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1. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author

Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology

Subjects
Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

Published
2022

2. Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia

Author

Francesco Lescai, Tarjinder Singh, Christopher P Morley, Evelyn Bromet, David Curtis, Nicholas James Bass, and Mark Daly

Subjects
Genetics, Schizophrenia (object-oriented programming), mental disorders, Odds ratio, Biology, Gene, Exome sequencing, Coding (social sciences)
Abstract

By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 - 50, P < 2.14 × 10-6), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We find significant evidence for an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD), and severe neurodevelopmental disorders (DD/ID), supporting a neurodevelopmental etiology for schizophrenia. We show that protein-truncating variants in GRIN2A, TRIO, and CACNA1G confer risk for schizophrenia whereas specific missense mutations in these genes confer risk for DD/ID. Nevertheless, few of the strongly associated schizophrenia genes appear to confer risk for DD/ID. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk, suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more schizophrenia risk genes await discovery using this approach.

Published
2020

3. EVALUATION OF THE IMPACT OF ULTRA-RARE VARIANTS IN CANNABIS USE DISORDER USING EXOME SEQUENCING

Author

Jinjie Duan, Francesco Lescai, Kyle Satterstrom, Carsten Rygaard Hjorthøj, Thomas Werge, Preben Bo Mortensen, Ole Mors, David Hougaard, Mark Daly, Merete Nordentoft, Benjamin Neale, null The iPSYCH-Broad Consortium, Anders Børglum, and Ditte Demontis

Subjects
Pharmacology, Genetics, biology, business.industry, Heritability, biology.organism_classification, Genetic architecture, Psychiatry and Mental health, Neurology, Medicine, SNP, Pharmacology (medical), Neurology (clinical), Cannabis, Cognitive decline, business, Exome, Biological Psychiatry, Exome sequencing, Genetic association
Abstract

Background Cannabis is the most widely used illicit drug in the world. Cannabis Use Disorder (CUD) is associated with adverse consequences, including psychiatric symptoms, cognitive decline, anxiety disorder and poor quality of life. 35–40% of adults in Denmark and the United States are reported with life-time use of cannabis. The prevalence of diagnosed CUD in Europeans and Americans is estimated to 1–1.5% and the heritability of CUD is estimated to 51–70%. With respect to the amount of risk explained by common variants, the SNP heritability has been estimated to 0.06–0.2. The difference between total heritability and SNP heritability suggests that rare variants might contribute to the risk of CUD, which require sequencing to find them. Methods We performed whole-exome sequencing of ~7,366 Danish individuals identified in the Danish Newborn Screening Biobank (DNSB), including 1,236 affected with CUD, and ~6,100 unaffected controls. We aligned exome sequence data against GRCh37 human genome reference with bwa and identified variants using GATK. We performed quality control of variants and individuals (including principal component analysis for exclusion of non-Europeans), annotated variants with respect to gene, functional impact and presence in the ExAC non-psych database using Hail. Subsequently various burden tests were performed. Results Here we will present results from analysis of the impact of Ultra-Rare Variants (URVs) in CUD. We will especially focus on the burden of these variants in CUD cases compared to controls in highly evolutionary constrained genes as well as specific gene-sets relevant to CUD. Furthermore, we will assess whether CUD risk genes identified based on the common variant analysis also carry an increased burden of URVs. In addition, we will conduct gene-based association analysis to identify top-ranking genes most frequently hit by rare deleterious variants in CUD cases compared with controls. Discussion We will discuss our comprehensive analyses of the role of URVs in CUD, which will further contribute to the understanding of the genetic architecture underlying the disorder, and help elucidating relevant biological mechanism contributing to disease risk.

Published
2019

4. Large-Scale Genetic Characterization of PTSD Across Ancestry, Gender and Trauma-Type

Author

Caroline Nievergelt, Adam Maihofer, Shareefa Dalvie, Andrew Ratanatharathorn, Laramie Duncan, Mark Daly, Kerry Ressler, Israel Liberzon, Karestan Koenen, and null The Psychiatric Genomics Consortium PTSD Working Group

Subjects
Pharmacology, Genome-wide association study, Heritability, Biology, Genetic correlation, Genetic architecture, Psychiatry and Mental health, Neurology, Sample size determination, Genotype, SNP, Pharmacology (medical), Neurology (clinical), Biological Psychiatry, Demography, Genetic association
Abstract

