron, Thomas, Beckmann, Noam, Kenigsberg, Ephraim, Charney, Alexander W, Kim-Schulze, Seunghee, Merad, Miriam, Kaufmann, Daniel E, Gnjatic, Sacha, Richards, J Brent, Rezk, Nardin [0000-0001-5358-7704], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository

Subjects
Proteomics, Somascan, Immunity, Covid-19
Abstract

IntroductionSevere COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions.MethodsWe measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support.Results580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p -4). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex.ConclusionsSevere COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection.

Published
2021

7. A Polygenic Risk Score to Predict Future Adult Short Stature Among Children

Author

Nicholas J. Timpson, Haoyu Wu, Tianyuan Lu, John R. B. Perry, Celia M. T. Greenwood, Despoina Manousaki, Ken K. Ong, Vincenzo Forgetta, J. Brent Richards, Lu, Tianyuan [0000-0002-5664-5698], Forgetta, Vincenzo [0000-0002-6061-4720], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Male, Longitudinal study, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, parental height, Biochemistry, 0302 clinical medicine, Endocrinology, Risk Factors, 030212 general & internal medicine, Longitudinal Studies, Child, Growth Disorders, education.field_of_study, ALSPAC, Middle Aged, Biobank, Area Under Curve, Child, Preschool, Cohort, Female, medicine.symptom, AcademicSubjects/MED00250, Adult, medicine.medical_specialty, UK Biobank, adult height prediction, Population, Context (language use), Short stature, Risk Assessment, White People, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, education, Clinical Research Articles, Genetic association, Aged, Receiver operating characteristic, business.industry, Biochemistry (medical), Body Height, United Kingdom, short stature, 030104 developmental biology, ROC Curve, polygenic risk score, business, Demography, Genome-Wide Association Study
Abstract

Context Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height. Objective To develop a polygenic risk score for adult height and evaluate its clinical utility. Design A polygenic risk score was constructed based on meta-analysis of genomewide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Subjects Participants included 442 599 genotyped White British individuals in the UK Biobank and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort. Interventions None. Main Outcome Measures Standing height was measured using stadiometer; Standing height 2 SDs below the sex-specific population average was considered as short stature. Results Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height or only one of the child’s parent’s height could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood. Conclusions A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.

Published
2021
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8. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity

Author

Zhou, Sirui, Butler-Laporte, Guillaume, Nakanishi, Tomoko, Morrison, David R, Afilalo, Jonathan, Afilalo, Marc, Laurent, Laetitia, Pietzner, Maik, Kerrison, Nicola, Zhao, Kaiqiong, Brunet-Ratnasingham, Elsa, Henry, Danielle, Kimchi, Nofar, Afrasiabi, Zaman, Rezk, Nardin, Bouab, Meriem, Petitjean, Louis, Guzman, Charlotte, Xue, Xiaoqing, Tselios, Chris, Vulesevic, Branka, Adeleye, Olumide, Abdullah, Tala, Almamlouk, Noor, Chen, Yiheng, Chassé, Michaël, Durand, Madeleine, Paterson, Clare, Normark, Johan, Frithiof, Robert, Lipcsey, Miklós, Hultström, Michael, Greenwood, Celia MT, Zeberg, Hugo, Langenberg, Claudia, Thysell, Elin, Pollak, Michael, Mooser, Vincent, Forgetta, Vincenzo, Kaufmann, Daniel E, Richards, J Brent, Butler-Laporte, Guillaume [0000-0001-5388-0396], Nakanishi, Tomoko [0000-0001-9510-5646], Morrison, David R [0000-0001-8380-3615], Brunet-Ratnasingham, Elsa [0000-0002-3613-1315], Afrasiabi, Zaman [0000-0003-4395-5168], Rezk, Nardin [0000-0001-5358-7704], Petitjean, Louis [0000-0002-9223-5100], Guzman, Charlotte [0000-0002-2979-4436], Frithiof, Robert [0000-0003-2278-7951], Hultström, Michael [0000-0003-4675-1099], Greenwood, Celia MT [0000-0002-2427-5696], Langenberg, Claudia [0000-0002-5017-7344], Kaufmann, Daniel E [0000-0003-4467-136X], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository

