Author: "Miaoxin Li" / Topic: genome-wide association study - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Miaoxin Li"' showing total 29 results

Start Over Author "Miaoxin Li" Topic genome-wide association study

29 results on '"Miaoxin Li"'

1. DESE: estimating driver tissues by selective expression of genes associated with complex diseases or traits

Author: Lin Jiang, Chao Xue, Sheng Dai, Shangzhen Chen, Peikai Chen, Pak Chung Sham, Haijun Wang, and Miaoxin Li
Subjects: Tissue-selective expression, Disease driver-tissues, Susceptibility genes, Gene-based association, Genome-wide association study, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract: Abstract The driver tissues or cell types in which susceptibility genes initiate diseases remain elusive. We develop a unified framework to detect the causal tissues of complex diseases or traits according to selective expression of disease-associated genes in genome-wide association studies (GWASs). This framework consists of three components which run iteratively to produce a converged prioritization list of driver tissues. Additionally, this framework also outputs a list of prioritized genes as a byproduct. We apply the framework to six representative complex diseases or traits with GWAS summary statistics, which leads to the estimation of the lung as an associated tissue of rheumatoid arthritis.
Published: 2019
Full Text: View/download PDF

2. Powerful and robust inference of complex phenotypes' causal genes with dependent expression quantitative loci by a median-based Mendelian randomization

Author: Lin Jiang, Lin Miao, Guorong Yi, Xiangyi Li, Chao Xue, Mulin Jun Li, Hailiang Huang, and Miaoxin Li
Subjects: Phenotype, Quantitative Trait Loci, Genetics, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Genetics (clinical), Genome-Wide Association Study
Abstract: Isolating the causal genes from numerous genetic association signals in genome-wide association studies (GWASs) of complex phenotypes remains an open and challenging question. In the present study, we proposed a statistical approach, the effective-median-based Mendelian randomization (MR) framework, for inferring the causal genes of complex phenotypes with the GWAS summary statistics (named EMIC). The effective-median method solved the high false-positive issue in the existing MR methods due to either correlation among instrumental variables or noises in approximated linkage disequilibrium (LD). EMIC can further perform a pleiotropy fine-mapping analysis to remove possible false-positive estimates. With the usage of multiple cis-expression quantitative trait loci (eQTLs), EMIC was also more powerful than the alternative methods for the causal gene inference in the simulated datasets. Furthermore, EMIC rediscovered many known causal genes of complex phenotypes (schizophrenia, bipolar disorder, and total cholesterol) and reported many new and promising candidate causal genes. In sum, this study provided an efficient solution to discriminate the candidate causal genes from vast amounts of GWAS signals with eQTLs. EMIC has been implemented in our integrative software platform KGGSEE.
Published: 2022
Full Text: View/download PDF

3. Genome-Wide Association Study Identifies New Risk Loci for Progression of Schistosomiasis Among the Chinese Population

Author: Miao Zhou, Chao Xue, Zhongdao Wu, Xiaoying Wu, and Miaoxin Li
Subjects: Microbiology (medical), China, Mice, Infectious Diseases, Liver, Schistosomiasis japonica, Immunology, Animals, Humans, Membrane Proteins, Schistosomiasis, Microbiology, Genome-Wide Association Study
Abstract: Schistosoma japonicum infections, which lead to local inflammatory responses to schistosome eggs trapped in host tissues, can result in long-term, severe complications. The development of schistosomiasis may result from a complex interaction between the pathogenic, environmental, and host genetic components. Notably, the genetic factors that influence the development of schistosomiasis complications are poorly understood. Here we performed a genome-wide association study on multiple schistosomiasis-related phenotypes of 637 unrelated schistosomiasis patients in the Chinese population. Among three indicators of liver damage, we identified two novel, genome-wide significant single-nucleotide polymorphisms (SNPs) rs34486793 (P = 1.415 × 10-8) and rs2008259 (P = 6.78 × 10-8) at locus 14q32.2 as well as a gene, PMEPA1, at 20q13.31 (index rs62205791, P = 6.52 × 10-7). These were significantly associated with serum levels of hyaluronic acid (HA). In addition, RASIP1 and MAMSTR at 19q13.33 (index rs62132778, P = 1.72 × 10-7) were significantly associated with serum levels of aspartate aminotransferase (AST), and TPM1 at 15q22.2 (index rs12442303, P = 4.39 × 10-7) was significantly associated with serum levels of albumin. In schistosomiasis clinical signs, ITIH4 at 3p21.1 (index rs2239548) was associated with portal vein diameter (PVD) class, an indicator of portal hypertension, and OGDHL at 10q11.23 (index rs1258172) was related to ascites grade. We also detected an increased expression of these six genes in livers of mice with severe schistosomiasis. Summary data-based Mendelian randomization analyses indicated that ITIH4, PMEPA1 and MAMSTR were pleiotropically associated with PVD class, HA and AST, respectively.
Published: 2022
Full Text: View/download PDF

4. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

Author: Gabriëlla A.M. Blokland, Jakob Grove, Chia-Yen Chen, Chris Cotsapas, Stuart Tobet, Robert Handa, David St Clair, Todd Lencz, Bryan J. Mowry, Sathish Periyasamy, Murray J. Cairns, Paul A. Tooney, Jing Qin Wu, Brian Kelly, George Kirov, Patrick F. Sullivan, Aiden Corvin, Brien P. Riley, Tõnu Esko, Lili Milani, Erik G. Jönsson, Aarno Palotie, Hannelore Ehrenreich, Martin Begemann, Agnes Steixner-Kumar, Pak C. Sham, Nakao Iwata, Daniel R. Weinberger, Pablo V. Gejman, Alan R. Sanders, Joseph D. Buxbaum, Dan Rujescu, Ina Giegling, Bettina Konte, Annette M. Hartmann, Elvira Bramon, Robin M. Murray, Michele T. Pato, Jimmy Lee, Ingrid Melle, Espen Molden, Roel A. Ophoff, Andrew McQuillin, Nicholas J. Bass, Rolf Adolfsson, Anil K. Malhotra, Nicholas G. Martin, Janice M. Fullerton, Philip B. Mitchell, Peter R. Schofield, Andreas J. Forstner, Franziska Degenhardt, Sabrina Schaupp, Ashley L. Comes, Manolis Kogevinas, José Guzman-Parra, Andreas Reif, Fabian Streit, Lea Sirignano, Sven Cichon, Maria Grigoroiu-Serbanescu, Joanna Hauser, Jolanta Lissowska, Fermin Mayoral, Bertram Müller-Myhsok, Beata Świątkowska, Thomas G. Schulze, Markus M. Nöthen, Marcella Rietschel, John Kelsoe, Marion Leboyer, Stéphane Jamain, Bruno Etain, Frank Bellivier, John B. Vincent, Martin Alda, Claire O’Donovan, Pablo Cervantes, Joanna M. Biernacka, Mark Frye, Susan L. McElroy, Laura J. Scott, Eli A. Stahl, Mikael Landén, Marian L. Hamshere, Olav B. Smeland, Srdjan Djurovic, Arne E. Vaaler, Ole A. Andreassen, Bernhard T. Baune, Tracy Air, Martin Preisig, Rudolf Uher, Douglas F. Levinson, Myrna M. Weissman, James B. Potash, Jianxin Shi, James A. Knowles, Roy H. Perlis, Susanne Lucae, Dorret I. Boomsma, Brenda W.J.H. Penninx, Jouke-Jan Hottenga, Eco J.C. de Geus, Gonneke Willemsen, Yuri Milaneschi, Henning Tiemeier, Hans J. Grabe, Alexander Teumer, Sandra Van der Auwera, Uwe Völker, Steven P. Hamilton, Patrik K.E. Magnusson, Alexander Viktorin, Divya Mehta, Niamh Mullins, Mark J. Adams, Gerome Breen, Andrew M. McIntosh, Cathryn M. Lewis, David M. Hougaard, Merete Nordentoft, Ole Mors, Preben B. Mortensen, Thomas Werge, Thomas D. Als, Anders D. Børglum, Tracey L. Petryshen, Jordan W. Smoller, Jill M. Goldstein, Stephan Ripke, Benjamin M. Neale, 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, 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, Jurgen Del Favero, Ditte Demontis, Dimitris Dikeos, Timothy Dinan, 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, Giulio Genovese, Lyudmila Georgieva, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, Lieuwe de Haan, Christian Hammer, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Mads V. Hollegaard, Masashi Ikeda, Inge Joa, Antonio Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, 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 Lönnqvist, Milan Macek, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Sara Marsal, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Sandra Meier, Carin J. Meijer, Bela Melegh, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Vihra Milanova, Younes Mokrab, Derek W. Morris, Kieran C. Murphy, Inez Myin-Germeys, 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, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, 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, Ulrich Schall, Christian R. Schubert, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Engilbert Sigurdsson, Teimuraz Silagadze, Jeremy M. Silverman, Kang Sim, Petr Slominsky, Hon-Cheong So, Chris C.A. Spencer, 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 Söderman, Srinivas Thirumalai, Draga Toncheva, 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, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Naomi R. Wray, Kari Stefansson, Peter M. Visscher, Douglas H.R. Blackwood, Ariel Darvasi, Enrico Domenici, Michael Gill, Hugh Gurling, Christina M. Hultman, Assen V. Jablensky, Kenneth S. Kendler, Jo Knight, Qingqin S. Li, Jianjun Liu, Steven A. McCarroll, Jennifer L. Moran, Michael J. Owen, Carlos N. Pato, Danielle Posthuma, Pamela Sklar, Jens R. Wendland, Mark J. Daly, Michael C. O’Donovan, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Matthew A. Brown, Juan P. Casas, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Gavin Band, Céline Bellenguez, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker, Sara Widaa, Mark I. McCarthy, Maria J. Arranz, Steven Bakker, Stephan Bender, Benedicto Crespo-Facorro, Jeremy Hall, Conrad Iyegbe, Stephen Lawrie, Kuang Lin, Don H. Linszen, Ignacio Mata, Muriel Walshe, Matthias Weisbrod, Durk Wiersma, Vassily Trubetskoy, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Jennifer M. Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Liam Abbott, Huda Akil, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, Miquel Casas, Felecia Cerrato, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni-Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Jurgen Del-Favero, J. Raymond DePaulo, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Christine Fraser, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Weihua Guan, Martin Hautzinger, Urs Heilbronner, Maria Hipolito, Dominic Holland, Laura Huckins, Jessica S. Johnson, Radhika Kandaswamy, Robert Karlsson, Sarah Kittel-Schneider, Anna C. Koller, Ralph Kupka, Catharina Lavebratt, Jacob Lawrence, William B. Lawson, Markus Leber, Phil H. Lee, Shawn E. Levy, Jun Z. Li, Chunyu Liu, Anna Maaser, Donald J. MacIntyre, Pamela B. Mahon, Lina Martinsson, Steve McCarroll, Peter McGuffin, Melvin G. McInnis, James D. McKay, Helena Medeiros, Sarah E. Medland, Fan Meng, Grant W. Montgomery, Thomas W. Mühleisen, Hoang Nguyen, Caroline M. Nievergelt, Annelie Nordin Adolfsson, Evaristus A. Nwulia, Claire O'Donovan, Loes M. Olde Loohuis, Anil P.S. Ori, Lilijana Oruc, Urban Ösby, Amy Perry, Andrea Pfennig, Eline J. Regeer, Céline S. Reinbold, John P. Rice, Fabio Rivas, Margarita Rivera, Euijung Ryu, Cristina Sánchez-Mora, Alan F. Schatzberg, William A. Scheftner, Nicholas J. Schork, Cynthia Shannon Weickert, Tatyana Shehktman, Paul D. Shilling, Claire Slaney, Janet L. Sobell, Christine Søholm Hansen, Anne T. Spijker, Michael Steffens, John S. Strauss, Szabolcs Szelinger, Robert C. Thompson, Thorgeir E. Thorgeirsson, Jens Treutlein, Helmut Vedder, Weiqing Wang, Stanley J. Watson, Thomas W. Weickert, Simon Xi, Wei Xu, Allan H. Young, Peter Zandi, Peng Zhang, Sebastian Zöllner, Abdel Abdellaoui, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Fernando S. Goes, Lynsey S. Hall, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Christel M. Middeldorp, Evelin Mihailov, Francis M. Mondimore, Sara Mostafavi, Matthias Nauck, Bernard Ng, Michel G. Nivard, Dale R. Nyholt, Paul F. O'Reilly, Hogni Oskarsson, Jodie N. Painter, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Katherine E. Tansey, Henning Teismann, Wesley Thompson, Pippa A. Thomson, Matthew Traylor, André G. Uitterlinden, Daniel Umbricht, Albert M. van Hemert, Shantel Marie Weinsheimer, Jürgen Wellmann, Yang Wu, Hualin S. Xi, Jian Yang, Futao Zhang, Volker Arolt, Klaus Berger, Udo Dannlowski, Katharina Domschke, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Pamela AF. Madden, Patrik K. Magnusson, Preben Bo Mortensen, Michael C. O'Donovan, Sara A. Paciga, Nancy L. Pedersen, David J. Porteous, Catherine Schaefer, Henry Völzke, Marco Bortolato, Janita Bralten, Cynthia M. Bulik, Christie L. Burton, Caitlin E. Carey, Lea K. Davis, Laramie E. Duncan, Howard J. Edenberg, Lauren Erdman, Stephen V. Faraone, Slavina B. Goleva, Wei Guo, Christopher Hübel, Laura M. Huckins, Ekaterina A. Khramtsova, Joanna Martin, Carol A. Mathews, Elise Robinson, Eli Stahl, Barbara E. Stranger, Michela Traglia, Raymond K. Walters, Lauren A. Weiss, Stacey J. Winham, Yin Yao, Kristjar Skajaa, Markus Nöthen, Michael Owen, Robert H. Yolken, Niels Plath, Jonathan Mill, Daniel Geschwind, Psychiatry 1, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Functional Genomics, Biological Psychology, APH - Mental Health, APH - Methodology, Sociology and Social Gerontology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Blokland, Gabriella AM, Grove, Jakob, Chen, Chia Yen, Cotsapas, Chris, Tobet, Stuart, Handa, Robert, Lee, Sang Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, iPSYCH, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Child and Adolescent Psychiatry / Psychology, Adult Psychiatry, ANS - Complex Trait Genetics, and ANS - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Male, Bipolar Disorder, Schizophrenia/genetics, LD SCORE REGRESSION, Genome-wide association study, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, Psychotic Disorders/genetics, KYNURENINE PATHWAY METABOLISM, Genetics, RISK, Sex Characteristics, Vascular Endothelial Growth Factor, Bipolar Disorder/genetics, Major/genetics, Single Nucleotide, AFFECTIVE STIMULI IMPACT, Schizophrenia, Sulfurtransferases, Major depressive disorder, Female, Depressive Disorder, Major/genetics, Bipolar disorder, Locus (genetics), Genomics, Biology, Polymorphism, Single Nucleotide, Article, DYSPHORIC MOOD, 03 medical and health sciences, Sex differences, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Genotype-by-sex interaction, Biological Psychiatry, Depressive Disorder, Major, Depressive Disorder, GENDER-DIFFERENCES, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], PARAVENTRICULAR NUCLEUS, 3112 Neurosciences, Endothelial Cells, MAJOR DEPRESSION, medicine.disease, Genetic architecture, 030104 developmental biology, Mood, Receptors, Vascular Endothelial Growth Factor, Psychotic Disorders, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Published: 2022
Full Text: View/download PDF

5. A conditional gene-based association framework integrating isoform-level eQTL data reveals new susceptibility genes for schizophrenia

Author: Lin Jiang, Xiangyi Li, Chao Xue, Mulin Jun Li, and Miaoxin Li
Subjects: General Immunology and Microbiology, General Neuroscience, Quantitative Trait Loci, Schizophrenia, Humans, Protein Isoforms, Genetic Predisposition to Disease, General Medicine, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Antipsychotic Agents, Genome-Wide Association Study
Abstract: Linkage disequilibrium and disease-associated variants in the non-coding regions make it difficult to distinguish the truly associated genes from the redundantly associated genes for complex diseases. In this study, we proposed a new conditional gene-based framework called eDESE that leveraged an improved effective chi-squared statistic to control the type I error rates and remove the redundant associations. eDESE initially performed the association analysis by mapping variants to genes according to their physical distance. We further demonstrated that the isoform-level eQTLs could be more powerful than the gene-level eQTLs in the association analysis using a simulation study. Then the eQTL-guided strategies, that is, mapping variants to genes according to their gene/isoform-level variant-gene cis-eQTLs associations, were also integrated with eDESE. We then applied eDESE to predict the potential susceptibility genes of schizophrenia and found that the potential susceptibility genes were enriched with many neuronal or synaptic signaling-related terms in the Gene Ontology knowledgebase and antipsychotics-gene interaction terms in the drug-gene interaction database (DGIdb). More importantly, seven potential susceptibility genes identified by eDESE were the target genes of multiple antipsychotics in DrugBank. Comparing the potential susceptibility genes identified by eDESE and other benchmark approaches (i.e., MAGMA and S-PrediXcan) implied that strategy based on the isoform-level eQTLs could be an important supplement for the other two strategies (physical distance and gene-level eQTLs). We have implemented eDESE in our integrative platform KGGSEE (http://pmglab.top/kggsee/#/) and hope that eDESE can facilitate the prediction of candidate susceptibility genes and isoforms for complex diseases in a multi-tissue context.
Published: 2021

