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1. Genetic association analysis of 77,539 genomes reveals rare disease etiologies

Author

Greene, Daniel, Genomics England Research Consortium, Pirri, Daniela, Frudd, Karen, Sackey, Ege, Al-Owain, Mohammed, Giese, Arnaud PJ, Ramzan, Khushnooda, Riaz, Sehar, Yamanaka, Itaru, Boeckx, Nele, Thys, Chantal, Gelb, Bruce D, Brennan, Paul, Hartill, Verity, Harvengt, Julie, Kosho, Tomoki, Mansour, Sahar, Masuno, Mitsuo, Ohata, Takako, Stewart, Helen, Taibah, Khalid, Turner, Claire LS, Imtiaz, Faiqa, Riazuddin, Saima, Morisaki, Takayuki, Ostergaard, Pia, Loeys, Bart L, Morisaki, Hiroko, Ahmed, Zubair M, Birdsey, Graeme M, Freson, Kathleen, Mumford, Andrew, Turro, Ernest, Giese, Arnaud PJ [0000-0001-7228-9542], Yamanaka, Itaru [0000-0003-0293-8070], Gelb, Bruce D [0000-0001-8527-5027], Kosho, Tomoki [0000-0002-8344-7507], Riazuddin, Saima [0000-0002-8645-4761], Ostergaard, Pia [0000-0002-2190-1356], Loeys, Bart L [0000-0003-3703-9518], Ahmed, Zubair M [0000-0003-2914-4502], Birdsey, Graeme M [0000-0002-0981-8672], Turro, Ernest [0000-0002-1820-6563], Apollo - University of Cambridge Repository, Giese, Arnaud P J [0000-0001-7228-9542], Freson, Kathleen [0000-0002-4381-2442], Giese, Arnaud P. J. [0000-0001-7228-9542], Gelb, Bruce D. [0000-0001-8527-5027], Loeys, Bart L. [0000-0003-3703-9518], Ahmed, Zubair M. [0000-0003-2914-4502], Birdsey, Graeme M. [0000-0002-0981-8672], and Genomics England Research Consortium

Subjects
Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], 631/208/2489/144, Genotype, 631/208/514/2254, 692/308/2056, article, Membrane Proteins, Bayes Theorem, General Medicine, General Biochemistry, Genetics and Molecular Biology, Chemistry, 631/208, All institutes and research themes of the Radboud University Medical Center, Rare Diseases, Phenotype, 631/114/2398, Humans, Human medicine, Biology, Genome-Wide Association Study
Abstract

Acknowledgements: This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and National Health Service (NHS) England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. GS was performed by Illumina at Illumina Laboratory Services and was overseen by Genomics England. We thank all NHS clinicians who have contributed clinical phenotype data to the 100,000 Genomes Rare Diseases Programme and all staff at Genomics England who have contributed to the sequencing, maintenance of the research environment and assembly of the standard bioinformatic files that were required for our analyses. We thank the participants of the rare diseases program who made this research possible. We are grateful to V. Keeley for providing access to paternal DNA (ERG), F. Elmslie for inviting a patient to the clinic (ERG) and T. Jaworek for technical assistance (GPR156). D.G. was supported by the Cambridge British Heart Foundation (BHF) Centre of Research Excellence (RE/18/1/34212) and the Wellcome Collaborative (219506/Z/19/Z). V.H. was supported by an Medical Research Council (MRC)/National Institute for Health and Care Research Clinical Academic Research Partnership (MR/V037617/1). G.M.B. and K. Frudd were funded by BHF (PG/17/33/32990). G.M.B. and D.P. were funded by BHF (PG/20/16/35047). E.S. was supported by the Swiss Federal National Fund for Scientific Research (CRSII5_177191/1). S.M. and P.O. were supported by the MRC (MR/P011543/1) and BHF (RG/17/7/33217). K. Freson was supported by Katholieke Universiteit (KU) Leuven Special Research Fund (BOF) (C14/19/096) and Research Foundation – Flanders (G072921N). Work at the University of Maryland, Baltimore was supported by the National Institute on Deafness and Other Communication Disorders/National Institutes of Health (R01DC016295 to Z.M.A.). M.A.-O., F.I. and K.R. were supported by the King Salman Center for Disability Research (85722). E.T. was supported by the Mindich Child Health and Development Institute, the Charles Bronfman Institute for Personalized Medicine and the Lowy Foundation USA., Funder: Cambridge BHF Centre of Research Excellence [RE/18/1/34212] and Wellcome Collaborative Award 219506/Z/19/Z, Funder: BHF Project grant PG/17/33/32990, Funder: Swiss National Science Foundation grant CRSII5_177191, Funder: King Salman Center for Disability Research # 85722, Funder: MRC/NIHR Clinical Academic Research Partnership MR/V037617/1, Funder: Medical Research Council grant MR/P011543/1 and British Heart Foundation grant RG/17/7/33217, Funder: NIDCD/NIH R01DC016295, Funder: BHF Project grants PG/20/16/35047 & PG/17/33/32990, Funder: KULeuven BOF grant C14/19/096, FWO grant G072921N, The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the ‘Rareservoir’, containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys–Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.

Published
2023
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2. TEFM variants impair mitochondrial transcription causing childhood-onset neurological disease

Author

Lindsey Van Haute, Emily O’Connor, Héctor Díaz-Maldonado, Benjamin Munro, Kiran Polavarapu, Daniella H. Hock, Gautham Arunachal, Alkyoni Athanasiou-Fragkouli, Mainak Bardhan, Magalie Barth, Dominique Bonneau, Nicola Brunetti-Pierri, Gerarda Cappuccio, Nikeisha J. Caruana, Natalia Dominik, Himanshu Goel, Guy Helman, Henry Houlden, Guy Lenaers, Karine Mention, David Murphy, Bevinahalli Nandeesh, Catarina Olimpio, Christopher A. Powell, Veeramani Preethish-Kumar, Vincent Procaccio, Rocio Rius, Pedro Rebelo-Guiomar, Cas Simons, Seena Vengalil, Maha S. Zaki, Alban Ziegler, David R. Thorburn, David A. Stroud, Reza Maroofian, John Christodoulou, Claes Gustafsson, Atchayaram Nalini, Hanns Lochmüller, Michal Minczuk, Rita Horvath, Van Haute, Lindsey [0000-0001-7809-1473], Polavarapu, Kiran [0000-0002-8879-6001], Hock, Daniella H [0000-0002-6940-4420], Bardhan, Mainak [0000-0002-4106-409X], Brunetti-Pierri, Nicola [0000-0002-6895-8819], Caruana, Nikeisha J [0000-0002-0817-1686], Helman, Guy [0000-0002-4784-7423], Houlden, Henry [0000-0002-2866-7777], Lenaers, Guy [0000-0003-2736-3349], Rius, Rocio [0000-0002-9871-3126], Rebelo-Guiomar, Pedro [0000-0002-5060-7519], Simons, Cas [0000-0003-3147-8042], Vengalil, Seena [0000-0002-0629-9221], Zaki, Maha S [0000-0001-7840-0002], Thorburn, David R [0000-0002-7725-9470], Stroud, David A [0000-0002-2048-3383], Christodoulou, John [0000-0002-8431-0641], Gustafsson, Claes [0000-0003-3531-8468], Minczuk, Michal [0000-0001-8242-1420], Horvath, Rita [0000-0002-9841-170X], Apollo - University of Cambridge Repository, Van Haute, Lindsey, O'Connor, Emily, Díaz-Maldonado, Héctor, Munro, Benjamin, Polavarapu, Kiran, Hock, Daniella H, Arunachal, Gautham, Athanasiou-Fragkouli, Alkyoni, Bardhan, Mainak, Barth, Magalie, Bonneau, Dominique, Brunetti-Pierri, Nicola, Cappuccio, Gerarda, Caruana, Nikeisha J, Dominik, Natalia, Goel, Himanshu, Helman, Guy, Houlden, Henry, Lenaers, Guy, Mention, Karine, Murphy, David, Nandeesh, Bevinahalli, Olimpio, Catarina, Powell, Christopher A, Preethish-Kumar, Veeramani, Procaccio, Vincent, Rius, Rocio, Rebelo-Guiomar, Pedro, Simons, Ca, Vengalil, Seena, Zaki, Maha S, Ziegler, Alban, Thorburn, David R, Stroud, David A, Maroofian, Reza, Christodoulou, John, Gustafsson, Clae, Nalini, Atchayaram, Lochmüller, Hann, Minczuk, Michal, and Horvath, Rita

Subjects
Transcription, Genetic, RNA, Mitochondrial, General Physics and Astronomy, 38/90, 13/106, 692/1807/1693, 14, DNA, Mitochondrial, General Biochemistry, Genetics and Molecular Biology, 38, 38/91, 82/80, Mitochondrial Proteins, 38/1, 692/420/2489/144, 692/617/375/374, 38/23, 38/22, Animals, Humans, Child, Zebrafish, 64, Multidisciplinary, 64/116, 692/308/2056, article, General Chemistry, 13/51, Mutation, 38/77, 692/700/139/422, Transcription Factors
Abstract

Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 309548, Funder: Lily Mae Foundation; doi: https://doi.org/10.13039/100012336, Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.