Subjects
Aged, 80 and over, Male, SARS-CoV-2, Quantitative Trait Loci, COVID-19, Mendelian Randomization Analysis, Middle Aged, Interleukin-10 Receptor beta Subunit, Severity of Illness Index, White People, Case-Control Studies, 2',5'-Oligoadenylate Synthetase, Animals, Humans, Protein Isoforms, Female, Genetic Predisposition to Disease, Aged, Neanderthals
Abstract

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10-8), hospitalization (OR = 0.61, P = 8 × 10-8) and susceptibility (OR = 0.78, P = 8 × 10-6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.

Published
2021

9. An atlas of genetic influences on osteoporosis in humans and mice

Author

Morris, John A, Kemp, John P, Youlten, Scott E, Laurent, Laetitia, Logan, John G, Chai, Ryan C, Vulpescu, Nicholas A, Forgetta, Vincenzo, Kleinman, Aaron, Mohanty, Sindhu T, Sergio, C Marcelo, Quinn, Julian, Nguyen-Yamamoto, Loan, Luco, Aimee-Lee, Vijay, Jinchu, Simon, Marie-Michelle, Pramatarova, Albena, Medina-Gomez, Carolina, Trajanoska, Katerina, Ghirardello, Elena J, Butterfield, Natalie C, Curry, Katharine F, Leitch, Victoria D, Sparkes, Penny C, Adoum, Anne-Tounsia, Mannan, Naila S, Komla-Ebri, Davide SK, Pollard, Andrea S, Dewhurst, Hannah F, Hassall, Thomas AD, Beltejar, Michael-John G, 23andMe Research Team, Adams, Douglas J, Vaillancourt, Suzanne M, Kaptoge, Stephen, Baldock, Paul, Cooper, Cyrus, Reeve, Jonathan, Ntzani, Evangelia E, Evangelou, Evangelos, Ohlsson, Claes, Karasik, David, Rivadeneira, Fernando, Kiel, Douglas P, Tobias, Jonathan H, Gregson, Celia L, Harvey, Nicholas C, Grundberg, Elin, Goltzman, David, Adams, David J, Lelliott, Christopher J, Hinds, David A, Ackert-Bicknell, Cheryl L, Hsu, Yi-Hsiang, Maurano, Matthew T, Croucher, Peter I, Williams, Graham R, Bassett, JH Duncan, Evans, David M, Richards, J Brent, Morris, John A [0000-0003-2769-8202], Kemp, John P [0000-0002-9105-2249], Youlten, Scott E [0000-0001-9314-2945], Vulpescu, Nicholas A [0000-0003-1310-0257], Sergio, C Marcelo [0000-0002-5426-0583], Medina-Gomez, Carolina [0000-0001-7999-5538], Reeve, Jonathan [0000-0002-4364-2682], Ntzani, Evangelia E [0000-0003-3712-4181], Rivadeneira, Fernando [0000-0001-9435-9441], Kiel, Douglas P [0000-0001-8474-0310], Gregson, Celia L [0000-0001-6414-0529], Harvey, Nicholas C [0000-0002-8194-2512], Lelliott, Christopher J [0000-0001-8087-4530], Hinds, David A [0000-0002-4911-803X], Williams, Graham R [0000-0002-8555-8219], Bassett, JH Duncan [0000-0003-0817-0082], Evans, David M [0000-0003-0663-4621], Richards, J Brent [0000-0002-3746-9086], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Mice, Knockout, Middle Aged, Polymorphism, Single Nucleotide, Fractures, Bone, Mice, Phenotype, Bone Density, Animals, Humans, Osteoporosis, Female, Genetic Predisposition to Disease, Aged, Genome-Wide Association Study
Abstract