Background Development of post-traumatic stress disorder (PTSD) is influenced by both environmental and genetic factors. In the most current data (freeze 2), the Psychiatric Genomics Consortium (PGC) PTSD group has accumulated over 50 studies with genomic data from over 20,000 PTSD cases and 50,000 trauma-exposed controls. Here we present findings from genome-wide association studies (GWAS) across ancestry groups, gender and trauma-type and present a genetic characterization of PTSD including SNP-based heritability analyses and genetic correlation across psychiatric disorders and other phenotypes / traits of interest. Methods Genotypes were processed with the PGC-pipeline, modified for ancestry assessment. GWAS were performed within European, African American, and Latino ancestry groups and meta-analyzed across studies and ancestries. Stratified analyses for gender and trauma type were also conducted. Standard methods were used to estimate SNP-based heritability and genetic correlations with other psychiatric disorders and traits in European-ancestry subsets. Results Stratified analyses showed genome-wide significant hits in the European and African American data, and some evidence for association in the smaller Latino ancestry group. Analyses across ancestry groups did not result in genome-wide significant hits. We will present results extending our findings from the PGC PTSD freeze 1, which found that PTSD liability was significantly influenced by genetics (p Conclusions Our current findings show that PTSD is significantly influenced by genetic factors, which vary between females and males and overlap with other psychiatric disorders. Unique challenges faced by the PGC PTSD group is the wide range of ancestry, high degree of admixed samples, and large number of studies contributing relatively small number of cases. Consistent with findings from other PGC disorders, much larger sample sizes are needed to fully characterize the genetic architecture of PTSD.

Published
2019

5. INITIAL RESULTS FROM THE META-ANALYSIS OF THE WHOLE-EXOMES OF OVER 20,000 SCHIZOPHRENIA CASES AND 45,000 CONTROLS

Author

Tarjinder Singh, Benjamin Neale, Mark Daly, and null Schizophrenia Exome Meta-Analysis Consortium

Subjects
Pharmacology, education.field_of_study, Schizophrenia (object-oriented programming), Gene sets, Population, Computational biology, Biology, 030227 psychiatry, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Neurology, Meta-analysis, Trait, Pharmacology (medical), Neurology (clinical), education, Exome, 030217 neurology & neurosurgery, Biological Psychiatry, Exome sequencing, Genetic association
Abstract

Background Schizophrenia is a debilitating psychiatric disorder that affects nearly 1% of the population. Schizophrenia has been demonstrated to have a substantial genetic component, with common and rare variants contributing to individual risk. While Genome-Wide Association Studies have implicated over a 140 common risk loci for schizophrenia, rare variant analyses from sequencing studies have had limited success in implicating individual genes, presumably owing to power limitations. Methods Here, we present the Schizophrenia Exome Meta-Analysis (SCHEMA) Consortium, a large multi-site collaboration to aggregate, generate, and analyze high-throughput sequencing data of schizophrenia to advance gene discovery. To date, we have sequenced and processed the whole exomes of over 20,000 schizophrenia cases and 45,000 matched controls using a standardized variant calling and QC pipeline based on GATK and Hail, yielding one of the largest sequencing data sets of a complex trait to date. Our study actively recruited from diverse global populations, and includes individuals of European, Latin American, East Asian, Ashkenazi Jewish, and African American ancestry. Because our exomes were sequenced with various capture technologies over seven years, we developed a novel pipeline to estimate exon-by-exon coverage of all sequencing batches in our data set, and incorporated this information in quality control and analysis. After adjusting for local differences in coverage, we observed comparable quality metrics between different cohorts and sequencing waves. Results We first replicated findings from earlier sequencing studies of schizophrenia, including a substantial enrichment of ultra-rare damaging variants in genes with a near-completion depletion of protein-truncating variants. We also recapitulated a significant burden of disruptive variants in genes and gene sets previously associated with other neurodevelopmental disorders. We present the first gene-based burden results from our exome meta-analysis, and extend the sample using an independent set of 4,000 whole-genome sequenced cases and 7,000 matched controls. Finally, we present a new exome association results browser that allows for easy viewing of identified variants and gene-based results. Discussion In summary, we introduce the largest multi-center effort to aggregate sequencing data of a psychiatric trait, and the initial results from the harmonization and analysis of over 65,000 exomes.