Published
2023
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3. A molecular barcode and web-based data analysis tool to identify imported Plasmodium vivax malaria

Author

Hidayat Trimarsanto, Roberto Amato, Richard D. Pearson, Edwin Sutanto, Rintis Noviyanti, Leily Trianty, Jutta Marfurt, Zuleima Pava, Diego F. Echeverry, Tatiana M. Lopera-Mesa, Lidia M. Montenegro, Alberto Tobón-Castaño, Matthew J. Grigg, Bridget Barber, Timothy William, Nicholas M. Anstey, Sisay Getachew, Beyene Petros, Abraham Aseffa, Ashenafi Assefa, Awab G. Rahim, Nguyen H. Chau, Tran T. Hien, Mohammad S. Alam, Wasif A. Khan, Benedikt Ley, Kamala Thriemer, Sonam Wangchuck, Yaghoob Hamedi, Ishag Adam, Yaobao Liu, Qi Gao, Kanlaya Sriprawat, Marcelo U. Ferreira, Moses Laman, Alyssa Barry, Ivo Mueller, Marcus V. G. Lacerda, Alejandro Llanos-Cuentas, Srivicha Krudsood, Chanthap Lon, Rezika Mohammed, Daniel Yilma, Dhelio B. Pereira, Fe E. J. Espino, Cindy S. Chu, Iván D. Vélez, Chayadol Namaik-larp, Maria F. Villegas, Justin A. Green, Gavin Koh, Julian C. Rayner, Eleanor Drury, Sónia Gonçalves, Victoria Simpson, Olivo Miotto, Alistair Miles, Nicholas J. White, Francois Nosten, Dominic P. Kwiatkowski, Ric N. Price, Sarah Auburn, Pearson, Richard D [0000-0002-7386-3566], Sutanto, Edwin [0000-0002-2997-4648], Marfurt, Jutta [0000-0002-3846-0825], Echeverry, Diego F [0000-0003-0301-4478], Tobón-Castaño, Alberto [0000-0002-1671-2649], Grigg, Matthew J [0000-0001-9914-8352], Alam, Mohammad S [0000-0001-8330-5499], Khan, Wasif A [0000-0002-7650-8068], Ley, Benedikt [0000-0002-5734-0845], Mueller, Ivo [0000-0001-6554-6889], Lacerda, Marcus VG [0000-0003-3374-9985], Pereira, Dhelio B [0000-0002-7761-5498], Espino, Fe EJ [0000-0003-1690-1711], Koh, Gavin [0000-0002-7336-1566], Rayner, Julian C [0000-0002-9835-1014], Drury, Eleanor [0000-0002-9887-6961], Miotto, Olivo [0000-0001-8060-6771], Nosten, Francois [0000-0002-7951-0745], Kwiatkowski, Dominic P [0000-0002-5023-0176], Price, Ric N [0000-0003-2000-2874], Auburn, Sarah [0000-0002-4638-536X], and Apollo - University of Cambridge Repository

Subjects
Likelihood Functions, Internet, Molecular medicine, 45, Epidemiology, 692/308/2056, article, Medicine (miscellaneous), 631/114/1305, General Biochemistry, Genetics and Molecular Biology, 692/4017, Malaria, Genetics research, Machine learning, Malaria, Vivax, 692/699/255/1629, Humans, PLASMODIUM, 692/308/174, Plasmodium vivax, General Agricultural and Biological Sciences
Abstract

Funder: HT was supported by a Charles Darwin University International PhD Scholarship (CDIPS), Funder: Malaysian Ministry of Health (BP00500420), Traditionally, patient travel history has been used to distinguish imported from autochthonous malaria cases, but the dormant liver stages of Plasmodium vivax confound this approach. Molecular tools offer an alternative method to identify, and map imported cases. Using machine learning approaches incorporating hierarchical fixation index and decision tree analyses applied to 799 P. vivax genomes from 21 countries, we identified 33-SNP, 50-SNP and 55-SNP barcodes (GEO33, GEO50 and GEO55), with high capacity to predict the infection's country of origin. The Matthews correlation coefficient (MCC) for an existing, commonly applied 38-SNP barcode (BR38) exceeded 0.80 in 62% countries. The GEO panels outperformed BR38, with median MCCs > 0.80 in 90% countries at GEO33, and 95% at GEO50 and GEO55. An online, open-access, likelihood-based classifier framework was established to support data analysis (vivaxGEN-geo). The SNP selection and classifier methods can be readily amended for other use cases to support malaria control programs.

Published
2022

4. Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells

Author

Mary-Ellen Lynall, Blagoje Soskic, James Hayhurst, Jeremy Schwartzentruber, Daniel F. Levey, Gita A. Pathak, Renato Polimanti, Joel Gelernter, Murray B. Stein, Gosia Trynka, Menna R. Clatworthy, Ed Bullmore, Lynall, Mary-Ellen [0000-0002-1939-7525], Soskic, Blagoje [0000-0003-3173-4528], Levey, Daniel F [0000-0001-8431-9569], Polimanti, Renato [0000-0003-0745-6046], Gelernter, Joel [0000-0002-4067-1859], Stein, Murray B [0000-0001-9564-2871], Trynka, Gosia [0000-0002-6955-9529], and Apollo - University of Cambridge Repository

Subjects
141, Multidisciplinary, 45, Mental Disorders, 692/308/2056, 45/43, article, General Physics and Astronomy, General Chemistry, 45/15, Polymorphism, Single Nucleotide, 631/250/2152/1566/1618, General Biochemistry, Genetics and Molecular Biology, 38, 631/250/248, 631/378/371, Catalytic Domain, Schizophrenia, Humans, Genetic Predisposition to Disease, Lymphocytes, 692/699/476, Genome-Wide Association Study
Abstract

Multiple psychiatric disorders have been associated with abnormalities in both the innate and adaptive immune systems. The role of these abnormalities in pathogenesis, and whether they are driven by psychiatric risk variants, remains unclear. We test for enrichment of GWAS variants associated with multiple psychiatric disorders (cross-disorder or trans-diagnostic risk), or 5 specific disorders (cis-diagnostic risk), in regulatory elements in immune cells. We use three independent epigenetic datasets representing multiple organ systems and immune cell subsets. Trans-diagnostic and cis-diagnostic risk variants (for schizophrenia and depression) are enriched at epigenetically active sites in brain tissues and in lymphoid cells, especially stimulated CD4+ T cells. There is no evidence for enrichment of either trans-risk or cis-risk variants for schizophrenia or depression in myeloid cells. This suggests a possible model where environmental stimuli activate T cells to unmask the effects of psychiatric risk variants, contributing to the pathogenesis of mental health disorders.