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

Published
2019

10. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author

Yolande F. M. Ramos, Tom Fiers, Jari Lahti, Tarunveer S. Ahluwalia, Elisa Kasbohm, Silvia Naitza, Hou-Feng Zheng, Charlotte Cerqueira, Ingrid Meulenbelt, Betina H. Thuesen, Ernst Rietzschel, Anne R. Cappola, John P. Walsh, Alessandro De Grandi, Johan G. Eriksson, Suzanne J. Brown, Jiaojiao Jing, Deborah Mascalzoni, Nicole Soranzo, Daniel Taliun, Margreet Kloppenburg, Purdey J Campbell, Kai-Uwe Eckardt, Yong Li, Mauro Pala, Marco Medici, Florian Kronenberg, Caterina Barbieri, Francesco Cucca, Allan Linneberg, Anna Köttgen, Bruce M. Psaty, Eric Boerwinkle, Ian J. Deary, Jennie Hui, Joris Deelen, Matthijs Moed, Astrid Petersmann, Graziano Ceresini, Michela Marina, Iris Postmus, Alice M. Arnold, Michiaki Kubo, J. Brent Richards, Marc De Buyzere, Henriette E. Meyer zu Schwabedissen, Eleonora Porcu, Christian Fuchsberger, Celia Di Munno, Dan E. Arking, David J. Stott, Toshiko Tanaka, Sofie Bekaert, Andrew A. Hicks, W. Edward Visser, Wouter den Hollander, Martin Gögele, Cinzia Sala, Peter P. Pramstaller, Georg Homuth, Yukinori Okada, Arne Astrup, Arif B. Ekici, Ulla T. Schultheiss, Richard A. Jensen, Christa Meisinger, Romana T. Netea-Maier, Rafael T. Mikolajczyk, Theo J. Visser, Marian Beekman, Michela Traglia, David C. Liewald, Koichi Matsuda, Thorkild I. A. Sørensen, Ilja M. Nolte, André G. Uitterlinden, David Schlessinger, Luigi Ferrrucci, Shuo Li, Alexander Teumer, Daniel Tiller, Sarah E. Harris, J. Wouter Jukema, Rajesh Rawal, Tim De Meyer, Kadri Haljas, Greet Roef, Yoichiro Kamatani, Karin Halina Greiser, Jean-Marc Kaufman, Serena Sanna, Bruce H. R. Wolffenbuttel, Scott Wilson, Daniela Toniolo, Ee Mun Lim, Stefan Groeneweg, Caroline S. Fox, Torben Hansen, Masato Akiyama, Christian Gieger, Layal Chaker, Tim D. Spector, Ian Ford, Martin den Heijer, P. Eline Slagboom, Elizabeth Selvin, Lambertus A. Kiemeney, Emil V. R. Appel, Niels Grarup, Diana van Heemst, Youri Taes, Robin P. Peeters, Henry Völzke, Cristian Pattaro, Daniel Medenwald, John M. Starr, Qiong Yang, Jerome I. Rotter, M. Arfan Ikram, Edoardo Fiorillo, Till Ittermann, Oluf Pedersen, Eero Kajantie, John Beilby, Tessel E. Galesloot, Fernando Rivadeneira, Paul Redmond, Bruno Lapauw, Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., van der Harst, P., Navis, G., Rots, M., Snieder, H., Swertz, M.A., Wijmenga, C., Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Department of Psychology and Logopedics, Doctoral Programme in Cognition, Learning, Instruction and Communication, Medicum, Lastentautien yksikkö, Children's Hospital, HUS Children and Adolescents, Developmental Psychology Research Group, Internal medicine, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Amsterdam Movement Sciences - Restoration and Development, APH - Aging & Later Life, Epidemiology, Internal Medicine, Teumer, Alexander [0000-0002-8309-094X], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Appel, Emil Vincent R [0000-0001-7704-6611], Astrup, Arne [0000-0001-8968-8996], Beekman, Marian [0000-0003-0585-6206], Beilby, John P [0000-0002-4915-2254], Ekici, Arif B [0000-0001-6099-7066], Grarup, Niels [0000-0001-5526-1070], Hansen, Torben [0000-0001-8748-3831], Hicks, Andrew A [0000-0001-6320-0411], Ikram, M Arfan [0000-0003-0372-8585], Jukema, J Wouter [0000-0002-3246-8359], Kamatani, Yoichiro [0000-0001-8748-5597], Kronenberg, Florian [0000-0003-2229-1120], Lahti, Jari [0000-0002-4310-5297], Li, Shuo [0000-0003-2331-2448], Liewald, David CM [0000-0002-0544-7368], Linneberg, Allan [0000-0002-0994-0184], Mascalzoni, Deborah [0000-0003-4156-1464], Meulenbelt, Ingrid [0000-0001-7786-7081], Netea-Maier, Romana T [0000-0002-9603-0460], Nolte, Ilja M [0000-0001-5047-4077], Okada, Yukinori [0000-0002-0311-8472], Ramos, Yolande FM [0000-0003-1459-413X], Richards, J Brent [0000-0002-3746-9086], Soranzo, Nicole [0000-0003-1095-3852], Yang, Qiong [0000-0002-3658-1375], Köttgen, Anna [0000-0002-4671-3714], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Genetic variants, endocrine system diseases, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Thyroid Gland, Thyrotropin, Metabolyzing hormone (AADAT), General Physics and Astronomy, EFFICIENT, Genome-wide association study, Thyroid hormone transporter (SLC17A4), Disease, VARIANTS, Bioinformatics, Hyperthyroidism, DISEASE, 0302 clinical medicine, SUBCLINICAL HYPOTHYROIDISM, Risk Factors, Genome-wide analysis, Chlorocebus aethiops, Faculty of Science, Medicine, lcsh:Science, POPULATION, RISK, education.field_of_study, Multidisciplinary, HERITABILITY, Thyroid disease, Thyroid, Thyroid dysfunction, ASSOCIATION, 3. Good health, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], COS Cells, Thyroid function, Sodium-Phosphate Cotransporter Proteins, Type I, Thyroid Hormones, endocrine system, PARTICIPANT DATA-ANALYSIS, Science, Population, 030209 endocrinology & metabolism, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Polymorphism, Single Nucleotide, White People, Article, General Biochemistry, Genetics and Molecular Biology, MONOCARBOXYLATE TRANSPORTER-8, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Hypothyroidism, Animals, Humans, ddc:610, education, METAANALYSIS, Genetic association, 2-Aminoadipate Transaminase, IDENTIFICATION, business.industry, Biology and Life Sciences, Biological Transport, General Chemistry, REFERENCE RANGE, medicine.disease, R1, 2-Aminoadipate Transaminase/genetics, 2-Aminoadipate Transaminase/metabolism, Cercopithecus aethiops, European Continental Ancestry Group, Gene Expression Regulation/genetics, Genome-Wide Association Study, Hyperthyroidism/genetics, Hyperthyroidism/physiopathology, Hypothyroidism/genetics, Hypothyroidism/physiopathology, Sodium-Phosphate Cotransporter Proteins, Type I/genetics, Sodium-Phosphate Cotransporter Proteins, Type I/metabolism, Thyroid Gland/metabolism, Thyroid Gland/physiopathology, Thyroid Hormones/genetics, Thyroid Hormones/metabolism, Thyrotropin/metabolism, 030104 developmental biology, Gene Expression Regulation, ATRIAL-FIBRILLATION, lcsh:Q, 3111 Biomedicine, business, Thyroid hormone regulation, Hormone
Abstract