Published
2019

6. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

Author

Bjarni J. Vilhjálmsson, Jian Yang, Hilary K. Finucane, Alexander Gusev, Sara Lindström, Stephan Ripke, Giulio Genovese, Po-Ru Loh, Gaurav Bhatia, Ron Do, Tristan Hayeck, Hong-Hee Won, Sekar Kathiresan, Michele Pato, Carlos Pato, Rulla Tamimi, Eli Stahl, Noah Zaitlen, Bogdan Pasaniuc, Gillian Belbin, Eimear E. Kenny, Mikkel H. Schierup, Philip De Jager, Nikolaos A. Patsopoulos, Steve McCarroll, Mark Daly, Shaun Purcell, Daniel Chasman, Benjamin Neale, Michael Goddard, Peter M. Visscher, Peter Kraft, Nick Patterson, Alkes L. Price, Benjamin M. Neale, Aiden Corvin, James T.R. Walters, Kai-How Farh, Peter A. Holmans, Phil Lee, Brendan Bulik-Sullivan, David A. Collier, Hailiang Huang, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Judit Bene, Sarah E. Bergen, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, William Byerley, Wiepke Cahn, Guiqing Cai, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberly D. Chambert, Raymond C.K. Chan, Ronald Y.L. Chen, Eric Y.H. Chen, Wei Cheng, Eric F.C. Cheung, Siow Ann Chong, C. Robert Cloninger, David Cohen, Nadine Cohen, Paul Cormican, Nick Craddock, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Lynn E. DeLisi, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Naser Durmishi, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Marion Friedl, Joseph I. Friedman, Menachem Fromer, Lyudmila Georgieva, Elliot S. Gershon, Ina Giegling, Paola Giusti-Rodrguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Jakob Grove, Lieuwe de Haan, Christian Hammer, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, David M. Hougaard, Masashi Ikeda, Inge Joa, Antonio Julia, Rene S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, Brian J. Kelly, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kahler, Claudine Laurent, Jimmy Lee Chee Keong, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Miaoxin Li, Tao Li, Kung-Yee Liang, Jeffrey Lieberman, Svetlana Limborska, Carmel M. Loughland, Jan Lubinski, Jouko Lnnqvist, Milan Macek, Patrik K.E. Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Bela Melegh, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Ole Mors, Preben B. Mortensen, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Mller-Myhsok, Mari Nelis, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Liene Nikitina-Zake, Laura Nisenbaum, Annelie Nordin, Eadbhard O’Callaghan, Colm O’Dushlaine, F. Anthony O’Neill, Sang-Yun Oh, Ann Olincy, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietilinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Ulrich Schall, Christian R. Schubert, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Jordan W. Smoller, Hon-Cheong So, Chris C.A. Spencer, Eli A. Stahl, Hreinn Stefansson, Stacy Steinberg, Elisabeth Stogmann, Richard E. Straub, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Mythily Subramaniam, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Erik Sderman, Srinivas Thirumalai, Draga Toncheva, Paul A. Tooney, Sarah Tosato, Juha Veijola, John Waddington, Dermot Walsh, Dai Wang, Qiang Wang, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Emily H.M. Wong, Brandon K. Wormley, Jing Qin Wu, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Rolf Adolfsson, Ole A. Andreassen, Douglas H.R. Blackwood, Elvira Bramon, Joseph D. Buxbaum, Anders D. Børglum, Sven Cichon, Ariel Darvasi, Enrico Domenici, Hannelore Ehrenreich, Tonu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jonsson, Kenneth S. Kendler, George Kirov, Jo Knight, Todd Lencz, Douglas F. Levinson, Qingqin S. Li, Jianjun Liu, Anil K. Malhotra, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Bryan J. Mowry, Markus M. Nthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P. Riley, Dan Rujescu, Pak C. Sham, Pamela Sklar, David St. Clair, Daniel R. Weinberger, Jens R. Wendland, Thomas Werge, Mark J. Daly, Patrick F. Sullivan, Michael C. O’Donovan, David J. Hunter, Muriel Adank, Habibul Ahsan, Kristiina Aittomäki, Laura Baglietto, Sonja Berndt, Carl Blomquist, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Laura Crisponi, Kamila Czene, Norbert Dahmen, Isabel dos Santos Silva, Douglas Easton, A. Heather Eliassen, Jonine Figueroa, Olivia Fletcher, Montserrat Garcia-Closas, Mia M. Gaudet, Lorna Gibson, Christopher A. Haiman, Per Hall, Aditi Hazra, Rebecca Hein, Brian E. Henderson, Albert Hofman, John L. Hopper, Astrid Irwanto, Mattias Johansson, Rudolf Kaaks, Muhammad G. Kibriya, Peter Lichtner, Eiliv Lund, Enes Makalic, Alfons Meindl, Hanne Meijers-Heijboer, Bertram Müller-Myhsok, Taru A. Muranen, Heli Nevanlinna, Petra H. Peeters, Julian Peto, Ross L. Prentice, Nazneen Rahman, María José Sánchez, Daniel F. Schmidt, Rita K. Schmutzler, Melissa C. Southey, Ruth Travis, Clare Turnbull, Andre G. Uitterlinden, Rob B. van der Luijt, Quinten Waisfisz, Zhaoming Wang, Alice S. Whittemore, Rose Yang, Wei Zheng, ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, Grove, Jakob, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Vilhjalmsson, Bjarni J, Yang, Jian, Finucane, Hilary K, Gusev, Alexander, Lee, SH, Price, Alkes L, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Study, Psychosis Endophenotype International Consortium, Wellcome Trust Case Control Consortium, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Human genetics, NCA - Brain mechanisms in health and disease, CCA - Oncogenesis, CCA - Quality of life, CCA - Cancer biology and immunology, Psychiatry, Department of Technology and Operations Management, Department of Organisation and Personnel Management, Child and Adolescent Psychiatry / Psychology, Clinical Genetics, Cell biology, and Internal Medicine

Subjects
Multifactorial Inheritance, Linkage disequilibrium, Complex disease, heritability, Bioinformatics, Medical and Health Sciences, Linkage Disequilibrium, 0302 clinical medicine, Theoretical, External reference, Models, Statistics, GWAS, Genetics(clinical), Genetics (clinical), Mathematics, Genetics & Heredity, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 0303 health sciences, Single Nucleotide, Biological Sciences, Serious Mental Illness, Prognosis, Thresholding, Regression, Mental Health, Phenotype, polygenic risk scores, Mixed model, Multiple Sclerosis, Genotype, Quantitative Trait Loci, polygenic risk score, schizophrenia, GWAS, Discovery, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetics, Humans, p-value, Pruning (decision trees), Polymorphism, Genome-Wide Association Study, Schizophrenia, Models, Theoretical, 030304 developmental biology, genome-wide association study, and Risk of Inherited Variants in Breast Cancer (DRIVE) study, Brain Disorders, Data set, schizophrenia, Sample size determination, polygenic risk score, Polygenic risk score, 030217 neurology & neurosurgery, linkage disequilibrium
Abstract