Published
2022
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5. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention

Author

Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J., Moore, Tim, Hemerich, Daiane, Cornelis, Marilyn C., Mazzaferro, Eugenia, Broos, Siacia, Ahluwalia, Tarunveer S., Bartz, Traci M., Bentley, Amy R., Bielak, Lawrence F., Chong, Mike, Chu, Audrey Y., Berry, Diane, Dorajoo, Rajkumar, Dueker, Nicole D., Kasbohm, Elisa, Feenstra, Bjarke, Feitosa, Mary F., Gieger, Christian, Graff, Mariaelisa, Hall, Leanne M., Haller, Toomas, Hartwig, Fernando P., Hillis, David A., Huikari, Ville, Heard-Costa, Nancy, Holzapfel, Christina, Jackson, Anne U., Johansson, Åsa, Jørgensen, Anja Moltke, Kaakinen, Marika A., Karlsson, Robert, Kerr, Kathleen F., Kim, Boram, Koolhaas, Chantal M., Kutalik, Zoltan, Lagou, Vasiliki, Lind, Penelope A., Lorentzon, Mattias, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Metzendorf, Christoph, Monroe, Kristine R., Pacolet, Alexander, Pérusse, Louis, Pool, Rene, Richmond, Rebecca C., Rivera, Natalia V., Robiou-du-Pont, Sebastien, Schraut, Katharina E., Schulz, Christina-Alexandra, Stringham, Heather M., Tanaka, Toshiko, Teumer, Alexander, Turman, Constance, van der Most, Peter J., Vanmunster, Mathias, van Rooij, Frank J. A., van Vliet-Ostaptchouk, Jana V., Zhang, Xiaoshuai, Zhao, Jing-Hua, Zhao, Wei, Balkhiyarova, Zhanna, Balslev-Harder, Marie N., Baumeister, Sebastian E., Beilby, John, Blangero, John, Boomsma, Dorret I., Brage, Søren Karl, Braund, Peter S., Brody, Jennifer A., Bruinenberg, Marcel, Ekelund, Ulf, Liu, Ching-Ti, Cole, John W., Collins, Francis S., Cupples, L. Adrienne, Esko, Tõnu, Enroth, Stefan, Faul, Jessica D., Fernandez-Rhodes, Lindsay, Fohner, Alison E., Franco, Oscar H., Galesloot, Tessel E., Gordon, Scott D., Grarup, Niels, Hartman, Catharina A., Heiss, Gerardo, Hui, Jennie, Illig, Thomas, Jago, Russell, James, Alan, Joshi, Peter K., Jung, Taeyeong, Kähönen, Mika, Kilpeläinen, Tuomas O., Koh, Woon-Puay, Kolcic, Ivana, Kraft, Peter P., Kuusisto, Johanna, Launer, Lenore J., Li, Aihua, Linneberg, Allan, Luan, Jian’an, Vidal, Pedro Marques, Medland, Sarah E., Milaneschi, Yuri, Moscati, Arden, Musk, Bill, Nelson, Christopher P., Nolte, Ilja M., Pedersen, Nancy L., Peters, Annette, Peyser, Patricia A., Power, Christine, Raitakari, Olli T., Reedik, Mägi, Reiner, Alex P., Ridker, Paul M., Rudan, Igor, Ryan, Kathy, Sarzynski, Mark A., Scott, Laura J., Scott, Robert A., Sidney, Stephen, Siggeirsdottir, Kristin, Smith, Albert V., Smith, Jennifer A., Sonestedt, Emily, Strøm, Marin, Tai, E. Shyong, Teo, Koon K., Thorand, Barbara, Tönjes, Anke, Tremblay, Angelo, Uitterlinden, Andre G., Vangipurapu, Jagadish, van Schoor, Natasja, Völker, Uwe, Willemsen, Gonneke, Williams, Kayleen, Wong, Quenna, Xu, Huichun, Young, Kristin L., Yuan, Jian Min, Zillikens, M. Carola, Zonderman, Alan B., Ameur, Adam, Bandinelli, Stefania, Bis, Joshua C., Boehnke, Michael, Bouchard, Claude, Chasman, Daniel I., Smith, George Davey, de Geus, Eco J. C., Deldicque, Louise, Dörr, Marcus, Evans, Michele K., Ferrucci, Luigi, Fornage, Myriam, Fox, Caroline, Garland, Theodore, Gudnason, Vilmundur, Gyllensten, Ulf, Hansen, Torben, Hayward, Caroline, Horta, Bernardo L., Hyppönen, Elina, Jarvelin, Marjo-Riitta, Johnson, W. Craig, Kardia, Sharon L. R., Kiemeney, Lambertus A., Laakso, Markku, Langenberg, Claudia, Lehtimäki, Terho, Marchand, Loic Le, Alizadeh, Behrooz Z., Boezen, H. Marike, Franke, Lude, Swertz, Morris, Wijmenga, Tjitske Nienke, van der Harst, Pim, Navis, Gerjan, Rots, Marianne, Wolffenbuttel, Bruce H. R., Magnusson, Patrik K. E., Martin, Nicholas G., Melbye, Mads, Metspalu, Andres, Meyre, David, North, Kari E., Ohlsson, Claes, Oldehinkel, Albertine J., Orho-Melander, Marju, Pare, Guillaume, Park, Taesung, Pedersen, Oluf, Penninx, Brenda W. J. H., Pers, Tune H., Polasek, Ozren, Prokopenko, Inga, Rotimi, Charles N., Samani, Nilesh J., Sim, Xueling, Snieder, Harold, Sørensen, Thorkild I. A., Spector, Tim D., Timpson, Nicholas J., van Dam, Rob M., van der Velde, Nathalie, van Duijn, Cornelia M., Vollenweider, Peter, Völzke, Henry, Voortman, Trudy, Waeber, Gérard, Wareham, Nicholas J., Weir, David R., Wichmann, Heinz-Erich, Wilson, James F., Hevener, Andrea L., Krook, Anna, Zierath, Juleen R., Thomis, Martine A. I., Loos, Ruth J. F., Hoed, Marcel den, Epidemiology, Internal Medicine, Tampere University, Department of Clinical Chemistry, Clinical Medicine, Department of Clinical Physiology and Nuclear Medicine, Wang, Zhe, Emmerich, Andrew, Pillon, Nicolas J, Moore, Tim, Hyppönen, Elina, den Hoed, Marcel, Lifelines Cohort Study, Alizadeh, B.Z., Boezen, H.M., Franke, L., Swertz, M., Wijmenga, C., van der Harst, P., Navis, G., Rots, M., Wolffenbuttel, BHR, Wang, Zhe [0000-0002-8046-4969], Emmerich, Andrew [0000-0002-0908-9924], Pillon, Nicolas J [0000-0003-1107-9490], Moore, Tim [0000-0003-4250-3370], Ameur, Adam [0000-0001-6085-6749], Bis, Joshua C [0000-0002-3409-1110], Boehnke, Michael [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Chasman, Daniel I [0000-0003-3357-0862], Smith, George Davey [0000-0002-1407-8314], de Geus, Eco JC [0000-0001-6022-2666], Dörr, Marcus [0000-0001-7471-475X], Ferrucci, Luigi [0000-0002-6273-1613], Fornage, Myriam [0000-0003-0677-8158], Garland, Theodore [0000-0002-7916-3552], Gyllensten, Ulf [0000-0002-6316-3355], Hansen, Torben [0000-0001-8748-3831], Horta, Bernardo L [0000-0001-9843-412X], Hyppönen, Elina [0000-0003-3670-9399], Johnson, W Craig [0000-0002-3161-3753], Kiemeney, Lambertus A [0000-0002-2368-1326], Laakso, Markku [0000-0002-3394-7749], Langenberg, Claudia [0000-0002-5017-7344], Lehtimäki, Terho [0000-0002-2555-4427], Magnusson, Patrik KE [0000-0002-7315-7899], Martin, Nicholas G [0000-0003-4069-8020], Melbye, Mads [0000-0001-8264-6785], Metspalu, Andres [0000-0002-3718-796X], Meyre, David [0000-0003-4850-7444], North, Kari E [0000-0002-8903-0366], Ohlsson, Claes [0000-0002-9633-2805], Oldehinkel, Albertine J [0000-0003-3925-3913], Orho-Melander, Marju [0000-0002-3578-2503], Pare, Guillaume [0000-0002-6795-4760], Park, Taesung [0000-0002-8294-590X], Pedersen, Oluf [0000-0002-3321-3972], Pers, Tune H [0000-0003-0207-4831], Polasek, Ozren [0000-0002-5765-1862], Prokopenko, Inga [0000-0003-1624-7457], Rotimi, Charles N [0000-0001-5759-053X], Sim, Xueling [0000-0002-1233-7642], Snieder, Harold [0000-0003-1949-2298], Sørensen, Thorkild IA [0000-0003-4821-430X], Spector, Tim D [0000-0002-9795-0365], Timpson, Nicholas J [0000-0002-7141-9189], Voortman, Trudy [0000-0003-2830-6813], Waeber, Gérard [0000-0003-4193-788X], Wareham, Nicholas J [0000-0003-1422-2993], Weir, David R [0000-0002-1661-2402], Wilson, James F [0000-0001-5751-9178], Krook, Anna [0000-0002-0891-0258], Zierath, Juleen R [0000-0001-6891-7497], Thomis, Martine AI [0000-0001-9093-2191], Loos, Ruth JF [0000-0002-8532-5087], Hoed, Marcel den [0000-0001-8081-428X], Apollo - University of Cambridge Repository, Center for Liver, Digestive and Metabolic Diseases (CLDM), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Geriatrics, AMS - Ageing & Vitality, APH - Aging & Later Life, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, and AMS - Sports