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets., Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.

Published
2018
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11. The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study

Author

Elisabete Weiderpass, J. Brent Richards, Peter Selby, Emily White, Peng Li, Ghislaine Scelo, David C. Muller, Garnet L. Anderson, Nicholas J. Timpson, David Zaridze, Mattias Johansson, Poulami Barman, Laura E. Beane Freeman, Alexander S. Parker, Simone Benhamou, Mark P. Purdue, Ingrid Winship, Victoria L. Stevens, Wong-Ho Chow, Valerie Gaborieau, Neal D. Freedman, Jean-François Deleuze, Juhua Luo, Philip C Haycock, Kevin M. Brown, Todd L. Edwards, Jeanette E. Eckel-Passow, Tony Fletcher, Ulrike Peters, Anush Mukeriya, Christel Häggström, Fiona Bruinsma, Timothy Eisen, Richard J. Kahnoski, George Davey Smith, I-Min Lee, Laurie Burdette, Lisa Johnson, Hallie Carol, Alicja Wolk, Jolanta Lissowska, Zhaoming Wang, Stephen J. Chanock, Yuanqing Ye, Sabrina L. Noyes, Jan Lubinski, Marie Navratilova, Matthew L. Freedman, Xifeng Wu, Ivana Holcatova, Stella Koutros, Vladimir Janout, Richard S. Houlston, James D. McKay, Toni K. Choueiri, Anne Boland, Susanna C. Larsson, Rosamonde E. Banks, Gabriella Andreotti, Sanja Radojevic-Skodric, Egor Prokhortchouk, Eunyoung Cho, Stefan Rascu, Paul Brennan, Hélène Blanché, David Petillo, James Larkin, Konstantin G. Skryabin, Börje Ljungberg, Marc J. Gunter, Viorel Jinga, Howard D. Sesso, Matthieu Foll, Brian R. Lane, Peter Rudnai, Jean-Guillaume Garnier, J. Michael Gaziano, Geraldine Cancel-Tassin, Caroline L Relton, Julie E. Buring, Meredith Yeager, Raviprakash T. Sitaram, Kristian Hveem, Loren Lipworth, Olivier Cussenot, Bin Tean Teh, Robert Carreras-Torres, Peter E. Clark, Vladimir Bencko, Simona Ognjanovic, Mark Pomerantz, Stephanie J. Weinstein, Mitchell J. Machiela, G. Mark Lathrop, Dana Mates, Lenka Foretova, Gianluca Severi, Bradley C. Leibovich, Leandro M. Colli, Daniela Mariosa, Marc Henrion, Satu Männistö, Susan J. Jordan, Kathryn M. Wilson, Richard M. Martin, Eleonora Fabianova, Jonathan N. Hofmann, Lars J. Vatten, Susan M. Gapstur, Cezary Cybulski, Wen-Yi Huang, Douglas F. Easton, Lee E. Moore, Cancer Research UK, Carreras-Torres, Robert [0000-0002-2925-734X], Timpson, Nicolas J [0000-0002-7141-9189], Haycock, Philip C [0000-0001-5001-3350], Brown, Kevin M [0000-0002-8558-6711], Machiela, Mitchell J [0000-0001-6538-9705], Li, Peng [0000-0002-0682-9819], Radojevic-Skodric, Sanja [0000-0002-5395-8285], Holcatova, Ivana [0000-0002-1366-0337], Mates, Dana [0000-0002-6219-9807], Mukeriya, Anush [0000-0002-6847-9295], Fabianova, Eleonora [0000-0002-5519-8427], Jinga, Viorel [0000-0001-7632-5328], Cancel-Tassin, Geraldine [0000-0002-9583-6382], Cussenot, Olivier [0000-0002-9912-0533], Weiderpass, Elisabete [0000-0003-2237-0128], Bruinsma, Fiona [0000-0002-9356-2015], Jordan, Susan J [0000-0002-4566-1414], Severi, Gianluca [0000-0001-7157-419X], Winship, Ingrid [0000-0001-8535-6003], Fletcher, Tony [0000-0003-3385-200X], Larsson, Susanna C [0000-0003-0118-0341], Wolk, Alicja [0000-0001-7387-6845], Banks, Rosamonde E [0000-0002-0042-8715], Beane Freeman, Laura E [0000-0003-1294-4124], Weinstein, Stephanie [0000-0002-3834-1535], Edwards, Todd L [0000-0003-4318-6119], Gapstur, Susan M [0000-0002-1934-2110], Stevens, Victoria L [0000-0003-0259-4407], Carol, Hallie [0000-0001-8890-9785], Pomerantz, Mark M [0000-0003-4914-1157], Freedman, Neal D [0000-0003-0074-1098], Huang, Wen-Yi [0000-0002-4440-3368], Petillo, David [0000-0001-7234-4644], Anderson, Garnet L [0000-0001-5087-7837], Moore, Lee E [0000-0002-5957-8283], Henrion, Marc [0000-0003-1242-839X], Barman, Poulami [0000-0002-4604-9868], Choueiri, Toni K [0000-0002-9201-3217], McKay, James D [0000-0002-1787-3874], Richards, J Brent [0000-0002-3746-9086], Martin, Richard M [0000-0002-7992-7719], Davey Smith, George [0000-0002-1407-8314], Brennan, Paul [0000-0002-0518-8714], and Apollo - University of Cambridge Repository