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R-2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. Refereed/Peer-reviewed

Published
2015

7. USING GENETIC DIVERSITY FROM EAST ASIA TO IMPROVE THE BIOLOGICAL INSIGHT INTO SCHIZOPHRENIA

Author

Hailiang Huang, Max Lam, Chia-Yen Chen, Alicia Martin, Zhiqiang Li, Stephan Ripke, Michael O'Donovan, Mark Daly, and null Psychiatric Genomics Consortium

Subjects
Pharmacology, Mainland China, education.field_of_study, Genetic diversity, Schizophrenia (object-oriented programming), Population, Genome-wide association study, Biology, European descent, Psychiatry and Mental health, Neurology, Evolutionary biology, mental disorders, Pharmacology (medical), East Asia, Neurology (clinical), Allele, education, Biological Psychiatry
Abstract

Background Schizophrenia is a chronic and disabling psychiatric disorder affecting about 1% of the world population. While the biological mechanisms of schizophrenia remain largely elusive, much progress has been made in schizophrenia genetics in the past few years, with over 100 genomic loci associated with schizophrenia reported by the recent large-scale genome-wide association study. However, to date, almost all large schizophrenia genetics studies are derived from primarily European descent population, severely limiting our understanding of schizophrenia biology. Methods Here we present a large-scale schizophrenia genetic study, comprising of 12 schizophrenia case-control cohorts from Singapore, Hong Kong, Taiwan, mainland China, Japan, and Indonesia. After quality control, there are 13,760 cases and 16,883 controls available for genome-wide association. A fixed effect meta-analysis across Asian and Caucasian populations was conducted resulting in a combined sample of 46,945 cases and 59,800 controls. A novel fine-mapping algorithm was designed and conducted to identify potential causal variants between Caucasian and Asian samples. Results Twelve loci (p Discussion The reported results consist of amongst the largest collection of Asian GWAS samples to date. Evidence indicates shared biology across major world populations in schizophrenia. Specifically, across the two populations, all known schizophrenia associations were congruent in effect directions, and effect sizes show no significant heterogeneity. Our approach not only serve to improve detection of common variant loci that implicates two major populations in the world, the approach we have undertaken, improved GWA resolution which in turn allows us to better isolate the causal alleles and facilitate the functional interpretation of schizophrenia associations.

Published
2019

8. 472 - NUDT15 Variants Contribute to Thiopurine-Induced Myelosuppression in European Populations

Author

Graham A. Heap, Gareth J. Walker, Michael N. Weedon, Claire Bewshea, Jukka Koskela, Dermot P.B. McGovern, Michiel D. Voskuil, Neel Heerasing, Tariq Ahmad, Mark Daly, Harry Sokol, Rinse K. Weersma, J Goodhand, Nicholas A. Kennedy, James W. Harrison, and Peter Hendy

Subjects
0301 basic medicine, Oncology, Sanger sequencing, medicine.medical_specialty, Hepatology, Thiopurine methyltransferase, biology, business.industry, Gastroenterology, Genome-wide association study, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, 0302 clinical medicine, Internal medicine, Genotype, Absolute neutrophil count, medicine, symbols, biology.protein, 030211 gastroenterology & hepatology, business, Exome, Exome sequencing, Chromosome 13
Abstract

Introduction Thiopurines are commonly used in the maintenance treatment of inflammatory bowel disease (IBD) but this is limited by myelosuppression in 7% of patients.1 Thiopurine S-methyltransferase (TPMT) variants only explain 20% of thiopurine-induced myelosuppression (TIM) in Europeans suggesting the presence of other genetic determinants.2 We aimed to identify the clinical features of TIM and to identify novel variants associated with TIM through a genome wide association study and whole exome sequencing. Method We recruited 491 IBD patients with TIM from 82 hospitals. Inclusion criteria included drug exposure in the 7 days prior to TIM, white blood cell count ≤2.5 ×109/L, or neutrophil count ≤1.0 ×109/L and that TIM necessitated dose reduction/drug withdrawal. After expert adjudication, 329 cases assigned a high likelihood of causality were genotyped and exome sequenced with 635 thiopurine-tolerant IBD controls for use in the final analyses. Results We first confirmed an association of TIM with TPMT in an initial GWAS. We then, using exome sequencing, discovered a novel 6 bp in-frame deletion (rs746071566; AGGAGTC/A,p.Gly17_Val18del) at position 48611918 of chromosome 13 in exon 1 of NUDT15 (5.8% cases, 0.2% controls, OR=38.2,p=1.33×10-8). This deletion was replicated in an independent cohort (3/75 [4%] cases vs. 2/785 [0.3%] thiopurine-tolerant IBD controls; OR=16.2, p=0.006). All NUDT15 coding variants were confirmed with complete concordance by Sanger sequencing. Multivariable logistic regression demonstrated that adjusted dose (OR 2.2,p=9.4×10-11), NUDT15 genotype (OR 21.7,p=2.0×10-8) and TPMT genotype (OR 2.2,p=2.6×10-4 for MUT/WT and OR 51.2,p=1.8×10-4 for MUT/MUT) were independently associated with TIM. Conclusion These are the largest ever clinical and genetic analyses of thiopurine-induced myelosuppression. We identified NUDT15 coding variants, including a novel 6 bp deletion; carriage of any coding variant confers a 22-fold increase in the odds of TIM, independent of TMPT genotype and thiopurine dose. Although NUDT15 variants are less common than TPMT variants, their effect size for heterozygotes is greater. The number of patients needed to genotype to prevent TIM due to NUDT15 coding variant heterozygosity is 100. The estimated absolute risk of TIM in NUDT15 heterozygotes is 59%. A future clinical decision tool incorporating NUDT15 and TPMT genotypes will offer personalised thiopurine therapy and prevent the considerable morbidity and costs associated with severe bone marrow toxicity. Reference . Gisbert JP & Gomollon F.doi10.1111/j.1572-0241.2008.01848.x (2008) . Yang SK et al. doi10.1038/ng.3060 (2014) Disclosure of Interest None Declared