Subjects
Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], 631/208/205/2138, 610 Medicine & health, heritability, Actinin/genetics, Cross-Sectional Studies, Exercise/physiology, Genome-Wide Association Study, Humans, Leisure Activities, Sedentary Behavior, apolipoprotein-e genotype, Lifelines Cohort Study, 360 Social problems & social services, 692/308/575, Genetics, Actinin, Exercise, Medicinsk genetik, exercise, APOLIPOPROTEIN-E GENOTYPE, LD SCORE REGRESSION, GENE-EXPRESSION, EXERCISE, COMPLEX, PERFORMANCE, GWAS, HERITABILITY, MORTALITY, FITNESS, 360 Soziale Probleme, Sozialdienste, 692/308/2056, article, gwas, gene-expression, mortality, 3142 Public health care science, environmental and occupational health, fitness, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], LD score regression, 3111 Biomedicine, 610 Medizin und Gesundheit, Medical Genetics, complex, performance
Abstract

Funder: Kjell och Märta Beijers Stiftelse (Kjell and Marta Beijer Foundation); doi: https://doi.org/10.13039/501100006353, Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Published
2022
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6. Diverse mutational landscapes in human lymphocytes

Author

Machado, Heather E, Mitchell, Emily, Øbro, Nina F, Kübler, Kirsten, Davies, Megan, Leongamornlert, Daniel, Cull, Alyssa, Maura, Francesco, Sanders, Mathijs A, Cagan, Alex TJ, McDonald, Craig, Belmonte, Miriam, Shepherd, Mairi S, Vieira Braga, Felipe A, Osborne, Robert J, Mahbubani, Krishnaa, Martincorena, Iñigo, Laurenti, Elisa, Green, Tony, Getz, Gad, Polak, Paz, Saeb-Parsy, Kourosh, Hodson, Daniel, Kent, David G, Campbell, Peter J, Hematology, Leongamornlert, Daniel [0000-0002-3486-3168], Cagan, Alex TJ [0000-0002-7857-4771], Mahbubani, Krishnaa [0000-0002-1327-2334], Martincorena, Iñigo [0000-0003-1122-4416], Laurenti, Elisa [0000-0002-9917-9092], Green, Tony [0000-0002-9795-0218], Getz, Gad [0000-0002-0936-0753], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Hodson, Daniel [0000-0001-6225-2033], Kent, David G [0000-0001-7871-8811], Campbell, Peter J [0000-0002-3921-0510], Apollo - University of Cambridge Repository, Hodson, Daniel J [0000-0001-6225-2033], Center of Experimental and Molecular Medicine, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
B-Lymphocytes, Multidisciplinary, 45, Cambridge Stem Cell Institute, 631/208/212/2306, 692/308/2056, article, 45/23, Cell Differentiation, 631/208/212/2304, 13, Germinal Center, SDG 3 - Good Health and Well-being, Cellular Microenvironment, Neoplasms, Mutation, 631/250/232/2058, Humans, Lymphocytes, Immunologic Memory, Cell Proliferation, DNA Damage
Abstract

Funder: Wellcome Trust, The lymphocyte genome is prone to many threats, including programmed mutation during differentiation1, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life. Off-target effects of immunological diversification accounted for approximately half of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity. DNA damage from ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory cells. The mutation burden and signatures of normal B cells were broadly similar to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes that are active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.

Published
2022
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7. Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis

Author

Siddhartha P. Kar, Pedro M. Quiros, Muxin Gu, Tao Jiang, Jonathan Mitchell, Ryan Langdon, Vivek Iyer, Clea Barcena, M. S. Vijayabaskar, Margarete A. Fabre, Paul Carter, Slavé Petrovski, Stephen Burgess, George S. Vassiliou, Kar, Siddhartha P [0000-0002-2314-1426], Quiros, Pedro M [0000-0002-7793-6291], Burgess, Stephen [0000-0001-5365-8760], Vassiliou, George S [0000-0003-4337-8022], Apollo - University of Cambridge Repository, Gu, Muxin [0000-0003-4376-795X], and Vassiliou, George [0000-0003-4337-8022]

Subjects
692/308/2056, 631/208/205/2138, article, 692/699/1541, Hematopoiesis, Cell Transformation, Neoplastic, Risk Factors, Mutation, Genetics, Humans, Genetic Predisposition to Disease, ICEP, Clonal Hematopoiesis, Genome-Wide Association Study
Abstract

Funder: British Heart Foundation, Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.

Published
2022
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8. Gut mucosa dissociation protocols influence cell type proportions and single-cell gene expression levels

Author

Werna T. C. Uniken Venema, Aarón D. Ramírez-Sánchez, Emilia Bigaeva, Sebo Withoff, Iris Jonkers, Rebecca E. McIntyre, Mennatallah Ghouraba, Tim Raine, Rinse K. Weersma, Lude Franke, Eleonora A. M. Festen, Monique G. P. van der Wijst, Uniken Venema, Werna TC [0000-0002-1515-0920], Jonkers, Iris [0000-0003-2304-7939], Ghouraba, Mennatallah [0000-0003-4671-3500], van der Wijst, Monique GP [0000-0003-1520-3970], Apollo - University of Cambridge Repository, Molecular Neuroscience and Ageing Research (MOLAR), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Multidisciplinary, Sequence Analysis, RNA, Gene Expression Profiling, Single-Cell Analysis/methods, 692/308/2056, article, Gene Expression, 631/337/2019, Sequence Analysis, RNA/methods, Flow Cytometry, Flow Cytometry/methods, Collagenases, Single-Cell Analysis, Gene Expression Profiling/methods, Intestinal Mucosa, RNA/methods, Sequence Analysis, Peptide Hydrolases
Abstract

Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of the cellular landscape of organs. Most single-cell protocols require fresh material, which limits sample size per experiment, and consequently, introduces batch effects. This is especially true for samples acquired through complex medical procedures, such as intestinal mucosal biopsies. Moreover, the tissue dissociation procedure required for obtaining single cells is a major source of noise; different dissociation procedures applied to different compartments of the tissue induce artificial gene expression differences between cell subsets. To overcome these challenges, we have developed a one-step dissociation protocol and demonstrated its use on cryopreserved gut mucosal biopsies. Using flow cytometry and scRNA-seq analysis, we compared this one-step dissociation protocol with the current gold standard, two-step collagenase digestion, and an adaptation of a recently published alternative, three-step cold-active Bacillus licheniformus protease digestion. Both cell viability and cell type composition were comparable between the one-step and two-step collagenase dissociation, with the former being more time-efficient. The cold protease digestion resulted in equal cell viability, but better preserves the epithelial cell types. Consequently, to analyze the rarer cell types, such as glial cells, larger total biopsy cell numbers are required as input material. The multi-step protocols affected cell types spanning multiple compartments differently. In summary, we show that cryopreserved gut mucosal biopsies can be used to overcome the logistical challenges and batch effects in large scRNA-seq studies. Furthermore, we demonstrate that using cryopreserved biopsies digested using a one-step collagenase protocol enables large-scale scRNA-seq, FACS, organoid generation and intraepithelial lymphocyte expansion.