Subjects
Blood Glucose, Male, Physiology, Epidemiology, Blood Pressure, Genome-wide association study, 030204 cardiovascular system & hematology, urologic and male genital diseases, Bioinformatics, Biochemistry, Vascular Medicine, Body Mass Index, Endocrinology, Mathematical and Statistical Techniques, 0302 clinical medicine, Risk Factors, Renal cell carcinoma, Medicine and Health Sciences, Insulin, Medicine, 030212 general & internal medicine, 2. Zero hunger, Cancer Risk Factors, Statistics, Public Health, Global Health, Social Medicine and Epidemiology, Mendelian Randomization Analysis, Genomics, 11 Medical And Health Sciences, General Medicine, Lipids, Kidney Neoplasms, 3. Good health, Oncology, Physiological Parameters, Physical Sciences, Female, ICEP, Research Article, Genetic Markers, medicine.medical_specialty, Research and Analysis Methods, Instrumental Variable Analysis, Carcinomas, 03 medical and health sciences, General & Internal Medicine, Mendelian randomization, Genome-Wide Association Studies, Genetics, Carcinoma, Humans, VDP::Medisinske Fag: 700, Obesity, Statistical Methods, Carcinoma, Renal Cell, Diabetic Endocrinology, Cancer och onkologi, business.industry, Body Weight, Renal Cell Carcinoma, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Cancer, Human Genetics, Genome Analysis, medicine.disease, Hormones, VDP::Medical disciplines: 700, Genitourinary Tract Tumors, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Diabetes Mellitus, Type 2, Medical Risk Factors, Cancer and Oncology, Etiology, business, Mathematics, Genome-Wide Association Study
Abstract

Background Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Using mendelian randomization approaches, Paul Brennan and colleagues reveal an association between 12 obesity-related factors, including insulin and the development of renal cell carcinoma., Author summary Why was this study done? Traditional observational studies wherein putative risk factors are measured directly have found several obesity-related factors associated with increased risk of renal cell carcinoma (RCC). Traditional observational studies are subject to confounding and reverse causation and have not been able to disentangle which obesity-related risk factors directly influence RCC risk. This study used an alternative methodology commonly referred to as mendelian randomization (MR). MR circumvents many of the inherent limitations of traditional observational study by use of genetic proxies of putative risk factors when evaluating their associations with disease risk, as they are not subject to reverse causation and are less likely to be confounded by other risk factors. What did the researchers do and find? First, we used large-scale genome-wide association studies (GWAS) to identify genetic variants associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose. Second, these genetic variants were used as proxies for the above-mentioned risk factors and evaluated in relation RCC risk using GWAS data from 10,000 RCC patients and 20,000 control participants. Based on these genetic data, we found that multiple measures of obesity, as well as diastolic blood pressure (DBP) and fasting insulin, are associated with RCC risk. In contrast, we found little evidence for an association with RCC risk for systolic blood pressure (SBP), circulating lipids, overall diabetes, or fasting glucose. What do these findings mean? This study provided robust and confirmatory evidence of an important role of obesity as an important risk factor of RCC. Further confirmatory evidence was found for elevated DBP as a risk factor of RCC, but it is not clear why DBP rather than SBP is important in RCC. The study, to our knowledge, provided novel evidence of an important role of circulating insulin in RCC etiology. This study provided some novel insights into the pathways involved in mediating the risk increase in RCC that is caused by obesity, most notably through insulin and DBP, but further research is needed to fully elucidate the important relationship between obesity and RCC.