6. Hippocampal transcriptome-wide association study and neurobiological pathway analysis for Alzheimer’s disease

Author: Yao Zhou, Mulin Jun Li, Miaoxin Li, Nana Liu, Chunshui Yu, Shijie Zhang, Huaigui Liu, Wen Qin, and Jiayuan Xu
Subjects: Apolipoprotein E, Male, Cancer Research, Single Nucleotide Polymorphisms, Gene Identification and Analysis, Hippocampus, Gene Expression, Genome-wide association study, Genetic Networks, Hippocampal formation, QH426-470, Alzheimer's Disease, Nucleus Accumbens, Transcriptome, 0302 clinical medicine, Medical Conditions, Mathematical and Statistical Techniques, Gene expression, Medicine and Health Sciences, Gene Regulatory Networks, Genetics (clinical), Aged, 80 and over, 0303 health sciences, Statistics, Brain, Neurodegenerative Diseases, Genomics, Magnetic Resonance Imaging, Neurology, Physical Sciences, Female, Anatomy, Network Analysis, Research Article, Computer and Information Sciences, Gene prediction, Single-nucleotide polymorphism, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, 03 medical and health sciences, Alzheimer Disease, Mental Health and Psychiatry, Genetics, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Statistical Methods, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Aged, Whole Genome Sequencing, Biology and Life Sciences, Computational Biology, Human Genetics, Genome Analysis, Dementia, Neuroscience, 030217 neurology & neurosurgery, Mathematics, Forecasting, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWASs) have identified multiple susceptibility loci for Alzheimer’s disease (AD), which is characterized by early and progressive damage to the hippocampus. However, the association of hippocampal gene expression with AD and the underlying neurobiological pathways remain largely unknown. Based on the genomic and transcriptomic data of 111 hippocampal samples and the summary data of two large-scale meta-analyses of GWASs, a transcriptome-wide association study (TWAS) was performed to identify genes with significant associations between hippocampal expression and AD. We identified 54 significantly associated genes using an AD-GWAS meta-analysis of 455,258 individuals; 36 of the genes were confirmed in another AD-GWAS meta-analysis of 63,926 individuals. Fine-mapping models further prioritized 24 AD-related genes whose effects on AD were mediated by hippocampal expression, including APOE and two novel genes (PTPN9 and PCDHA4). These genes are functionally related to amyloid-beta formation, phosphorylation/dephosphorylation, neuronal apoptosis, neurogenesis and telomerase-related processes. By integrating the predicted hippocampal expression and neuroimaging data, we found that the hippocampal expression of QPCTL and ERCC2 showed significant difference between AD patients and cognitively normal elderly individuals as well as correlated with hippocampal volume. Mediation analysis further demonstrated that hippocampal volume mediated the effect of hippocampal gene expression (QPCTL and ERCC2) on AD. This study identifies two novel genes associated with AD by integrating hippocampal gene expression and genome-wide association data and reveals candidate hippocampus-mediated neurobiological pathways from gene expression to AD., Author summary The hippocampus is a potential neuroimaging endophenotype for Alzheimer’s disease (AD). This study identifies genes whose expression in hippocampal tissue is associated with AD and establishes the pathways from hippocampal gene expression to hippocampal volume to AD. We demonstrate that 24 genes are associated with AD in hippocampal tissue, and these genes are enriched for AD-related biological processes of amyloid-beta formation, phosphorylation/dephosphorylation, neuronal apoptosis, neurogenesis and telomerase-related processes. We further show that hippocampal volume mediates the effects of the hippocampal gene expression of QPCTL and ERCC2 on AD. These findings improve our understanding of the genetic and neural mechanisms of AD.
Published: 2021

7. A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts

Author: Guiyan Ni, Jian Zeng, Joana A. Revez, Ying Wang, Zhili Zheng, Tian Ge, Restuadi Restuadi, Jacqueline Kiewa, Dale R. Nyholt, Jonathan R.I. Coleman, Jordan W. Smoller, Jian Yang, Peter M. Visscher, Naomi R. Wray, Stephan Ripke, 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, Kimberley 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, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, 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, Giulio Genovese, Lyudmila Georgieva, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Vera Golimbet, Srihari Gopal, Jacob Gratten, 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 Julià, René S. Kahn, Luba Kalaydjieva, Sena Karachanak-Yankova, Juha Karjalainen, David Kavanagh, Matthew C. Keller, James L. Kennedy, Andrey Khrunin, Yunjung Kim, Janis Klovins, James A. Knowles, Bettina Konte, Vaidutis Kucinskas, Zita Ausrele Kucinskiene, Hana Kuzelova-Ptackova, Anna K. Kähler, Claudine Laurent, Jimmy Lee, 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 Lönnqvist, 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, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Bertram Müller-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, Psychosis Endophenotypes International Consortium, Christos Pantelis, George N. Papadimitriou, Sergi Papiol, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinen, 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, 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 Söderman, Srinivas Thirumalai, Draga Toncheva, 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, Hualin Simon Xi, Clement C. Zai, Xuebin Zheng, Fritz Zimprich, Kari Stefansson, Wellcome Trust Case-Control Consortium, 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, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, 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, Preben B. Mortensen, Bryan J. Mowry, Markus M. Nöthen, 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, Maciej Trzaskowski, Enda M. Byrne, Abdel Abdellaoui, Mark J. Adams, Tracy M. Air, Till F.M. Andlauer, Silviu-Alin Bacanu, Marie Bækvad-Hansen, Aartjan T.F. Beekman, Elisabeth B. Binder, Julien Bryois, Henriette N. Buttenschøn, Jonas Bybjerg-Grauholm, Na Cai, Enrique Castelao, Jane Hvarregaard Christensen, Toni-Kim Clarke, Lucía Colodro-Conde, Baptiste Couvy-Duchesne, Gregory E. Crawford, Gail Davies, Ian J. Deary, Eske M. Derks, Nese Direk, Conor V. Dolan, Erin C. Dunn, Thalia C. Eley, Farnush Farhadi Hassan Kiadeh, Hilary K. Finucane, Jerome C. Foo, Andreas J. Forstner, Héléna A. Gaspar, Fernando S. Goes, Scott D. Gordon, Jakob Grove, Lynsey S. Hall, Christine Søholm Hansen, Thomas F. Hansen, Ian B. Hickie, Georg Homuth, Carsten Horn, Jouke-Jan Hottenga, David M. Howard, Marcus Ising, Rick Jansen, Ian Jones, Lisa A. Jones, Eric Jorgenson, Isaac S. Kohane, Julia Kraft, Warren W. Kretzschmar, Zoltán Kutalik, Yihan Li, Penelope A. Lind, Donald J. MacIntyre, Dean F. MacKinnon, Robert M. Maier, Jonathan Marchini, Hamdi Mbarek, Patrick McGrath, Peter McGuffin, Sarah E. Medland, Divya Mehta, Christel M. Middeldorp, Evelin Mihailov, Yuri Milaneschi, Francis M. Mondimore, Grant W. Montgomery, Sara Mostafavi, Niamh Mullins, Matthias Nauck, Bernard Ng, Michel G. Nivard, Paul F. O’Reilly, Hogni Oskarsson, Jodie N. Painter, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Roseann E. Peterson, Wouter J. Peyrot, Giorgio Pistis, Jorge A. Quiroz, Per Qvist, John P. Rice, Margarita Rivera, Saira Saeed Mirza, Robert Schoevers, Eva C. Schulte, Ling Shen, Stanley I. Shyn, Grant C.B. Sinnamon, Johannes H. Smit, Daniel J. Smith, Fabian Streit, Katherine E. Tansey, Henning Teismann, Alexander Teumer, Wesley Thompson, Pippa A. Thomson, Thorgeir E. Thorgeirsson, Matthew Traylor, Jens Treutlein, Vassily Trubetskoy, André G. Uitterlinden, Daniel Umbricht, Sandra Van der Auwera, Albert M. van Hemert, Alexander Viktorin, Yunpeng Wang, Shantel Marie Weinsheimer, Jürgen Wellmann, Gonneke Willemsen, Yang Wu, Hualin S. Xi, Futao Zhang, Volker Arolt, Bernhard T. Baune, Klaus Berger, Dorret I. Boomsma, Udo Dannlowski, E.J.C. de Geus, J. Raymond DePaulo, Katharina Domschke, Hans J. Grabe, Steven P. Hamilton, Caroline Hayward, Andrew C. Heath, Stefan Kloiber, Glyn Lewis, Susanne Lucae, Pamela A.F. Madden, Patrik K. Magnusson, Nicholas G. Martin, Preben Bo Mortensen, Merete Nordentoft, Sara A. Paciga, Nancy L. Pedersen, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Ni, Guiyan, Zeng, Jian, Revez, Joana A., Wang, Ying, Zhili, Zheng, Ge, Tian, Restuadi, Restuadi, Kiewa, Jacqueline, Nyholt, Dale R, Coleman, Jonathan RI, Smoller, Jordan W, Lee, S Hong, APH - Methodology, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Econometrics, Psychiatry, Department of Technology and Operations Management, Child and Adolescent Psychiatry / Psychology, Epidemiology, Erasmus MC other, Urology, Internal Medicine, Medical Informatics, Immunology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Multifactorial Inheritance, medicine.medical_specialty, LDpred2, BF, Genomics, Disease, Major depressive disorder, risk prediction, 03 medical and health sciences, 0302 clinical medicine, MegaPRS, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetic risk, Psychiatry, Biological Psychiatry, Genetic association, Depressive Disorder, Major, business.industry, Mental Disorders, medicine.disease, Genetic architecture, Polygenic scores, Risk prediction, polygenic scores, PRS-CS, psychiatric disorders, 030104 developmental biology, SBayesR, Schizophrenia, Cohort, Lassosum, RC0321, business, Psychiatric disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: BACKGROUND: Polygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors.METHODS: The Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared.RESULTS: Compared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively.CONCLUSIONS: Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.
Published: 2021
Full Text: View/download PDF

8. Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma

Author: Chou Yang, Deke Jiang, Changzheng Dong, S. Lilly Zheng, Xiaolong Qi, Irene Oi-Lin Ng, Yuan Ji, Qianyi Xiao, Jianfeng Xu, Jinlin Hou, Lin Wei, Bin Zhou, Pak C. Sham, Carly Conran, Long Yu, Miaoxin Li, Xiao-Pin Ma, Jiaen Deng, and Guangwen Cao
Subjects: 0301 basic medicine, Knowledge-based genetic association, Male, Cancer Research, Candidate gene, Hepatitis B virus, Carcinoma, Hepatocellular, Hepatocellular carcinoma, Knowledge Bases, Single-nucleotide polymorphism, Biology, medicine.disease_cause, lcsh:RC254-282, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Gene, Genetic association, Liver Neoplasms, Cell cycle, Heritability, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Hepatitis B, Prognosis, digestive system diseases, 030104 developmental biology, Oncology, Susceptibility, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Research Article, Follow-Up Studies, Genome-Wide Association Study
Abstract: Background Recent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. In the present study, we aimed to identify additional susceptibility loci of HBV-related HCC using advanced knowledge-based analysis. Methods We performed knowledge-based analysis (including gene- and gene-set-based association tests) on variant-level association p-values from two existing GWASs of HBV-related HCC. Five different types of gene-sets were collected for the association analysis. A number of SNPs within the gene prioritized by the knowledge-based association tests were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls. Results The gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk: SLC39A8, GOLGA8M, SMIM31, and WHAMMP2. The gene-set-based association analysis prioritized two promising gene sets for HCC, cell cycle G1/S transition and NOTCH1 intracellular domain regulates transcription. Within the gene sets, three promising candidate genes (CDC45, NCOR1 and KAT2A) were further prioritized for HCC. Among genes of liver-specific expression, multiple genes previously implicated in HCC were also highlighted. However, probably due to small sample size, none of the genes prioritized by the knowledge-based association analyses were successfully replicated by variant-level association test in the independent sample. Conclusions This comprehensive knowledge-based association mining study suggested several promising genes and gene-sets associated with HBV-related HCC risks, which would facilitate follow-up functional studies on the pathogenic mechanism of HCC.
Published: 2020