Published
2018

9. Partitioning heritability by functional category using GWAS summary statistics

Author

Hilary Kiyo Finucane, Brendan Bulik-Sullivan, Alexander Gusev, Gosia Trynka, Yakir Reshef, Po-Ru Loh, Verneri Anttilla, Han Xu, Chongzhi Zang, Kyle Farh, Stephan Ripke, Felix Day, ReproGen Consortium, Schizophrenia Working Group of the Psychiatric Genetics Consortium, RACI Consortium, Shaun Purcell, Eli Stahl, Sara Lindstrom, John R.B. Perry, Yukinori Okada, Soumya Raychaudhuri, Mark Daly, Nick Patterson, Benjamin M. Neale, and Alkes L. Price

Subjects
Genetics, 0303 health sciences, Genome-wide association study, Computational biology, Heritability, Biology, Summary statistics, Genome, Genetic correlation, Smoking behavior, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here, we analyze a broad set of functional elements, including cell-type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits spanning a total of 1.3 million phenotype measurements. To enable this analysis, we introduce a new method for partitioning heritability from GWAS summary statistics while controlling for linked markers. This new method is computationally tractable at very large sample sizes, and leverages genome-wide information. Our results include a large enrichment of heritability in conserved regions across many traits; a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers; and many cell-type-specific enrichments including significant enrichment of central nervous system cell types in body mass index, age at menarche, educational attainment, and smoking behavior. These results demonstrate that GWAS can aid in understanding the biological basis of disease and provide direction for functional follow-up.

Published
2015

10. Regulatory variants explain much more heritability than coding variants across 11 common diseases

Author

Alexander Gusev, S Hong Lee, Benjamin M Neale, Gosia Trynka, Bjarni J Vilhjalmsson, Hilary Finucane, Han Xu, Chongzhi Zang, Stephan Ripke, Eli Stahl, n/a Schizophrenia Working Group of the PGC, n/a SWE-SCZ Consortium, Anna K Kahler, Christina M Hultman, Shaun M Purcell, Steven A McCarroll, Mark Daly, Bogdan Pasaniuc, Patrick F Sullivan, Naomi R Wray, Soumya Raychaudhuri, and Alkes L Price

Subjects
Genetics, 0303 health sciences, Linkage disequilibrium, Single-nucleotide polymorphism, Genome-wide association study, Heritability, Biology, Genome, 03 medical and health sciences, 0302 clinical medicine, Genotype, Exome, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

Common variants implicated by genome-wide association studies (GWAS) of complex diseases are known to be enriched for coding and regulatory variants. We applied methods to partition the heritability explained by genotyped SNPs (h2g) across functional categories (while accounting for shared variance due to linkage disequilibrium) to genotype and imputed data for 11 common diseases. DNaseI Hypersensitivity Sites (DHS) from 218 cell-types, spanning 16% of the genome, explained an average of 79% of h2g (5.1× enrichment; P < 10−20); further enrichment was observed at enhancer and cell-type specific DHS elements. The enrichments were much smaller in analyses that did not use imputed data or were restricted to GWAS- associated SNPs. In contrast, coding variants, spanning 1% of the genome, explained only 8% of h2g (13.8× enrichment; P = 5 × 10−4). We replicated these findings but found no significant contribution from rare coding variants in an independent schizophrenia cohort genotyped on GWAS and exome chips.