Published
2022

9. Cells of the adult human heart

Author

Litviňuková, Monika, Talavera-López, Carlos, Maatz, Henrike, Reichart, Daniel, Worth, Catherine L., Lindberg, Eric L., Kanda, Masatoshi, Polanski, Krzysztof, Heinig, Matthias, Lee, Michael, Nadelmann, Emily R., Roberts, Kenny, Tuck, Liz, Fasouli, Eirini S., DeLaughter, Daniel M., McDonough, Barbara, Wakimoto, Hiroko, Gorham, Joshua M., Samari, Sara, Mahbubani, Krishnaa T., Saeb-Parsy, Kourosh, Patone, Giannino, Boyle, Joseph J., Zhang, Hongbo, Zhang, Hao, Viveiros, Anissa, Oudit, Gavin Y., Bayraktar, Omer Ali, Seidman, J. G., Seidman, Christine E., Noseda, Michela, Hubner, Norbert, Teichmann, Sarah A., Worth, Catherine L. [0000-0002-1796-9606], Kanda, Masatoshi [0000-0003-3468-3586], Polanski, Krzysztof [0000-0002-2586-9576], Heinig, Matthias [0000-0002-5612-1720], Lee, Michael [0000-0002-0186-4439], Roberts, Kenny [0000-0001-6155-0821], Wakimoto, Hiroko [0000-0003-0225-6424], Mahbubani, Krishnaa T. [0000-0002-1327-2334], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Patone, Giannino [0000-0002-7242-0341], Boyle, Joseph J. [0000-0002-4337-3320], Bayraktar, Omer Ali [0000-0001-6055-277X], Seidman, Christine E. [0000-0001-6380-1209], Noseda, Michela [0000-0002-9553-5029], Hubner, Norbert [0000-0002-1218-6223], Teichmann, Sarah A. [0000-0002-6294-6366], Apollo - University of Cambridge Repository, Worth, Catherine L [0000-0002-1796-9606], Mahbubani, Krishnaa T [0000-0002-1327-2334], Boyle, Joseph J [0000-0002-4337-3320], Seidman, Christine E [0000-0001-6380-1209], Teichmann, Sarah A [0000-0002-6294-6366], and British Heart Foundation

Subjects
Male, PROTEIN, 13, Epithelium, Heart development, ENRICHMENT ANALYSIS, Genetics research, Adipocytes, Homeostasis, Myocytes, Cardiac, RNA-SEQ, Neurons, Multidisciplinary, SMOOTH-MUSCLE, Research Highlight, Multidisciplinary Sciences, ADIPOSE-TISSUE, Science & Technology - Other Topics, Female, Angiotensin-Converting Enzyme 2, Single-Cell Analysis, EXPRESSION, Adult, GROWTH-FACTOR, General Science & Technology, 45/62, Heart Ventricles, Article, 38/91, 14/32, Humans, Heart Atria, Muscle, Skeletal, RESIDENT CARDIAC MACROPHAGES, Science & Technology, SARS-CoV-2, Gene Expression Profiling, Macrophages, Myocardium, 692/308/2056, Epithelial Cells, Fibroblasts, ENDOTHELIAL-CELLS, GENE, 631/208/199, Cardiovascular and Metabolic Diseases, MYOCARDIAL INJURY, Gene expression, Stromal Cells, Pericytes, Transcriptome, Genome-Wide Association Study, Receptors, Coronavirus
Abstract

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies., Single-cell and single-nucleus RNA sequencing are used to construct a cellular atlas of the human heart that will aid further research into cardiac physiology and disease.

Published
2020

10. Polygenic basis and biomedical consequences of telomere length variation

Author

Christopher P. Nelson, Veryan Codd, John R Thompson, Crispin Musicha, Tao Jiang, Angela M. Wood, Shilpi Sheth, Charley A. Budgeon, Willem H. Ouwehand, Emanuele Di Angelantonio, Svetlana Stoma, Vasiliki Bountziouka, Matthew Denniff, Peter S. Braund, James Eales, Stephen E. Hamby, Sophie C Warner, Dominika E Nanus, Qingning Wang, Stephen Kaptoge, Chloe Swinfield, Amit Khera, Manolo Papakonstantinou, Nilesh J. Samani, Adam S. Butterworth, John Danesh, Minxian Wang, Elias Allara, Codd, Veryan [0000-0002-9430-8254], Allara, Elias [0000-0002-1634-8330], Braund, Peter S. [0000-0001-8540-5709], Papakonstantinou, Manolo [0000-0003-2664-9046], Wang, Minxian [0000-0002-3753-508X], Khera, Amit V. [0000-0001-6535-5839], Eales, James [0000-0001-6238-5952], Ouwehand, Willem H. [0000-0002-7744-1790], Thompson, John R. [0000-0003-4819-1611], Butterworth, Adam S. [0000-0002-6915-9015], Samani, Nilesh J. [0000-0002-3286-8133], Apollo - University of Cambridge Repository, Braund, Peter S [0000-0001-8540-5709], Khera, Amit V [0000-0001-6535-5839], Ouwehand, Willem H [0000-0002-7744-1790], Thompson, John R [0000-0003-4819-1611], Butterworth, Adam S [0000-0002-6915-9015], Samani, Nilesh J [0000-0002-3286-8133], Kaptoge, Stephen [0000-0002-1155-4872], Ouwehand, Willem [0000-0002-7744-1790], Di Angelantonio, Emanuele [0000-0001-8776-6719], Wood, Angela [0000-0002-7937-304X], Butterworth, Adam [0000-0002-6915-9015], and Danesh, John [0000-0003-1158-6791]

Subjects
Senescence, Multifactorial Inheritance, media_common.quotation_subject, Quantitative Trait Loci, 631/208/205/2138, 45/43, Computational biology, Biology, Genome-wide association studies, Health data, Length variation, Genetics research, Genetics, Humans, media_common, Basis (linear algebra), Genome, Human, Longevity, 692/308/2056, article, Telomere Homeostasis, Mendelian Randomization Analysis, Biobank, Phenotype, Genetic architecture, Telomere, Evolutionary biology, Function (biology), Genome-Wide Association Study
Abstract

Funder: Health Data Research UK EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart (11607)., Funder: Health Data Research UK, Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

Published
2021

11. Prognostic implications of troponin T variations in inherited cardiomyopathies using systems biology

Author

Alan J. Robinson, Aneesh Chandran, Abhishek Niroula, Mauno Vihinen, Lorenzo Monserrat, Rameen Shakur, Taufiq Rahman, Juan Pablo Ochoa, Shakur, Rameen [0000-0001-5515-2296], Monserrat, Lorenzo [0000-0001-5776-0623], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, medicine.medical_specialty, 32 Biomedical and Clinical Sciences, QH426-470, Cardiovascular, Article, 3105 Genetics, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Internal medicine, Genetics research, medicine, Genetics, 2.1 Biological and endogenous factors, Family history, Molecular Biology, Genotyping, Genetics (clinical), Survival analysis, 2 Aetiology, Troponin T, biology, business.industry, 692/308/2056, Dilated cardiomyopathy, medicine.disease, Troponin, 3. Good health, 030104 developmental biology, Heart Disease, Heart failure, biology.protein, Cardiology, Medicine, 631/553, business, Systems biology, 030217 neurology & neurosurgery, 31 Biological Sciences
Abstract

[Abstract] The cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90–129 and 130–179 when compared to amino acids 1–89 and 200–288. Our data support variations among 90–130 as being a hotspot for sudden cardiac death and the region 131–179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90–129 and 130–180) and low risk (regions 1–89 and 200–288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification. Medical Research Council (UK); MC_U105674181 R.S. was supported by an independent Wellcome Trust Fellowship. A.J.R. was supported by the Medical Research Council UK (MC_U105674181). A.C. was funded by the Newton Fellowship from the Royal Society, UK. M.V. was supported from Vetenskapsrådet.