9. A powerful approach reveals numerous expression quantitative trait haplotypes in multiple tissues

Author: Dingge Ying, Mulin Jun Li, Pak C. Sham, and Miaoxin Li
Subjects: 0301 basic medicine, Statistics and Probability, Multifactorial Inheritance, Quantitative Trait Loci, Haplotype, Single-nucleotide polymorphism, Computational biology, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Biochemistry, Computer Science Applications, 03 medical and health sciences, Computational Mathematics, Phenotype, 030104 developmental biology, Haplotypes, Computational Theory and Mathematics, Expression quantitative trait loci, SNP, Enhancer, Molecular Biology, Gene, Genome-Wide Association Study, Genetic association
Abstract: Motivation Recently many studies showed single nucleotide polymorphisms (SNPs) affect gene expression and contribute to development of complex traits/diseases in a tissue context-dependent manner. However, little is known about haplotype’s influence on gene expression and complex traits, which reflects the interaction effect between SNPs. Results In the present study, we firstly proposed a regulatory region guided eQTL haplotype association analysis approach, and then systematically investigate the expression quantitative trait loci (eQTL) haplotypes in 20 different tissues by the approach. The approach has a powerful design of reducing computational burden by the utilization of regulatory predictions for candidate SNP selection and multiple testing corrections on non-independent haplotypes. The application results in multiple tissues showed that haplotype-based eQTLs not only increased the number of eQTL genes in a tissue specific manner, but were also enriched in loci that associated with complex traits in a tissue-matched manner. In addition, we found that tag SNPs of eQTL haplotypes from whole blood were selectively enriched in certain combination of regulatory elements (e.g. promoters and enhancers) according to predicted chromatin states. In summary, this eQTL haplotype detection approach, together with the application results, shed insights into synergistic effect of sequence variants on gene expression and their susceptibility to complex diseases. Availability and implementation The executable application ‘eHaplo’ is implemented in Java and is publicly available at http://grass.cgs.hku.hk/limx/ehaplo/. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2018
Full Text: View/download PDF

10. Estimating driver-tissues by robust selective expression of genes associated with complex diseases or traits

Author: Pak C. Sham, Shangzhen Chen, Haijun Wang, Sheng Dai, Miaoxin Li, Lin Jiang, Chao Xue, and Peikai Chen
Subjects: Genome-wide association study, Susceptibility gene, Disease, Computational biology, Biology, Gene, Expression (mathematics)
Abstract: The driver tissues or cell-types of many human diseases, in which susceptibility genes cause the diseases, remain elusive. We developed a framework to detect the causal-tissues of complex diseases or traits according to selective expression of disease-associated genes in genome-wide association study (GWAS). The core method of the framework is a new robust z-score to estimate genes’ expression selectivity. Through extensive computing simulations and comparative analyses in a large-scale schizophrenia GWAS, we demonstrate the robust z-score is more sensitive than existing methods to detect multiple selectively expressed tissues, which further lead to the estimation of more biological sensible driver tissues. The effectiveness of this framework is further validated in five representative complex diseases with the usage of GWAS summary statistics and transcript-level expression in GTEx project. Finally, we also demonstrate that the prioritized tissues and the robust selective expression can enhance characterization of directly associated genes of a disease as well. Interesting results include the estimation of lung as a driver tissue of rheumatoid arthritis, consistent with clinical observations of morbidity between rheumatoid arthritis and lung diseases.
Published: 2018
Full Text: View/download PDF

11. FAPI: Fast and accurate P-value Imputation for genome-wide association study

Author: Miaoxin Li, Johnny S. H. Kwan, Pak C. Sham, and Jiaen Deng
Subjects: 0301 basic medicine, Genotype, Computer science, Software tool, Genome-wide association study, Computational biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Standard procedure, 03 medical and health sciences, 030104 developmental biology, Genetics, Humans, p-value, Spurious relationship, Software, Genetics (clinical), Imputation (genetics), Genome-Wide Association Study, Genetic association
Abstract: Imputing individual-level genotypes (or genotype imputation) is now a standard procedure in genome-wide association studies (GWAS) to examine disease associations at untyped common genetic variants. Meta-analysis of publicly available GWAS summary statistics can allow more disease-associated loci to be discovered, but these data are usually provided for various variant sets. Thus imputing these summary statistics of different variant sets into a common reference panel for meta-analyses is impossible using traditional genotype imputation methods. Here we develop a fast and accurate P-value imputation (FAPI) method that utilizes summary statistics of common variants only. Its computational cost is linear with the number of untyped variants and has similar accuracy compared with IMPUTE2 with prephasing, one of the leading methods in genotype imputation. In addition, based on the FAPI idea, we develop a metric to detect abnormal association at a variant and showed that it had a significantly greater power compared with LD-PAC, a method that quantifies the evidence of spurious associations based on likelihood ratio. Our method is implemented in a user-friendly software tool, which is available at http://statgenpro.psychiatry.hku.hk/fapi.
Published: 2015
Full Text: View/download PDF

12. A powerful conditional gene-based association approach implicated functionally important genes for schizophrenia

Author: Johnny S. H. Kwan, Peikai Chen, Timothy Shin Heng Mak, Liqian Cui, Miaoxin Li, Henry C. M. Leung, Pak C. Sham, Lin Jiang, Tao Li, and Chao Xue
Subjects: Statistics and Probability, Schizophrenia (object-oriented programming), Genome-wide association study, Disease, Biology, Biochemistry, Polymorphism, Single Nucleotide, 03 medical and health sciences, Polymorphism (computer science), medicine, Humans, Association (psychology), Molecular Biology, Gene, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, 030302 biochemistry & molecular biology, Human brain, Computer Science Applications, Computational Mathematics, medicine.anatomical_structure, Computational Theory and Mathematics, Schizophrenia, Genome-Wide Association Study
Abstract: Motivation It remains challenging to unravel new susceptibility genes of complex diseases and the mechanisms in genome-wide association studies. There are at least two difficulties, isolation of the genuine susceptibility genes from many indirectly associated genes and functional validation of these genes. Results We first proposed a novel conditional gene-based association test which can use only summary statistics to isolate independently associated genes of a disease. Applying this method, we detected 185 genes of independent association with schizophrenia. We then designed an in-silico experiment based on expression/co-expression to systematically validate pathogenic potential of these genes. We found that genes of independent association with schizophrenia formed more co-expression pairs in normal post-natal but not pre-natal human brain regions than expected. Interestingly, no co-expression enrichment was found in the brain regions of schizophrenia patients. The genes with independent association also had more significant P-values for differential expression between schizophrenia patients and controls in the brain regions. In contrast, indirectly associated genes or associated genes by other widely-used gene-based tests had no such differential expression and co-expression patterns. In summary, this conditional gene-based association test is effective for isolating directly associated genes from indirectly associated genes, and the results insightfully suggest that common variants might contribute to schizophrenia largely by distorting expression and co-expression in post-natal brains. Availability and implementation The conditional gene-based association test has been implemented in a platform ‘KGG’ in Java and is publicly available at http://grass.cgs.hku.hk/limx/kgg/. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2018

13. Knowledge-Based Genetic Association Study of Hepatitis B Virus Related Hepatocellular Carcinoma in Chinese Populations

Author: Deke Jiang, Guangwen Cao, Jiaen Deng, Changzheng Dong, Ci Song, Xiaopin Ma, Qianyi Xiao, Bin Zhou, Chou Yang, Lin Wei, Meng Zhu, Zijin Ge, Carly Conran, S. Lilly Zheng, Irene Oi-lin Ng, Long Yu, Jianfeng Xu, Pak C. Sham, Zhibin Hu, Yuan Ji, Jinlin Hou, Xiaolong Qi, and Miaoxin Li
Subjects: Hepatitis B virus, Oncology, medicine.medical_specialty, business.industry, Mechanism (biology), Genome-wide association study, Single-nucleotide polymorphism, Medical research, medicine.disease_cause, Informed consent, Internal medicine, Medicine, business, Genetic association, Declaration of Helsinki
Abstract: Background: Recent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. Methods: In the present study, we aimed to identify additional susceptibility loci in two existing HBV-related HCC GWAS datasets using advanced gene- and gene-set-based association tests. Findings: The gene-based association analysis suggested that five genes are associated with HBV-related HCC risk: RNY4, GOLGA8M, LINC01207, WHAMMP2 and SLC39A8 with statistical significance. Through gene-set-based association analysis, we found that the genes in systemic lupus erythematosus pathway may be relevant to development of HBV-related HCC. Three previously reported genes, NAT2, GSTA1 and GSTA2, were also highlighted when genes were stratified in a liver-specific expression set. Furthermore, our analyses suggested that susceptibility loci of HBV-related HCC are unlikely to be enriched in several functional gene sets of HCC defined by our current knowledge. However, our failure to replicate significance at individual SNPs selected from the knowledge-based association analyses in independent cohorts calls for larger replication studies. Interpretation: This comprehensive knowledge-based association mining study suggested several promising genes significantly associated with HBV-related HCC risk, which may shed insights into the pathogenic mechanism of this fatal disorder. Funding Statement: This study was supported by Hong Kong Health and the Medical Research Fund (01121436 and 02132236 to M.X.L.), the National Natural Science Foundation of China (31100895, 81472618 and 81670535 to D.K.J., 81402297 to Q.L.X.), the National Science and Technology Major Project (No. 2018ZX10301202 to D.K.J. and J.H.), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (No. 2017BT01S131 to D.K.J. and J.H.), the Grant for Recruited Talents to Start Scientific Research from Nanfang Hospital (to D.K.J.), and the Distinguished Youth Scholars Incubation Project of Nanfang Hospital (No. 2017J001 to D.K.J.) Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: The study was performed in accordance with guidelines approved by the local ethical committees from all participating centers involved in both the GWAS stage and the replication stage. An informed consent to participate in the study was obtained from each subject in accordance with the declaration of Helsinki principles. All study participants approved the storage of their frozen DNA specimens, for research purposes, in our laboratory.
Published: 2018
Full Text: View/download PDF