Published
2014

11. Wains: a pattern-seeking artificial life species

Author

Mark Daly, Amy de Buitléir, and Michael Russell

Subjects
Self-organizing map, education.field_of_study, business.industry, Population, Biology, Machine learning, computer.software_genre, General Biochemistry, Genetics and Molecular Biology, First generation, Pattern Recognition, Automated, Hebbian theory, Artificial Intelligence, Initial phase, Artificial life, Data Mining, Artificial intelligence, Neural Networks, Computer, Architecture, business, education, computer, Algorithms
Abstract

We describe the initial phase of a research project to develop an artificial life framework designed to extract knowledge from large data sets with minimal preparation or ramp-up time. In this phase, we evolved an artificial life population with a new brain architecture. The agents have sufficient intelligence to discover patterns in data and to make survival decisions based on those patterns. The species uses diploid reproduction, Hebbian learning, and Kohonen self-organizing maps, in combination with novel techniques such as using pattern-rich data as the environment and framing the data analysis as a survival problem for artificial life. The first generation of agents mastered the pattern discovery task well enough to thrive. Evolution further adapted the agents to their environment by making them a little more pessimistic, and also by making their brains more efficient.

Published
2012

12. Common variants at five new loci associated with early-onset inflammatory bowel disease

Author

Marcin, Imielinski, Robert N, Baldassano, Anne, Griffiths, Richard K, Russell, Vito, Annese, Marla, Dubinsky, Subra, Kugathasan, Jonathan P, Bradfield, Thomas D, Walters, Patrick, Sleiman, Cecilia E, Kim, Aleixo, Muise, Kai, Wang, Joseph T, Glessner, Shehzad, Saeed, Haitao, Zhang, Edward C, Frackelton, Cuiping, Hou, James H, Flory, George, Otieno, Rosetta M, Chiavacci, Robert, Grundmeier, Massimo, Castro, Anna, Latiano, Bruno, Dallapiccola, Joanne, Stempak, Debra J, Abrams, Kent, Taylor, Dermot, McGovern, Gary, Silber, Iwona, Wrobel, Antonio, Quiros, Jeffrey C, Barrett, Sarah, Hansoul, Dan L, Nicolae, Judy H, Cho, Richard H, Duerr, John D, Rioux, Steven R, Brant, Mark S, Silverberg, Kent D, Taylor, M Michael, Barmuda, Alain, Bitton, Themistocles, Dassopoulos, Lisa Wu, Datta, Todd, Green, Anne M, Griffiths, Emily O, Kistner, Michael T, Murtha, Miguel D, Regueiro, Jerome I, Rotter, L Philip, Schumm, A Hillary, Steinhart, Stephen R, Targan, Ramnik J, Xavier, Cécile, Libioulle, Cynthia, Sandor, Mark, Lathrop, Jacques, Belaiche, Olivier, Dewit, Ivo, Gut, Simon, Heath, Debby, Laukens, Myriam, Mni, Paul, Rutgeerts, André, Van Gossum, Diana, Zelenika, Denis, Franchimont, J P, Hugot, Martine, de Vos, Severine, Vermeire, Edouard, Louis, Lon R, Cardon, Carl A, Anderson, Hazel, Drummond, Elaine, Nimmo, Tariq, Ahmad, Natalie J, Prescott, Clive M, Onnie, Sheila A, Fisher, Jonathan, Marchini, Jilur, Ghori, Suzannah, Bumpstead, Rhian, Gwillam, Mark, Tremelling, Panos, Delukas, John, Mansfield, Derek, Jewell, Jack, Satsangi, Christopher G, Mathew, Miles, Parkes, Michel, Georges, Mark J, Daly, Melvin B, Heyman, George D, Ferry, Barbara, Kirschner, Jessica, Lee, Jonah, Essers, Richard, Grand, Michael, Stephens, Arie, Levine, David, Piccoli, John, Van Limbergen, Salvatore, Cucchiara, Dimitri S, Monos, Stephen L, Guthery, Lee, Denson, David C, Wilson, Straun F A, Grant, Mark, Daly, Hakon, Hakonarson, UCL - (SLuc) Service de gastro-entérologie, and UCL - MD/MINT - Département de médecine interne

Subjects
Genome-wide association study, Disease, Biology, Inflammatory bowel disease, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetics, Humans, Colitis, Young adult, Age of Onset, 030304 developmental biology, Colitis, Ulcerative - genetics, 0303 health sciences, Crohn's disease, Genome, Human, Chromosome Mapping, Genetic Variation, medicine.disease, Inflammatory Bowel Diseases, Ulcerative colitis, digestive system diseases, 3. Good health, Immunology, Inflammatory Bowel Diseases - epidemiology, genetics, 030211 gastroenterology & hepatology, Colitis, Ulcerative, Age of onset, Genome-Wide Association Study
Abstract

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

Published
2009

13. The complex genetic locus polyhomeotic in Drosophila melanogaster potentially encodes two homologous zinc-finger proteins

Author

Hugh W. Brock, Neel B. Randsholt, Janet Deatrick, and Mark Daly

Subjects
Genetics, Zinc finger, Base Sequence, Sequence analysis, Polyhomeotic, Protein domain, Molecular Sequence Data, Chromosome Mapping, Locus (genetics), Zinc Fingers, General Medicine, DNA, Exons, Biology, Regulatory Sequences, Nucleic Acid, Biological Evolution, Drosophila melanogaster, Tandem repeat, Homeotic selector gene, Animals, Amino Acid Sequence, Homeotic gene, Sequence Alignment
Abstract