Published
2019
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12. Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease

Author

Siobhan E. Guilfoyle, John A. Morris, Scott E. Youlten, Graham R. Williams, Michael R.G. Dack, Elena J. Ghirardello, Amelia R. McGlade, Davide Komla-Ebri, John P. Kemp, Paul A. Baldock, David J. Adams, David M. Evans, J. H. Duncan Bassett, John G. Logan, Victoria D. Leitch, Fernando Rivadeneira, Eleftheria Zeggini, Michelle M. McDonald, Ryan C. Chai, Tri Giang Phan, Nenad Bartonicek, Melita Irving, Konstantinos Hatzikotoulas, Christopher J. Lelliott, Matt Jansson, Robert Brink, James T. Smith, Peter I. Croucher, Ana Beleza-Meireles, Claudio M Sergio, Sindhu T. Mohanty, J. Brent Richards, Alexander P. Corr, Natalie C. Butterfield, Emma L. Duncan, John A. Eisman, Julian M.W. Quinn, Youlten, Scott E [0000-0001-9314-2945], Kemp, John P [0000-0002-9105-2249], Sergio, Claudio M [0000-0002-5426-0583], Leitch, Victoria D [0000-0001-5760-2887], Butterfield, Natalie C [0000-0002-5209-7508], Komla-Ebri, Davide [0000-0002-8381-5381], Corr, Alexander P [0000-0002-8450-012X], Smith, James T [0000-0003-0528-0649], Mohanty, Sindhu T [0000-0001-7512-8808], Morris, John A [0000-0003-2769-8202], Quinn, Julian MW [0000-0001-9674-9646], Hatzikotoulas, Konstantinos [0000-0002-4699-3672], Rivadeneira, Fernando [0000-0001-9435-9441], Duncan, Emma [0000-0002-8143-4403], Richards, J Brent [0000-0002-3746-9086], Adams, David J [0000-0001-9490-0306], Lelliott, Christopher J [0000-0001-8087-4530], Phan, Tri Giang [0000-0002-4909-2984], Evans, David M [0000-0003-0663-4621], Zeggini, Eleftheria [0000-0003-4238-659X], Bassett, JH Duncan [0000-0003-0817-0082], Williams, Graham R [0000-0002-8555-8219], Croucher, Peter I [0000-0002-7102-2413], Apollo - University of Cambridge Repository, Wellcome Trust, and Internal Medicine

Subjects
0301 basic medicine, Male, General Physics and Astronomy, Transcriptome, Mice, 0302 clinical medicine, Skeletal disease, Gene expression, Homeostasis, Mice, Knockout, 0303 health sciences, Multidisciplinary, Age Factors, RNA sequencing, Skeleton (computer programming), Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Osteocyte, Knockout mouse, Female, Bone Diseases, Sequence analysis, Bioinformatics, Science, Biology, Osteocytes, General Biochemistry, Genetics and Molecular Biology, Article, Bone and Bones, 03 medical and health sciences, Gene expression analysis, Sex Factors, SDG 3 - Good Health and Well-being, medicine, Animals, Humans, Gene, Skeleton, 030304 developmental biology, Sequence Analysis, RNA, Computational Biology, General Chemistry, 030104 developmental biology, Osteoporosis, Bone structure, 030217 neurology & neurosurgery, Function (biology)
Abstract

Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10−22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10−13) and osteoarthritis (P = 1.6 × 10−7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease., Osteocytes are the master regulatory cells within the skeleton. Here, the authors map the transcriptome of osteocytes from diverse skeletal sites, ages and between sexes and identify an osteocyte transcriptome signature associated with rare skeletal disorders and common complex skeletal diseases.

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