14. 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
Full Text: View/download PDF

15. Sharing of Genes and Pathways Across Complex Phenotypes: A Multilevel Genome-Wide Analysis

Author: Johnny S. H. Kwan, Pak C. Sham, Stacey S. Cherny, Miaoxin Li, and Hongsheng Gui
Subjects: 0301 basic medicine, Genetics, Genetic Linkage, Genome, Human, Datasets as Topic, Single-nucleotide polymorphism, Genome-wide association study, Genetic Pleiotropy, Biology, Investigations, Genome, Polymorphism, Single Nucleotide, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Pleiotropy, Genetic linkage, Humans, Genetic Predisposition to Disease, Gene, 030217 neurology & neurosurgery, Genetic association, Genome-Wide Association Study
Abstract: Evidence from genome-wide association studies (GWAS) suggest that pleiotropic effects on human complex phenotypes are very common. Recently, an atlas of genetic correlations among complex phenotypes has broadened our understanding of human diseases and traits. Here, we examine genetic overlap, from a gene-centric perspective, among the same 24 phenotypes previously investigated for genetic correlations. After adopting the multilevel pipeline (freely available at http://grass.cgs.hku.hk/limx/kgg/), which includes intragenic single nucleotide polymorphisms (SNPs), genes, and gene-sets, to estimate genetic similarities across phenotypes, a large amount of sharing of several biologically related phenotypes was confirmed. In addition, significant genetic overlaps were also found among phenotype pairs that were previously unidentified by SNP-level approaches. All these pairs with new genetic links are supported by earlier epidemiological evidence, although only a few of them have pleiotropic genes in the GWAS Catalog. Hence, our gene and gene-set analyses are able to provide new insights into cross-phenotype connections. The investigation on genetic sharing at three different levels presents a complementary picture of how common DNA sequence variations contribute to disease comorbidities and trait manifestations.
Published: 2017

16. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Author: Cristina Cereda, Jurjen J. Luykx, Sandra Meier, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Lyudmila Georgieva, John Landers, Silvana Penco, Marian L. Hamshere, Frank Dudbridge, Mari Nelis, Dick Schijven, Jimmy Lee, Sarah E. Bergen, Alessandro Padovani, Nicholas W. Wood, Meraida Polak, Hannelore Ehrenreich, Nancy G. Buccola, Noa Carrera, Stefan Herms, Panos Roussos, Marion Friedl, Teimuraz Silagadze, Jim van Os, Annette M. Hartmann, Ole A. Andreassen, R. Jeroen Pasterkamp, Sibylle G. Schwab, Aleksey Shatunov, Eli A. Stahl, David A. Collier, Farooq Amin, Michael Conlon O'Donovan, Guiqing Cai, Kung-Yee Liang, Denis C. Bauer, Charles Curtis, Brion S. Maher, Ashley R. Jones, Sara L. Pulit, Sarah Tosato, Milan Macek, Vivianna M. Van Deerlin, Vincenzo Silani, Pietro Fratta, Bettina Konte, Rosanna Tortelli, Dan Rujescu, T. Scott Stroup, Elizabeth Bevilacqua, Christian Lunetta, Bradley T. Webb, Christophe Tzourio, Patrick Vourc'h, Joel N. Hirschhorn, Gilbert Bensimon, Timothy G. Dinan, Thomas G. Schulze, Richard A. Belliveau, Daniel R. Weinberger, Andrew McQuillin, Qingqin S. Li, Orla Hardiman, Claudine Laurent, Masashi Ikeda, Tim Kahlke, Rodney J. Scott, Frans Henskens, Tune H. Pers, Wolfgang Lieb, Christian Hammer, Elvira Bramon, Hana Kuzelova-Ptackova, Raquelle I. Mesholam-Gately, Ingrid Melle, Nadine Cohen, David Cohen, Nazli Basak, Elisabeth Stögmann, Nelson B. Freimer, Peter Eichhammer, J. Mallet, Preben Bo Mortensen, Robert H. Brown, Wouter van Rheenen, Roberto Del Bo, Dai Wang, Laurent Essioux, Larry J. Seidman, Hreinn Stefansson, Erik G. Jönsson, Mads V. Hollegaard, Raymond C.K. Chan, Susana Pinto, Alexander Richards, Jubao Duan, Peter Holmans, George Kirov, Pablo V. Gejman, Philippe Amouyel, Stephanie Godard, Dieter B. Wildenauer, Martina Wiedau-Pazos, Stacy Steinberg, Ole Mors, Andres Metspalu, Rolf Adolfsson, Shaun Purcell, Hugh Gurling, Joseph I. Friedman, Erik Söderman, Mark Weiser, Giacomo P. Comi, James A. Knowles, Peter M. Andersen, Brien P. Riley, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Digby Quested, Srinivas Thirumalai, Ulrich Schall, Jan Lubinski, Dragan M. Svrakic, Aaron R. Wolen, S. Hong Lee, Andrew Pocklington, Bernard Lerer, Vahram Haroutunian, Matthew C. Kiernan, Kenneth L. Davis, Assen Jablensky, William Byerley, Karol Estrada, Aarno Palotie, Cinzia Tiloca, Eadbhard O'Callaghan, Perry T.C. van Doormaal, Colm McDonald, Federico Casale, Thomas Meitinger, Robert Freedman, Gerome Breen, Milena Blagojevic-Radivojkov, Ian P. Blair, Ann E. Pulver, Jan H. Veldink, Giancarlo Logroscino, Miaoxin Li, Abraham Reichenberg, Esben Agerbo, Siddharthan Chandran, Patrik K. E. Magnusson, Andrew M. McIntosh, Gianni Sorarù, Maura Brunetti, Xuebin Zheng, Madeline Alexander, James L. Kennedy, Douglas Blackwood, Menachem Fromer, Martilias S. Farrell, Alan R. Sanders, Dominic B. Rowe, Alexis Brice, Jonathan Pimm, Emily H. M. Wong, Jana Strohmaier, André G. Uitterlinden, Andrea Calvo, Carsten Drepper, John Q. Trojanowski, Marcella Rietschel, Siow Ann Chong, Karen E. Morrison, Sang-Yun Oh, Laura Nisenbaum, Margaret O'Brien, Alkes L. Price, Carin J. Meijer, Michael Davidson, John Powell, Petr Slominsky, Wiepke Cahn, Cinzia Gellera, Vihra Milanova, Peter M. Visscher, Patricia T. Michie, Dimitris Dikeos, Jianxin Shi, Veikko Salomaa, Philip Van Damme, James J. Crowley, Younes Mokrab, Valentina Escott-Price, Jesus S. Mora, Stanley V. Catts, David St Clair, Bernhard Landwehrmeyer, John Hardy, Kristin K. Nicodemus, Dominique Campion, Juha Veijola, Wim Robberecht, Thomas Meyer, Peter Lichtner, Christos Pantelis, Markus Weber, Nilo Riva, Jin P. Szatkiewicz, Michele T. Pato, Cinzia Bertolin, Frank P. Diekstra, Simon Arcuti, Bryan J. Mowry, Hon-Cheong So, Adriano Chiò, Viviana Pensato, Yunjung Kim, Jean-François Dartigues, Zita Ausrele Kucinskiene, Inez Myin-Germeys, Jaana Suvisaari, Sophie E. Legge, Roel A. Ophoff, Philippe Corcia, Gerald Nestadt, Stephan Ripke, Kuang Lin, Paola Giusti-Rodríguez, Michael John Owen, Chris C. A. Spencer, Safa Saker-Delye, Robert W. McCarley, Kimberley D. Chambert, Brandon Wormley, Isabella Fogh, Mamede de Carvalho, Pamela J. Shaw, Tõnu Esko, Ronald Y. L. Chan, Jianjun Liu, Tim B. Bigdeli, Christian R. Andres, David M. Hougaard, Michael Gill, Ammar Al-Chalabi, Colm O'Dushlaine, Rick A.A. van der Spek, Gary Donohoe, Tao Li, Jonathan D. Glass, Christopher Shaw, Draga Toncheva, Leonard H. van den Berg, Liene Nikitina-Zake, Morten Mattingsdal, François Salachas, Andrey Khrunin, Line Olsen, Jochen H. Weishaupt, Jo Knight, Katie Sidle, Filip Eftimov, Massimiliano Filosto, Russell L. McLaughlin, Pak C. Sham, Joshua L. Roffman, Thomas Hansen, Naser Durmishi, Deborah A. Nertney, Juha Karjalainen, Robert Swingler, Ditte Demontis, Vaidutis Kučinskas, Jennifer L. Moran, Leo McCluskey, Donald W. Black, Eric F.C. Cheung, Qiang Wang, Olli Pietilainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Annelie Nordin, Wolfgang Maier, Bradley N. Smith, Ettore Beghi, Rosa Capozzo, Garth A. Nicholson, Markus M. Nöuthen, Jordan W. Smoller, Eric Y.H. Chen, Joseph D. Buxbaum, Letizia Mazzini, Andrea Malaspina, Antonio Julià, Stephanie Williams, Tracey L. Petryshen, Christine Payan, Johan G. Eriksson, Carmel M. Loughland, Elodie Drapeau, Lieuwe de Haan, Martin Begemann, Lukas Tittmann, Franziska Degenhardt, Mark Reimers, Jurgen Del Favero, Jacqueline I. Goldstein, Annelot M. Dekker, Sergi Papiol, Svetlana A. Limborska, René S. Kahn, Shuna Colville, Kelly L. Williams, Pamela Sklar, Diana O. Perkins, Lili Milani, Ayman H. Fanous, Nicola Ticozzi, Fernando Rivadeneira, Marianne de Visser, P. Nigel Leigh, James T.R. Walters, Josef Frank, Aiden Corvin, Silviu Alin Bacanu, John L. Waddington, Stephanie H. Witt, Tiina Paunio, Margot Albus, Catherine Lomen-Hoerth, Sara Marsal, Per Hoffmann, David Curtis, Cindy Maurel, Todd Lencz, Orietta Pansarasa, Manuel Mattheisen, Anneke J. van der Kooi, A. Hofman, Dermot Walsh, Hailiang Huang, Ann Olincy, Anders D. Børglum, Ricardo Rojas-García, William Sproviero, Albert C. Ludolph, Edward M. Scolnick, Danielle Posthuma, George N. Papadimitriou, Michael A. van Es, Fritz Zimprich, F. Anthony O'Neill, Lude Franke, Jouko Lönnqvist, Daniel G. Bradley, Sven Cichon, Susanna Abdulla, Kristel R. van Eijk, Ingrid Agartz, Elisabetta Pupillo, Milica Pejovic-Milovancevic, Antonia Ratti, Henrik B. Rasmussen, Kari Stefansson, Brendan Bulik-Sullivan, Béla Melegh, Stéphanie Millecamps, Janis Klovins, Enrico Domenici, Michael Sendtner, Kai-How Farh, Randy L. Buckner, Albert Hofman, Benjamin M. Neale, Naomi R. Wray, An Goris, Kang Sim, Lauren Elman, Giulio Genovese, Jens R. Wendland, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Sandra D'Alfonso, Cristina Moglia, Carlos N. Pato, Sena Karachanak-Yankova, Nicholas John Craddock, Richard W. Orrell, Richard Bruggeman, Kenneth S. Kendler, Alan M. Pittman, Robin M. Murray, Richard E. Straub, Cathryn M. Lewis, Srdjan Djurovic, Vincent Meininger, Jeffrey A. Lieberman, Bertram Müller-Myhsok, Phil Lee, David J. Kavanagh, Srihari Gopal, Igor Nenadic, Matthew C. Keller, Christian R. Schubert, Jacob Gratten, Alexandra Durr, Roger Pamphlett, Douglas F. Levinson, Luba Kalaydjieva, Chiara Zecca, Anil K. Malhotra, Andre Franke, Vaughan J. Carr, Steven A. McCarroll, C. Robert Cloninger, Judit Bene, Ina Giegling, Wei Cheng, Hualin Simon Xi, Thomas Werge, Eric Strengman, Susanne Petri, Engilbert Sigurdsson, Mark Hansen, Patrick F. Sullivan, Kieran C. Murphy, Inge Joa, Complex Trait Genetics, McLaughlin, Russell L, Schijven, Dick, Van Rheenen, Wouter, Van Eijk, Kristel R, O'Brien, Margaret, Kahn, René S, Ophoff, Roel A, Goris, An, Bradley, Daniel G, Al-Chalabi, Ammar, Van Den Berg, Leonard H, Luykx, Jurjen J, Hardiman, Orla, Veldink, Jan H, Lee, S Hong, Project MinE GWAS Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Kučinskas, Vaidutis, Kučinskienė, Zita Aušrelė, Other departments, Neurology, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Adult Psychiatry, Schizophrenia Working Group of the Psychiatric Genomics Consortiumz, Germeys, Inez, Robberecht, Wim, and Van Damme, Philip
Subjects: 0301 basic medicine, Oncology, Genetics and Molecular Biology (all), Linkage disequilibrium, Multifactorial Inheritance, General Physics and Astronomy, Genome-wide association study, Comorbidity, VARIANTS, Neurodegenerative, Biochemistry, DISEASE, 3124 Neurology and psychiatry, Linkage Disequilibrium, Cohort Studies, 0302 clinical medicine, Genetics research, Odds Ratio, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, ARCHITECTURE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Multidisciplinary, Chemistry (all), Motor neuron disease, Schizophrenia, BIPOLAR DISORDER, Single Nucleotide, Serious Mental Illness, 3. Good health, Mental Health, RC0346, motor neuron disease, Project MinE GWAS Consortium, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Science, European Continental Ancestry Group, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, Physics and Astronomy (all), Rare Diseases, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, MD Multidisciplinary, mental disorders, medicine, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, Family, Bipolar disorder, GENOME-WIDE ASSOCIATION, Polymorphism, Biology, METAANALYSIS, business.industry, Amyotrophic Lateral Sclerosis, Human Genome, Case-control study, 3112 Neurosciences, Neurosciences, General Chemistry, Odds ratio, medicine.disease, R1, Brain Disorders, 030104 developmental biology, genetics research, Case-Control Studies, RC0321, Linear Models, PLEIOTROPY, Human medicine, 3111 Biomedicine, Biochemistry, Genetics and Molecular Biology (all), ALS, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.
Published: 2017
Full Text: View/download PDF