Differential expression of the homeotic gene complexes, ANT-C and BX-C ., of Drosophila melanogaster is partly controlled by trans -regulating factors located outside the two complexes. The complex genetic locus, polyhomeotic ( ph ), is one of these trans regulators required during development for correct expression of the homeotic selector genes. The ph locus comprises two genetically independent units whose functions are largely redundant. There are two duplicated sequences arranged as a tandem repeat in the ph region, defining two molecular ph units. Sequence analysis of the 28.6 kb of DNA comprising the locus shows varying degrees of sequence conservation between these two molecular units. Long open reading frames with a high degree of conservation have been localized in each tandem repeat. Putative protein products encoded by both the proximal and the distal unit contain several identical or practically identical protein domains: a zinc-finger-forming motif, an α-helix motif, a domain rich in serine and threonine residues and stretches of glutamine residues. The presence of these protein domains supports the hypothesis that ph encodes a transcription factor that may function as part of a protein complex. Possible molecular mechanisms leading to the particular structure of the locus are discussed.

Published
1991

14. Duplication of CaMV 35 S Promoter Sequences Creates a Strong Enhancer for Plant Genes

Author

Amy M. Chan, Mark Daly, Joan C. McPherson, and Robert J. Kay

Subjects
Genetics, Multidisciplinary, biology, Base pair, Gene duplication, Genetic transfer, Promoter, Cauliflower mosaic virus, Tandem exon duplication, biology.organism_classification, Enhancer, Gene
Abstract

A variant of the cauliflower mosaic virus 35S promoter with transcriptional activity approximately tenfold higher than that of the natural promoter was constructed by tandem duplication of 250 base pairs of upstream sequences. The duplicated region also acted as a strong enhancer of heterologous promoters, increasing the activity of an adjacent and divergently transcribed transferred DNA gene several hundredfold, and to a lesser extent, that of another transferred DNA gene from a remote downstream position. This optimized enhancer element should be very useful for obtaining high levels of expression of foreign genes in transgenic plants.

Published
1987

15. The functional spectrum of low-frequency coding variation

Author

Gabor T, Marth, Fuli, Yu, Amit R, Indap, Kiran, Garimella, Simon, Gravel, Wen Fung, Leong, Chris, Tyler-Smith, Matthew, Bainbridge, Tom, Blackwell, Xiangqun, Zheng-Bradley, Yuan, Chen, Danny, Challis, Laura, Clarke, Edward V, Ball, Kristian, Cibulskis, David N, Cooper, Bob, Fulton, Chris, Hartl, Dan, Koboldt, Donna, Muzny, Richard, Smith, Carrie, Sougnez, Chip, Stewart, Alistair, Ward, Jin, Yu, Yali, Xue, David, Altshuler, Carlos D, Bustamante, Andrew G, Clark, Mark, Daly, Mark, DePristo, Paul, Flicek, Stacey, Gabriel, Elaine, Mardis, Aarno, Palotie, Richard, Gibbs, and Reed A, Cartwright

Subjects
Genotype, Sequence analysis, Population, Human genetic variation, Biology, Polymorphism, Single Nucleotide, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, INDEL Mutation, Humans, Allele, 1000 Genomes Project, education, Allele frequency, Alleles, Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Base Sequence, Genome, Human, Research, Exons, Sequence Analysis, DNA, Genetics, Population, Sequence Alignment, Algorithms, 030217 neurology & neurosurgery
Abstract

Background Rare coding variants constitute an important class of human genetic variation, but are underrepresented in current databases that are based on small population samples. Recent studies show that variants altering amino acid sequence and protein function are enriched at low variant allele frequency, 2 to 5%, but because of insufficient sample size it is not clear if the same trend holds for rare variants below 1% allele frequency. Results The 1000 Genomes Exon Pilot Project has collected deep-coverage exon-capture data in roughly 1,000 human genes, for nearly 700 samples. Although medical whole-exome projects are currently afoot, this is still the deepest reported sampling of a large number of human genes with next-generation technologies. According to the goals of the 1000 Genomes Project, we created effective informatics pipelines to process and analyze the data, and discovered 12,758 exonic SNPs, 70% of them novel, and 74% below 1% allele frequency in the seven population samples we examined. Our analysis confirms that coding variants below 1% allele frequency show increased population-specificity and are enriched for functional variants. Conclusions This study represents a large step toward detecting and interpreting low frequency coding variation, clearly lays out technical steps for effective analysis of DNA capture data, and articulates functional and population properties of this important class of genetic variation.