Published
2021

12. STAT3 and TP53 mutations associate with poor prognosis in anaplastic large cell lymphoma

Author

Geeta G. Sharma, Daniel Filip, Marek Mráz, Ivonne-Aidee Montes-Mojarro, Falko Fend, Šárka Pospíšilová, Andrea Janíková, David Belada, Boris Tichy, Nina Prokoph, Katerina Kamaradova, Vojtech Bystry, Luca Mologni, Hugo Larose, Carlo Gambacorti-Passerini, Suzanne D. Turner, Cosimo Lobello, Lenka Radová, Olaf Merkel, Huan-Chang Liang, Lobello, C, Tichy, B, Bystry, V, Radova, L, Filip, D, Mraz, M, Montes-Mojarro, I, Prokoph, N, Larose, H, Liang, H, Sharma, G, Mologni, L, Belada, D, Kamaradova, K, Fend, F, Gambacorti Passerini, C, Merkel, O, Turner, S, Janikova, A, Pospisilova, S, Lobello, Cosimo [0000-0003-1329-2113], Prokoph, Nina [0000-0002-6429-9895], Larose, Hugo [0000-0003-4678-6048], Liang, Huan-Chang [0000-0003-2612-3714], Fend, Falko [0000-0002-5496-293X], Gambacorti-Passerini, Carlo [0000-0001-6058-515X], Turner, Suzanne D. [0000-0002-8439-4507], Pospisilova, Sarka [0000-0001-7136-2680], Apollo - University of Cambridge Repository, and Turner, Suzanne D [0000-0002-8439-4507]

Subjects
Adult, Male, STAT3 Transcription Factor, Cancer Research, Letter, Anaplastic Lymphoma, Adolescent, 45/22, 45/23, 631/67/69, CHOP, medicine.disease_cause, Tp53 mutation, ALK P53, Young Adult, hemic and lymphatic diseases, Genetics research, Cancer genomics, medicine, Humans, Young adult, 631/208/69, STAT3, Child, Anaplastic large-cell lymphoma, Aged, Aged, 80 and over, Mutation, biology, business.industry, 692/308/2056, 45/77, Hematology, Middle Aged, medicine.disease, Prognosis, Lymphoma, Oncology, Child, Preschool, 13/51, biology.protein, Cancer research, Lymphoma, Large-Cell, Anaplastic, Female, Tumor Suppressor Protein p53, business
Abstract

Funder: European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712 Czech Science Foundation (GA CR), junior project no. 19-23424Y MEYS CZ project CEITEC 2020 (LQ1601), Funder: MEYS CZ project CEITEC 2020 (LQ1601) NCMG research infrastructure (LM22018132 funded by MEYS CR), Funder: European Union’s Horizon 2020 Marie Skłodowska – Curie Innovative Training Networks (ITN - ETN) under grant agreement No.: 675712., Funder: MH CZ-RVO 65269705

Published
2021
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13. Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

Author

Kamil Sicinski, B. Gwen Windham, Nathalie van der Velde, Luigi Ferrucci, Jian'an Luan, Fernando Rivadeneira, Thuy Vy Duong, Ryan Cvejkus, David A. Bennett, José A. Carnicero, Megan L. Grove, Stefan Walter, Cheryl L. Ackert-Bicknell, Joshua R. Lewis, Adam J. Santanasto, David Melzer, Aron S. Buchman, Janice L. Atkins, Garan Jones, Joanne M. Murabito, Shengjun Hong, Stefania Bandinelli, Michelle C. Odden, Leocadio Rodríguez-Mañas, Magnus Karlsson, Erika Kague, Najada Stringa, Francisco J. Garcia, Chia-Ling Kuo, Dominik Spira, Maria Nethander, André G. Uitterlinden, Claes Ohlsson, Jingyun Yang, Sahar Ghasemi, George A. Kuchel, Dan Mellström, Eric Boerwinkle, Pamela Herd, Lisette C. P. G. M. de Groot, Alexander Teumer, M. Carola Zillikens, Alison E. Fohner, Dan E. Arking, Douglas P. Kiel, Kathryn L. Lunetta, Claudia Langenberg, Toshiko Tanaka, David Karasik, Natasja M. van Schoor, Thomas Kocher, Luke C. Pilling, Lars Bertram, Bruce M. Psaty, Philip L. De Jager, Katerina Trajanoska, Martijn Huisman, Joseph M. Zmuda, Mary L. Biggs, Misa Graff, Qihua Tan, Ilja Demuth, Mary K. Wojczynski, Nicholas J. Wareham, Uwe Völker, Chloé Sarnowski, Jones, Garan [0000-0002-8917-3930], Trajanoska, Katerina [0000-0002-3792-4296], Santanasto, Adam J. [0000-0002-6912-2909], Stringa, Najada [0000-0001-6350-452X], Atkins, Janice L. [0000-0003-4919-9068], Lewis, Joshua R. [0000-0003-1003-8443], Luan, Jian’an [0000-0003-3137-6337], Sarnowski, Chloe [0000-0002-6090-7099], Lunetta, Kathryn L. [0000-0002-9268-810X], Cvejkus, Ryan [0000-0001-5287-5341], Nethander, Maria [0000-0003-3688-906X], Yang, Jingyun [0000-0002-3495-3710], Walter, Stefan [0000-0002-6010-7550], Kague, Erika [0000-0002-0266-9424], Graff, Misa [0000-0001-6380-1735], de Groot, Lisette C. P. G. M. [0000-0003-2778-2789], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas J. [0000-0003-1422-2993], Tan, Qihua [0000-0003-3194-0030], Buchman, Aron S. [0000-0002-6426-2742], De Jager, Philip L. [0000-0002-8057-2505], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Kocher, Thomas [0000-0001-9605-2822], Teumer, Alexander [0000-0002-8309-094X], Bertram, Lars [0000-0002-0108-124X], Melzer, David [0000-0002-0170-3838], Kuchel, George A. [0000-0001-8387-7040], Ferrucci, Luigi [0000-0002-6273-1613], Karasik, David [0000-0002-8826-0530], Rivadeneira, Fernando [0000-0001-9435-9441], Kiel, Douglas P. [0000-0001-8474-0310], Pilling, Luke C. [0000-0002-3332-8454], Apollo - University of Cambridge Repository, Epidemiology, Internal Medicine, VU University medical center, General practice, Epidemiology and Data Science, APH - Aging & Later Life, APH - Personalized Medicine, APH - Societal Participation & Health, Geriatrics, AMS - Ageing & Vitality, Santanasto, Adam J [0000-0002-6912-2909], Atkins, Janice L [0000-0003-4919-9068], Lewis, Joshua R [0000-0003-1003-8443], Luan, Jian'an [0000-0003-3137-6337], Lunetta, Kathryn L [0000-0002-9268-810X], de Groot, Lisette CPGM [0000-0003-2778-2789], Wareham, Nicholas J [0000-0003-1422-2993], Buchman, Aron S [0000-0002-6426-2742], De Jager, Philip L [0000-0002-8057-2505], Uitterlinden, Andre G [0000-0002-7276-3387], Kuchel, George A [0000-0001-8387-7040], Kiel, Douglas P [0000-0001-8474-0310], and Pilling, Luke C [0000-0002-3332-8454]

Subjects
Male, 0301 basic medicine, Aging, Sarcopenia, 45/43, General Physics and Astronomy, Arthritis, Bioinformatics, Cohort Studies, Grip strength, 0302 clinical medicine, Growth Differentiation Factor 5, Genetics research, Aged, 80 and over, Geriatrics, Muscle Weakness, Multidisciplinary, article, Genomics, 631/208/205, Middle Aged, Nutritional Biology, Europe, Meta-analysis, 631/208/212, Medical genetics, Female, medicine.symptom, Cohort study, medicine.medical_specialty, Science, Predictive markers, Polymorphism, Single Nucleotide, HLA-DQ alpha-Chains, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, 692/53/2423, Mendelian randomization, medicine, Life Science, Humans, Genetic Predisposition to Disease, Muscle Strength, Genetic association study, Aged, VLAG, Autoimmune disease, 45, business.industry, 692/308/2056, Muscle weakness, General Chemistry, medicine.disease, 030104 developmental biology, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10−17), arthritis (GDF5 p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing., Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.