17. cepip: context-dependent epigenomic weighting for prioritization of regulatory variants and disease-associated genes

Author: Junwen Wang, Dingge Ying, Pak C. Sham, Zhengyuan Xia, Zipeng Liu, Panwen Wang, Zhicheng Pan, Dandan Huang, Mulin Jun Li, Bin Yan, Feng Xu, Hongcheng Yao, Jun Liu, Jean Pierre A. Kocher, Qian Liang, and Miaoxin Li
Subjects: Epigenomics, 0301 basic medicine, Quantitative Trait Loci, Regulatory variant, Gene Expression, Method, Context (language use), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Epigenesis, Genetic, Histones, Epigenome, 03 medical and health sciences, Cell type-specific, Disease-susceptible gene, Cluster Analysis, Humans, Genetic Predisposition to Disease, Gene, Genetics, Regulation of gene expression, Variant prioritization, Genetic Variation, Chromatin, Human genetics, Phenotype, 030104 developmental biology, Gene Expression Regulation, Organ Specificity, Expression quantitative trait loci, Genome-Wide Association Study
Abstract: It remains challenging to predict regulatory variants in particular tissues or cell types due to highly context-specific gene regulation. By connecting large-scale epigenomic profiles to expression quantitative trait loci (eQTLs) in a wide range of human tissues/cell types, we identify critical chromatin features that predict variant regulatory potential. We present cepip, a joint likelihood framework, for estimating a variant's regulatory probability in a context-dependent manner. Our method exhibits significant GWAS signal enrichment and is superior to existing cell type-specific methods. Furthermore, using phenotypically relevant epigenomes to weight the GWAS single-nucleotide polymorphisms, we improve the statistical power of the gene-based association test., published_or_final_version
Published: 2017

18. Genetic overlap between epilepsy and schizophrenia: Evidence from cross phenotype analysis in Hong Kong Chinese population

Author: Patrick Kwan, Larry Baum, Stacey S. Cherny, Miaoxin Li, Pak C. Sham, and Hongsheng Gui
Subjects: 0301 basic medicine, Adult, Male, Multifactorial Inheritance, Population, Genome-wide association study, Comorbidity, Genetic correlation, 03 medical and health sciences, Cellular and Molecular Neuroscience, Epilepsy, 0302 clinical medicine, Asian People, Risk Factors, mental disorders, medicine, Odds Ratio, Humans, Genetic Predisposition to Disease, education, Genetics (clinical), education.field_of_study, business.industry, Odds ratio, Middle Aged, medicine.disease, Mental illness, Psychiatry and Mental health, 030104 developmental biology, Phenotype, Schizophrenia, Hong Kong, Female, business, 030217 neurology & neurosurgery, Clinical psychology, Genome-Wide Association Study
Abstract: Epilepsy and schizophrenia are common and typical neurological or mental illness respectively, and sometimes they comorbid in the same patients, however the underlying genetic relationship between the two brain diseases is still not fully understood. To investigate the possible genetic contribution to their comorbidity, we performed polygenic risk score (PRS) analyses and genetic correlation estimation so as to identify the overall genetic overlap between the two diseases. The global schizophrenia PRS is strongly associated with schizophrenia phenotype in Hong Kong population (odds ratio = 1.7, p = 2.26E-16), and focal epilepsy PRS is moderately associated with epilepsy phenotype in Hong Kong population (odds ratio = 1.14, p = 0.013). However the disease-specific PRS can only predict its own well-matched phenotype but not the other ones (p > 0.05). This pattern is further supported by non-significant pairwise genetic correlation and insufficient statistical power for PRS association from the cross-phenotype analyses. Our study reveals there's limited shared genetic aetiology between schizophrenia and epilepsy, and thus supports a model of shared environmental factors to explain the comorbidity between the two phenotypes.
Published: 2016

19. HYST: A Hybrid Set-Based Test for Genome-wide Association Studies, with Application to Protein-Protein Interaction-Based Association Analysis