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16. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Author

Lim, Elaine T., Uddin, Mohammed, De Rubeis, Silvia, Chan, Yingleong, Kamumbu, Anne S., Zhang, Xiaochang, D'Gama, Alissa M., Kim, Sonia N., Hill, Robert Sean, Goldberg, Arthur P., Poultney, Christopher, Minshew, Nancy J., Kushima, Itaru, Aleksic, Branko, Ozaki, Norio, Parellada, Mara, Arango, Celso, Penzol, Maria J., Carracedo, Angel, Kolevzon, Alexander, Hultman, Christina M., Weiss, Lauren A., Fromer, Menachem, Chiocchetti, Andreas G., Freitag, Christine M., Church, George M., Scherer, Stephen W., Buxbaum, Joseph D., Walsh, Christopher A, Aleksic, B, Anney, R, Barbosa, M, Barrett, J, Betancur, C, Bishop, S, Brusco, A, Buxbaum, Jd, Carracedo, A, Chiocchetti, Ag, Chung, Bhy, Cook, E, Coon, H, Cutler, Dj, Daly, M, De Rubeis, S, Doan, R, Fernández-Prieto, M, Ferrero, Gb, Freitag, Cm, Fromer, M, Gargus, J, Geschwind, D, Gill, M, Gómez-Guerrero, L, Hansen-Kiss, E, He, X, Herman, G, Hertz-Picciotto, I, Hultman, C, Iliadou, B, Ionita-Laza, I, Jugessur, A, Knudsen, Gp, Kolevzon, A, Kosmicki, J, Kushima, I, Lee, Sl, Lehner, T, Lennertz, S, Lim, E, Maciel, P, Magnus, P, Manoach, D, Minshew, N, Morrow, E, Mulle, J, Neale, B, Ozaki, N, Palotie, A, Parellada, M, Passos-Bueno, Mr, Pericak-Vance, M, Persico, A, Pessah, I, Reichenberg, A, Reichert, J, Renieri, A, Robinson, E, Samocha, K, Sanders, S, Sandin, S, Santangelo, Sl, Satterstrom, K, Schafer, C, Schellenberg, G, Scherer, S, Senthil, G, Silva, M, Singh, T, Siper, Pm, Soares, G, Stevens, C, Stoltenberg, C, Surén, P, Sutcliffe, Js, Szatmari, P, Tassone, F, Thurm, A, Walsh, C, Weiss, L, Werling, D, Willsey, J, Xu, X, Yu, Tw, Yuen, R, Zwick, Me., Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard University [Cambridge], Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Nagoya University, Hospital General Universitario 'Gregorio Marañón' [Madrid], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Universidade de Santiago de Compostela [Spain] (USC ), CIBER de Enfermedades Raras (CIBERER), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), King Abdulaziz University, Karolinska Institutet [Stockholm], University of California [San Francisco] (UCSF), University of California, Goethe-University Frankfurt am Main, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa [Ottawa], Autism Sequencing Consortium: Branko Aleksic, Richard Anney, Mafalda Barbosa, Jeffrey Barrett, Catalina Betancur, Somer Bishop, Alfredo Brusco, Joseph D Buxbaum, Angel Carracedo, Andreas G Chiocchetti, Brian H Y Chung, Edwin Cook, Hilary Coon, David J Cutler, Mark Daly, Silvia De Rubeis, Ryan Doan, Montserrat Fernández-Prieto, Giovanni Battista Ferrero, Christine M Freitag, Menachem Fromer, Jay Gargus, Dan Geschwind, Michael Gill, Lorena Gómez-Guerrero, Emily Hansen-Kiss, Xin He, Gail Herman, Irva Hertz-Picciotto, Christina Hultman, Bozenna Iliadou, Iuliana Ionita-Laza, Anil Jugessur, Gun Peggy Knudsen, Alexander Kolevzon, Jack Kosmicki, Itaru Kushima, S L Lee, Thomas Lehner, Savannah Lennertz, Elaine Lim, Patricia Maciel, Per Magnus, Dara Manoach, Nancy Minshew, Eric Morrow, Jennifer Mulle, Benjamin Neale, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio Persico, Isaac Pessah, Avi Reichenberg, Jennifer Reichert, Alessandra Renieri, Elise Robinson, Kaitlin Samocha, Stephan Sanders, Sven Sandin, Susan L Santangelo, Kyle Satterstrom, Chad Schafer, Gerry Schellenberg, Stephen Scherer, Geetha Senthil, Marisol Silva, Tarjinder Singh, Paige M Siper, Gabriela Soares, Christine Stevens, Camilla Stoltenberg, Pål Surén, James S Sutcliffe, Peter Szatmari, Flora Tassone, Audrey Thurm, Christopher Walsh, Lauren Weiss, Donna Werling, Jeremy Willsey, Xinyi Xu, Timothy W Yu, Ryan Yuen, Michael E Zwick., University of California [San Francisco] (UC San Francisco), University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Betancur, Catalina

Subjects
0301 basic medicine, Proband, Nonsynonymous substitution, Autism Spectrum Disorder, Databases, Genetic, Genetic Predisposition to Disease, Genetic Variation, Humans, Mosaicism, Mutation, Missense, Zygote, Neuroscience (all), Mutation, Missense, Epigenetics of autism, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, Article, 03 medical and health sciences, Genetic variation, mental disorders, Databases, Genetic, medicine, Missense mutation, Heritability of autism, MESH: Genetic Variation, MESH: Databases, Genetic, Genetics, MESH: Autism Spectrum Disorder, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, General Neuroscience, MESH: Genetic Predisposition to Disease, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, MESH: Zygote, MESH: Mosaicism
Abstract

International audience; We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

Published
2017

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