Published
2021

14. Reference exome data for Australian Aboriginal populations to support health-based research

Author

Melita McKinnon, Alexia L. Weeks, Jenefer M. Blackwell, Michael Inouye, Lesley Ann Gray, Heather D'Antoine, Andrew C Steer, Steven Y. C. Tong, Bo Remenyi, Genevieve Syn, Ngiare Brown, Jonathan R. Carapetis, Dawn Bessarab, Timo Lassmann, Tong, Steven Y. C. [0000-0002-1368-8356], Blackwell, Jenefer M. [0000-0002-0784-7277], Lassmann, Timo [0000-0002-0138-2691], Apollo - University of Cambridge Repository, Tong, Steven YC [0000-0002-1368-8356], and Blackwell, Jenefer M [0000-0002-0784-7277]

Subjects
Statistics and Probability, Data Descriptor, Native Hawaiian or Other Pacific Islander, Population, Genomics, Library and Information Sciences, Education, Cohort Studies, 03 medical and health sciences, 631/208, 0302 clinical medicine, Genetics research, Genetics, Northern Territory, Humans, Exome, education, Northern territory, lcsh:Science, Exome sequencing, 030304 developmental biology, Uncategorized, 0303 health sciences, education.field_of_study, 692/308/2056, Western Australia, Computer Science Applications, Reference data, Geography, Cohort, lcsh:Q, Statistics, Probability and Uncertainty, data-descriptor, 030217 neurology & neurosurgery, Cohort study, Demography, Information Systems
Abstract

Whole exome sequencing (WES) is a popular and successful technology which is widely used in both research and clinical settings. However, there is a paucity of reference data for Aboriginal Australians to underpin the translation of health-based genomic research. Here we provide a catalogue of variants called after sequencing the exomes of 50 Aboriginal individuals from the Northern Territory (NT) of Australia and compare these to 72 previously published exomes from a Western Australian (WA) population of Martu origin. Sequence data for both NT and WA samples were processed using an ‘intersect-then-combine’ (ITC) approach, using GATK and SAMtools to call variants. A total of 289,829 variants were identified in at least one individual in the NT cohort and 248,374 variants in at least one individual in the WA cohort. Of these, 166,719 variants were present in both cohorts, whilst 123,110 variants were private to the NT cohort and 81,655 were private to the WA cohort. Our data set provides a useful reference point for genomic studies on Aboriginal Australians., Measurement(s)Aboriginal Australian • DNA • sequence feature annotationTechnology Type(s)Whole Exome Sequencing • DNA sequencing • sequence annotationFactor Type(s)ancestry • sex • ageSample Characteristic - OrganismHomo sapiensSample Characteristic - LocationNorthern Territory Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12040638

Published
2021
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15. Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

Author

Henry Houlden, Valentina Cipriani, Evan Reid, Alkyoni Athanasiou-Fragkouli, Patrick F. Chinnery, Arianna Tucci, Nicholas W. Wood, Raquel Real, Huw R. Morris, Victoria Harrison, Damian Smedley, Thomas Bourinaris, Isabella Sheikh, Jana Vandrovcova, Smedley, Damian [0000-0002-5836-9850], Sheikh, Isabella [0000-0002-3952-371X], Chinnery, Patrick [0000-0002-7065-6617], Morris, Huw [0000-0002-5473-3774], Real, Raquel [0000-0001-8117-742X], Houlden, Henry [0000-0002-2866-7777], Tucci, Arianna [0000-0001-5644-0070], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Adolescent, Hereditary spastic paraplegia, Degenerative Disorder, 45/23, Biology, Brief Communication, Genome, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Genetics research, Genetics, medicine, Juvenile, Humans, 692/699/375, Child, Gene, Genetics (clinical), 030304 developmental biology, Aged, 0303 health sciences, Spastic Paraplegia, Hereditary, Parkinsonism, brief-communication, 692/308/2056, 45/77, Middle Aged, medicine.disease, Phenotype, Mutation, Identification (biology), Female, Carrier Proteins, 82/1, 030217 neurology & neurosurgery, Neurological disorders
Abstract

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

Published
2020
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16. Genome-wide association analysis of type 2 diabetes in the EPIC-InterAct study

Author

Peter M. Nilsson, Olov Rolandsson, Eleanor Wheeler, Nicholas J. Wareham, Nita G. Forouhi, Matthias B. Schulze, Kim Overvad, Claudia Langenberg, Nicola D. Kerrison, Pilar Amiano, Catalina Bonet, Mark I. McCarthy, Inês Barroso, Yvonne T. van der Schouw, Lina Cai, Giovanna Masala, José María Huerta, Eva Ardanaz, Anne Tjønneland, Miguel Rodríguez-Barranco, Panos Deloukas, Leif Groop, Guy Fagherazzi, Jian'an Luan, Valeria Pala, Elio Riboli, Carlotta Sacerdote, Rosario Tumino, Paul W. Franks, Annemieke M.W. Spijkerman, Stephen J. Sharp, Salvatore Panico, Rudolf Kaaks, Cai, Lina [0000-0003-2598-8388], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Deloukas, Panos [0000-0001-9251-070X], Groop, Leif C [0000-0002-0187-3263], Huerta, José María [0000-0002-9637-3869], Masala, Giovanna [0000-0002-5758-9069], Nilsson, Peter M [0000-0002-5652-8459], Overvad, Kim [0000-0001-6429-7921], Schulze, Matthias B [0000-0002-0830-5277], Tumino, Rosario [0000-0003-2666-414X], van der Schouw, Yvonne T [0000-0002-4605-435X], Forouhi, Nita G [0000-0002-5041-248X], Barroso, Inês [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Luan, Jian’an [0000-0003-3137-6337], Groop, Leif C. [0000-0002-0187-3263], Nilsson, Peter M. [0000-0002-5652-8459], Schulze, Matthias B. [0000-0002-0830-5277], van der Schouw, Yvonne T. [0000-0002-4605-435X], and Forouhi, Nita G. [0000-0002-5041-248X]

Subjects
Gerontology, Data Descriptor, endocrine system diseases, Epidemiology, Type 2 diabetes, 0302 clinical medicine, Risk Factors, Genetics research, 692/699/2743/137/773, 692/308/174, Prospective Studies, lcsh:Science, Prospective cohort study, 0303 health sciences, Diabetis, Diabetes, Computer Science Applications, Europe, Cardiovascular diseases, Endokrinologi och diabetes, Cohort, Statistics, Probability and Uncertainty, data-descriptor, Information Systems, Statistics and Probability, medicine.medical_specialty, MEDLINE, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Endocrinology and Diabetes, Library and Information Sciences, Education, 03 medical and health sciences, medicine, Mortalitat, Humans, Mortality, Life Style, 030304 developmental biology, Genetic association, business.industry, Malalties cardiovasculars, Public health, 692/308/2056, nutritional and metabolic diseases, medicine.disease, Summary statistics, Diabetes Mellitus, Type 2, lcsh:Q, business, Genome-Wide Association Study
Abstract

Funder: European Union FP6 programme grant number LSHM_CT_2006_037197, Type 2 diabetes (T2D) is a global public health challenge. Whilst the advent of genome-wide association studies has identified >400 genetic variants associated with T2D, our understanding of its biological mechanisms and translational insights is still limited. The EPIC-InterAct project, centred in 8 countries in the European Prospective Investigations into Cancer and Nutrition study, is one of the largest prospective studies of T2D. Established as a nested case-cohort study to investigate the interplay between genetic and lifestyle behavioural factors on the risk of T2D, a total of 12,403 individuals were identified as incident T2D cases, and a representative sub-cohort of 16,154 individuals was selected from a larger cohort of 340,234 participants with a follow-up time of 3.99 million person-years. We describe the results from a genome-wide association analysis between more than 8.9 million SNPs and T2D risk among 22,326 individuals (9,978 cases and 12,348 non-cases) from the EPIC-InterAct study. The summary statistics to be shared provide a valuable resource to facilitate further investigations into the genetics of T2D.