Author: Miaoxin Li, Johnny S. H. Kwan, and Pak C. Sham
Subjects: Genetics, Linkage disequilibrium, Single-nucleotide polymorphism, Genome-wide association study, HapMap Project, Computational biology, Biology, Polymorphism, Single Nucleotide, Article, chemistry.chemical_compound, chemistry, Humans, SNP, Genetic Predisposition to Disease, Genetics(clinical), SIMes, Protein Interaction Maps, International HapMap Project, Genetics (clinical), Genome-Wide Association Study, Type I and type II errors, Genetic association
Abstract: The extended Simes' test (known as GATES) and scaled chi-square test were proposed to combine a set of dependent genome-wide association signals at multiple single-nucleotide polymorphisms (SNPs) for assessing the overall significance of association at the gene or pathway levels. The two tests use different strategies to combine association p values and can outperform each other when the number of and linkage disequilibrium between SNPs vary. In this paper, we introduce a hybrid set-based test (HYST) combining the two tests for genome-wide association studies (GWASs). We describe how HYST can be used to evaluate statistical significance for association at the protein-protein interaction (PPI) level in order to increase power for detecting disease-susceptibility genes of moderate effect size. Computer simulations demonstrated that HYST had a reasonable type 1 error rate and was generally more powerful than its parents and other alternative tests to detect a PPI pair where both genes are associated with the disease of interest. We applied the method to three complex disease GWAS data sets in the public domain; the method detected a number of highly connected significant PPI pairs involving multiple confirmed disease-susceptibility genes not found in the SNP- and gene-based association analyses. These results indicate that HYST can be effectively used to examine a collection of predefined SNP sets based on prior biological knowledge for revealing additional disease-predisposing genes of modest effects in GWASs. © 2012 The American Society of Human Genetics., link_to_subscribed_fulltext
Published: 2012
Full Text: View/download PDF

20. Evaluating the effective numbers of independent tests and significant p-value thresholds in commercial genotyping arrays and public imputation reference datasets

Author: Stacey S. Cherny, Miaoxin Li, Pak C. Sham, and Juilian M. Y. Yeung
Subjects: Genetic Markers, Genotype, Statistics as Topic, Genome-wide association study, Computational biology, HapMap Project, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Genetics(clinical), p-value, 1000 Genomes Project, International HapMap Project, Genotyping, Genetics (clinical), 030304 developmental biology, Original Investigation, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Databases as Topic, Multiple comparisons problem, 030217 neurology & neurosurgery, Imputation (genetics), Algorithms, Software, Type I and type II errors, Genome-Wide Association Study
Abstract: Current genome-wide association studies (GWAS) use commercial genotyping microarrays that can assay over a million single nucleotide polymorphisms (SNPs). The number of SNPs is further boosted by advanced statistical genotype-imputation algorithms and large SNP databases for reference human populations. The testing of a huge number of SNPs needs to be taken into account in the interpretation of statistical significance in such genome-wide studies, but this is complicated by the non-independence of SNPs because of linkage disequilibrium (LD). Several previous groups have proposed the use of the effective number of independent markers (Me) for the adjustment of multiple testing, but current methods of calculation for Me are limited in accuracy or computational speed. Here, we report a more robust and fast method to calculate Me. Applying this efficient method [implemented in a free software tool named Genetic type 1 error calculator (GEC)], we systematically examined the Me, and the corresponding p-value thresholds required to control the genome-wide type 1 error rate at 0.05, for 13 Illumina or Affymetrix genotyping arrays, as well as for HapMap Project and 1000 Genomes Project datasets which are widely used in genotype imputation as reference panels. Our results suggested the use of a p-value threshold of ~10−7 as the criterion for genome-wide significance for early commercial genotyping arrays, but slightly more stringent p-value thresholds ~5 × 10−8 for current or merged commercial genotyping arrays, ~10−8 for all common SNPs in the 1000 Genomes Project dataset and ~5 × 10−8 for the common SNPs only within genes. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-1118-2) contains supplementary material, which is available to authorized users.
Published: 2011

21. Increased co-expression of genes harboring the damaging de novo mutations in Chinese schizophrenic patients during prenatal development

Author: Mingli Li, Wanjun Guo, Pak C. Sham, Qiang Wang, Xiaohong Ma, Hei-Man Wu, Yingcheng Wang, Liansheng Zhao, Peiyan Ni, Wei Lei, Miaoxin Li, Hongyan Ren, Zhenxing Yang, Xun Hu, Wei Deng, Tao Li, and Bo Xiang
Subjects: Adult, Male, China, Adolescent, DNA Copy Number Variations, Embryonic Development, Gene Expression, Genome-wide association study, Genes, Recessive, Haploinsufficiency, Biology, medicine.disease_cause, Article, Young Adult, Asian People, mental disorders, medicine, Humans, Exome, Genetic Predisposition to Disease, Child, Exome sequencing, Genetic Association Studies, Genetics, Mutation, Multidisciplinary, Gene Expression Profiling, Brain, Computational Biology, High-Throughput Nucleotide Sequencing, Infant, medicine.disease, Prenatal development, Gene expression profiling, Schizophrenia, Child, Preschool, Female, Genome-Wide Association Study
Abstract: Schizophrenia is a heritable, heterogeneous common psychiatric disorder. In this study, we evaluated the hypothesis that de novo variants (DNVs) contribute to the pathogenesis of schizophrenia. We performed exome sequencing in Chinese patients (N = 45) with schizophrenia and their unaffected parents (N = 90). Forty genes were found to contain DNVs. These genes had enriched transcriptional co-expression profile in prenatal frontal cortex (Bonferroni corrected p −3) and in prenatal temporal and parietal regions (Bonferroni corrected p LRP1, MACF1, DICER1 and ABCA2) harboring the damaging de novo mutations are strongly prioritized as susceptibility genes by multiple evidences. Our findings in Chinese schizophrenic patients indicate the pathogenic role of DNVs, supporting the hypothesis that schizophrenia is a neurodevelopmental disease.
Published: 2015

22. MGAS: a powerful tool for multivariate gene-based genome-wide association analysis

Author: Conor V. Dolan, Danielle Posthuma, You-Qiang Song, Sophie van der Sluis, Miaoxin Li, Pak C. Sham, Jiang Li, Human genetics, NCA - Brain mechanisms in health and disease, Complex Trait Genetics, Biological Psychology, Functional Genomics, and Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease
Subjects: Statistics and Probability, False discovery rate, Multivariate statistics, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Biochemistry, Statistical power, 03 medical and health sciences, Multivariate analysis of variance, Humans, Molecular Biology, 030304 developmental biology, Genetic association, Metabolic Syndrome, Genetics, 0303 health sciences, Genome, Human, Genetics and Population Analysis, 030305 genetics & heredity, Univariate, Original Papers, Computer Science Applications, Computational Mathematics, Phenotype, Computational Theory and Mathematics, Multivariate Analysis, Multiple comparisons problem, Software, Genome-Wide Association Study
Abstract: Motivation: Standard genome-wide association studies, testing the association between one phenotype and a large number of single nucleotide polymorphisms (SNPs), are limited in two ways: (i) traits are often multivariate, and analysis of composite scores entails loss in statistical power and (ii) gene-based analyses may be preferred, e.g. to decrease the multiple testing problem. Results: Here we present a new method, multivariate gene-based association test by extended Simes procedure (MGAS), that allows gene-based testing of multivariate phenotypes in unrelated individuals. Through extensive simulation, we show that under most trait-generating genotype-phenotype models MGAS has superior statistical power to detect associated genes compared with gene-based analyses of univariate phenotypic composite scores (i.e. GATES, multiple regression), and multivariate analysis of variance (MANOVA). Re-analysis of metabolic data revealed 32 False Discovery Rate controlled genome-wide significant genes, and 12 regions harboring multiple genes; of these 44 regions, 30 were not reported in the original analysis. Conclusion: MGAS allows researchers to conduct their multivariate gene-based analyses efficiently, and without the loss of power that is often associated with an incorrectly specified genotype-phenotype models. © The Author 2014., link_to_OA_fulltext
Published: 2015
Full Text: View/download PDF