Published
2020

17. Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

Author

Töpf, Ana, Pyle, Angela, Griffin, Helen, Matalonga, Leslie, Schon, Katherine, Sickmann, Albert, Schara–Schmidt, Ulrike, Hentschel, Andreas, Chinnery, Patrick F., Kölbel, Heike, Roos, Andreas, Horvath, Rita, Cohen, Enzo, Cuesta, Isabel, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Gilissen, Christian, Johari, Mridul, Laurie, Steven, Li, Shuang, Nelson, Isabelle, Paramonov, Ida, Peters, Sophia, Prasanth, Sivakumar, Robinson, Peter, Sablauskas, Karolis, Savarese, Marco, Steyaert, Wouter, Van Der Velde, Joeri K., Vitobello, Antonio, Baets, Jonathan, Beijer, Danique, Bonne, Gisèle, Cossins, Judith, Evangelista, Teresinha, Ferlini, Alessandra, Hackman, Peter, Hanna, Michael G., Houlden, Henry, Lau, Jarred, Lochmüller, Hanns, Macken, William L., Musacchia, Francesco, Nascimento, Andres, Natera-De Benito, Daniel, Nigro, Vincenzo, Piluso, Giulio, Pini, Veronica, Pitceathly, Robert D. S., Polavarapu, Kiran, Cruz, Pedro M. Rodriguez, Sarkozy, Anna, Selvatici, Rita, Thompson, Rachel, Torella, Annalaura, Udd, Bjarne, Van De Vondel, Liedewei, Vandrovcova, Jana, Zaharieva, Irina, Schon, Katherine [0000-0001-8054-8954], Horvath, Rita [0000-0002-9841-170X], Apollo - University of Cambridge Repository, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Barcelona Institute of Science and Technology (BIST), University of Cambridge [UK] (CAM), Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Aberdeen, Ruhr-Universität Bochum [Bochum], University Children's Hospital of Essen [Essen, Germany], Enzo Cohen, Isabel Cuesta, Daniel Danis, Anne-Sophie Denommé-Pichon, Yannis Duffourd, Christian Gilissen, Mridul Johari, Steven Laurie, Shuang Li, Isabelle Nelson, Ida Paramonov, Sophia Peters, Sivakumar Prasanth, Peter Robinson, Karolis Sablauskas, Marco Savarese, Wouter Steyaert, Joeri K van der Velde, Antonio Vitobello, Jonathan Baets, Danique Beijer, Gisèle Bonne, Judith Cossins, Teresinha Evangelista, Alessandra Ferlini, Peter Hackman, Michael G Hanna, Henry Houlden, Jarred Lau, Hanns Lochmüller, William L Macken, Francesco Musacchia, Andres Nascimento, Daniel Natera-de Benito, Vincenzo Nigro, Giulio Piluso, Veronica Pini, Robert D S Pitceathly, Kiran Polavarapu, Pedro M Rodriguez Cruz, Anna Sarkozy, Rita Selvatici, Rachel Thompson, Annalaura Torella, Bjarne Udd, Liedewei Van de Vondel, Jana Vandrovcova, Irina Zaharieva, Töpf, Ana, Pyle, Angela, Griffin, Helen, Matalonga, Leslie, Schon, Katherine, Sickmann, Albert, Schara-Schmidt, Ulrike, Hentschel, Andrea, Chinnery, Patrick F, Kölbel, Heike, Roos, Andrea, Horvath, Rita, Nigro, Vincenzo, Torella, Annalaura, and Piluso, Giulio

Subjects
0301 basic medicine, Male, Proteome, 45/41, Developmental Disabilities, Medizin, 45/22, Biology, Bioinformatics, Nervous System Malformations, Brief Communication, 82/80, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, Cerebellum, 38/23, Genetics research, Genetics, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Exome, Genetic Testing, Gene, Cerebellar hypoplasia, Genetics (clinical), Exome sequencing, Proteomic Profile, Proteomic Profiling, 82/58, 631/208/514/2254, brief-communication, 692/308/2056, Infant, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Spinal muscular atrophy, medicine.disease, 3. Good health, 030104 developmental biology, Congenital muscular dystrophy, Next-generation sequencing, 030217 neurology & neurosurgery, Transcription Factors
Abstract

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient's fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. Several authors of this study are members of the European Reference Network for Neuromuscular disease, Project ID No 739543. This study was supported by the AFM (grant 21644 to AR), the framework of the NME-GPS project by the European Regional Development Fund (AR/US/AS), the support by the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, the Regierende Bürgermeister von Berlin-inkl. Wissenschaft und Forschung, and the Bundesministerium für Bildung und Forschung (AH and AS), the European Research Council (RH), the Wellcome Investigator Award (109915/Z/15/Z to RH), the Medical Research Council UK (MR/N025431/1 to RH), the Newton Fund (MR/N027302/1 to RH), the Lily Foundation (RH) and the Evelyn Trust (RH). This research was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1 and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care

Published
2020

18. Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Author

Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., S. M. E., Ng, Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., S. M., Ng, Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., Ng, S. M. E., Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., Ng, S. M., Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. 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[0000-0002-0949-8752], Apollo - University of Cambridge Repository, Hugot, Jean-Pierre [0000-0002-8446-6056], UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Romagnoni, A, Jegou, S, VAN STEEN, Kristel, Wainrib, G, Hugot, JP, Peyrin-Biroulet, L, Chamaillard, M, Colombel, JF, Cottone, M, D'Amato, M, D'Inca, R, Halfvarson, J, Henderson, P, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Ng, SME, Oikonomou, I, Peeters, H, Proctor, DD, Rahier, JF, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Andrews, JM, Bampton, PA, Barclay, M, Florin, TH, Gearry, R, Krishnaprasad, K, Lawrance, IC, Mahy, G, Montgomery, GW, Radford-Smith, G, Roberts, RL, Simms, LA, Hanigan, K, Croft, A, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie, AM, Beck, K, Bernard, EJ, Binion, DG, Bitton, A, Brant, SR, Cho, JH, Cohen, A, Croitoru, K, Daly, MJ, Datta, LW, Deslandres, C, Duerr, RH, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, GR, Haritunians, T, Jobin, G, Katz, S, Lahaie, RG, McGovern, DP, Nelson, L, Ng, SM, Ning, K, Pare, P, Regueiro, MD, Rioux, JD, Ruggiero, E, Schumm, LP, Schwartz, M, Scott, R, Sharma, Y, Silverberg, MS, Spears, D, Steinhart, AH, Stempak, JM, Swoger, JM, Tsagarelis, C, Zhang, C, Zhao, HY, AERTS, Jan, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barnes, C, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, CM, Coffey, AJ, Mc Connell, J, Conrad, DF, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Frayling, TM, Freathy, RM, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Marchini, JL, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, McVean, G, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Munroe, PB, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Ovington, NR, Owen, MJ, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, JRB, Phillips, A, Plagnol, V, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Sawcer, SJ, Schuilenburg, H, Scott, CE, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stirrups, K, Stone, MA, Strachan, DP, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Tobin, MD, Travers, ME, Turnbull, C, Vukcevic, D, Wain, LV, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Yau, C, Young, AH, Zeggini, E, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Hurles, ME, Duncanson, A, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Kwiatkowski, DP, McCarthy, MI, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, JM, Bramon, E, Casas, JP, Corvin, A, Jankowski, J, Markus, HS, Palmer, CNA, Plomin, R, Rautanen, A, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, and Kwiatkowski, D

Subjects
Male, 692/4020/1503/257/1402, Genotype, Genotyping Techniques, LOCI, 45/43, lcsh:Medicine, Polymorphism, Single Nucleotide, Crohn's disease, genetics, genome wide association, Article, Deep Learning, Crohn Disease, INDEL Mutation, Genetics research, Humans, genetics, Genetic Predisposition to Disease, 129, lcsh:Science, Alleles, Science & Technology, genome wide association, RISK PREDICTION, 45, Models, Genetic, lcsh:R, Decision Trees, 692/308/2056, ASSOCIATION, Multidisciplinary Sciences, Crohn's disease, Logistic Models, Nonlinear Dynamics, ROC Curve, Area Under Curve, Science & Technology - Other Topics, lcsh:Q, Female, Neural Networks, Computer, INFLAMMATORY-BOWEL-DISEASE, Genome-Wide Association Study
Abstract

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers. Tis work was supported by Fondation pour la Recherche Médical (ref DEI20151234405) and Investissements d’Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Laboratoire d’excellence INFLAMEX. Te authors thank the students that participated to the wisdom of the crowd exercise.

Published
2019

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