23. Biological insights from 108 schizophrenia-associated genetic loci

Author: Svetlana A. Limborska, Panos Roussos, Benjamin M. Neale, Naser Durmishi, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Alexander Richards, Margot Albus, Lyudmila Georgieva, Sandra Meier, Ulrich Schall, Giulio Genovese, Pak C. Sham, Kai-How Farh, Randy L. Buckner, Qingqin S. Li, Jubao Duan, Carlos N. Pato, Sena Karachanak-Yankova, Nicholas John Craddock, Ole Mors, Chris C. A. Spencer, Miaoxin Li, Jim van Os, Richard Bruggeman, Antonio Julià, Srinivas Thirumalai, Vahram Haroutunian, Michael Davidson, Rodney J. Scott, George N. Papadimitriou, Noa Carrera, Nelson B. Freimer, Michele T. Pato, Mads V. Hollegaard, Hon-Cheong So, Annette M. Hartmann, Ole A. Andreassen, Rolf Adolfsson, Milica Pejovic-Milovancevic, Sarah E. Bergen, S. Hong Lee, Kang Sim, Steven A. McCarroll, Sarah Tosato, Milan Macek, Béla Melegh, Qiang Wang, Ina Giegling, Wei Cheng, Mari Nelis, Assen Jablensky, Jens R. Wendland, Christian Hammer, Paola Giusti-Rodríguez, Jonathan Pimm, Petr Slominsky, Raymond C.K. Chan, Thomas Werge, Jaana Suvisaari, Shaun Purcell, Tõnu Esko, Masashi Ikeda, Bryan J. Mowry, Janis Klovins, C. Robert Cloninger, Mark Hansen, Wiepke Cahn, Olli Pietiläinen, Naomi R. Wray, John L. Waddington, Xuebin Zheng, Eric F.C. Cheung, Madeline Alexander, Jordan W. Smoller, Jacqueline I. Goldstein, Veikko Salomaa, Gary Donohoe, Enrico Domenici, Colm McDonald, Martilias S. Farrell, Stanley V. Catts, Stacy Steinberg, Stephanie Williams, Carmel M. Loughland, Jo Knight, Zita Ausrele Kucinskiene, Jin P. Szatkiewicz, Stephan Ripke, Robert W. McCarley, Yunjung Kim, David St Clair, David Curtis, Todd Lencz, Michael John Owen, Srdjan Djurovic, Nancy G. Buccola, Frans Henskens, Michael Gill, Joshua L. Roffman, Dan Rujescu, Danielle Posthuma, Tao Li, Phil Lee, Thomas Hansen, Wolfgang Maier, Judit Bene, Michael Conlon O'Donovan, Josef Frank, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Kenneth L. Davis, Sophie E. Legge, Roel A. Ophoff, Gerald Nestadt, Claudine Laurent, Pamela Sklar, Diana O. Perkins, Stefan Herms, Fritz Zimprich, Juha Karjalainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Joseph D. Buxbaum, Ann Olincy, Anders D. Børglum, Andrey Khrunin, Jianjun Liu, Bettina Konte, Guiqing Cai, Henrik B. Rasmussen, René S. Kahn, Lili Milani, John Powell, Srihari Gopal, Johan G. Eriksson, David Cohen, Eric Y.H. Chen, James L. Kennedy, Thomas G. Schulze, Richard A. Belliveau, Colm O'Dushlaine, Peter M. Visscher, Valentina Escott-Price, Hana Kuzelova-Ptackova, Stephanie Godard, Martin Begemann, Morten Mattingsdal, Sara Marsal, Alan R. Sanders, Kari Stefansson, Brendan Bulik-Sullivan, Andres Metspalu, Per Hoffmann, Erik Söderman, James T.R. Walters, Hannelore Ehrenreich, Marion Friedl, Brion S. Maher, Teimuraz Silagadze, Annelie Nordin, Raquelle I. Mesholam-Gately, Ingrid Melle, Peter Eichhammer, Dragan M. Svrakic, A. Hofman, Kenneth S. Kendler, Laura Nisenbaum, Hailiang Huang, Sang-Yun Oh, Alkes L. Price, Mark Weiser, Preben Bo Mortensen, J. Mallet, Robin M. Murray, Bradley T. Webb, Vihra Milanova, Ayman H. Fanous, Vaidutis Kučinskas, Jennifer L. Moran, Donald W. Black, Elodie Drapeau, Nadine Cohen, George Kirov, Daniel R. Weinberger, Andrew McQuillin, Patrik K. E. Magnusson, Elvira Bramon, Tune H. Pers, Jianxin Shi, Richard E. Straub, Aiden Corvin, Jimmy Lee Chee Keong, Tiina Paunio, Brien P. Riley, Douglas Blackwood, Juha Veijola, Peter Holmans, Larry J. Seidman, Ronald Y.L. Chen, Pablo V. Gejman, Digby Quested, Erik G. Jönsson, Jeffrey A. Lieberman, Emily H. M. Wong, Tracey L. Petryshen, Franziska Degenhardt, Mark Reimers, Jurgen Del Favero, Markus M. Noethen, Hugh Gurling, Joseph I. Friedman, Andrew Pocklington, Aaron R. Wolen, Abraham Reichenberg, T. Scott Stroup, Elizabeth Bevilacqua, Silviu Alin Bacanu, Aarno Palotie, Robert Freedman, Patricia T. Michie, David M. Hougaard, F. Anthony O'Neill, Kung-Yee Liang, Jouko Lönnqvist, Inez Myin-Germeys, Draga Toncheva, Liene Nikitina-Zake, David J. Kavanagh, Rita M. Cantor, Kimberly Chambert, James J. Crowley, Ann E. Pulver, Ariel Darvasi, Christina M. Hultman, Brandon Wormley, Dai Wang, Deborah A. Nertney, Menachem Fromer, Younes Mokrab, Marcella Rietschel, Christos Pantelis, Dimitris Dikeos, Jan Lubinski, Laurent Essioux, Lieuwe de Haan, Eadbhard O'Callaghan, James A. Knowles, William Byerley, Manuel Mattheisen, Edward M. Scolnick, Line Olsen, Ingrid Agartz, Jana Strohmaier, Siow Ann Chong, Eli A. Stahl, David A. Collier, Farooq Amin, Joel N. Hirschhorn, Timothy G. Dinan, Elisabeth Stögmann, Hreinn Stefansson, Inge Joa, Dieter B. Wildenauer, Marian L. Hamshere, Frank Dudbridge, Sibylle G. Schwab, Esben Agerbo, Bernard Lerer, Andrew M. McIntosh, Carin J. Meijer, Stephanie H. Witt, Dermot Walsh, Lude Franke, Sven Cichon, Kristin K. Nicodemus, Dominique Campion, Tim B. Bigdeli, Ditte Demontis, Sergi Papiol, Hualin Simon Xi, Eric Strengman, Engilbert Sigurdsson, Patrick F. Sullivan, Kieran C. Murphy, Bertram Mueller-Myhsok, Vaughan J. Carr, Igor Nenadic, Matthew C. Keller, Christian R. Schubert, Jacob Gratten, Douglas F. Levinson, Luba Kalaydjieva, Anil K. Malhotra, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, Myin-Germeys, Inez, Perceptual and Cognitive Neuroscience (PCN), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Complex Trait Genetics, Functional Genomics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Walters, James TR, Lee, S Hong, O'Donovan, Michael C, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case-Control Consortium, NCA - Brain mechanisms in health and disease, Human genetics, ANS - Amsterdam Neuroscience, Adult Psychiatry, Other departments, Medical Oncology, Epidemiology, Pharmacy, Clinical Genetics, and Child and Adolescent Psychiatry / Psychology
Subjects: Multifactorial Inheritance, Glutamatergic system, Genome-wide association study, Disease, heritability, genetic risk, Synaptic Transmission, Conferring risk, drugs, DISEASE, glutamatergic neurotransmission, Odds Ratio, 2.1 Biological and endogenous factors, GWAS, Aetiology, Psychiatric genetics, Genetics, Complement component 4, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Multidisciplinary, Genome-wide association, PSYCHIATRIC-DISORDERS, Brain, BIPOLAR DISORDER, Single Nucleotide, Serious Mental Illness, 3. Good health, Multidisciplinary Sciences, Mental Health, Enhancer Elements, Genetic, Schizophrenia, Biological plausibility, Engineering sciences. Technology, Mutations, Enhancer Elements, General Science & Technology, Glutamic Acid, schizophrenia, Genome-Wide Association Study, Biology, Polymorphism, Single Nucleotide, Genetic, medicine, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, METAANALYSIS, Alleles, Genetic association, IDENTIFICATION, Prevention, Common variants, Human Genome, Neurosciences, Immunity, medicine.disease, FRAMEWORK, Brain Disorders, immune system, Genetic Loci, genome-wide association studies, Mutation
Abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. ispartof: Nature vol:511 issue:7510 pages:421-7 ispartof: location:England status: published
Published: 2014
Full Text: View/download PDF

24. Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations

Author: Rosana Shuhama, Gonzalo López, Viviana Storbini, Tolga Binbay, Ma Soledad Olmeda, Maria Calem, Marina Mihaljevic, Christos Pantelis, Halis Ulaş, Eva Velthorst, Jeroen Decoster, J. Malte Bumb, Ruud van Winkel, E. Cem Atbasoglu, Wolfgang Viechtbauer, Mirella Ruggeri, Erich Studerus, Daniele La Barbera, Domenico Berardi, Anita Riecher-Rössler, Stefan Borgwardt, Elsje van der Ven, Charlotte Rapp, Desiree Hilboll, Mark van der Gaag, Chiara Bonetto, Marie-Odile Krebs, Silvia Tenan, Monika Schlögelhofer, Robin M. Murray, Caterina La Cascia, Philip McGuire, Simona A. Stilo, Desmond Campbell, Fabienne Harrisberger, Teresa Sánchez, Catherine Derom, Franck Schürhoff, Philippe Delespaul, Jose Luis Santos, Emilio Sánchez, Stephan Ruhrmann, Luigi Rocco Chiri, Sabrina Cruz, Handan Noyan, Dominika Julkowski, Celso Arango, Merete Nordentoft, Stacey S. Cherny, Anne-Marie Galliot, Daniella van Dam, María Pouso, Asier Urruela Mora, G. Paul Amminger, Enrique García Bernardo, Ahmet Ayer, Tijana Mirjanic, Andrei Szöke, Anna Walter, Antonio Lasalvia, Isla Humphreys, Flora Frijda, Lieuwe de Haan, Neus Barrantes-Vidal, Nigel Williams, Burçin Cihan, Matthew J. Kempton, Ceren Akdeniz, Tamar Kraan, Andrea Tortelli, Barnaby Nelson, Marta Di Forti, Angelo Fioritti, Pedro Cuadrado, Eylem Sahin Cankurtaran, Emanuel Schwarz, Andreas Meyer-Lindenberg, Ilaria Tarricone, Laura Ferraro, Dan Rujescu, Anne-Marie Tronche, Laura Roldan, Bibiana Cabrera, Alp Üçok, Craig Morgan, Julio Sanjuán, Mauro Braca, Julio Bobes, Eric Y.H. Chen, Michael Conlon O'Donovan, Peter Holmans, Harald N. Aschauer, Sarah Ittig, Covadonga Martínez, Iris Lasser, Emiliano González, Aitziber Emaldi Cirión, Rachele Sartorio, F. Seminerio, Rodrigo A. Bressan, Ulrich Reininghaus, Elisa Brietzke, François Bourque, G Tripoli, Inez Myin-Germeys, Aziz Ferchiou, Gemma Modinos, Grégoire Baudin, Fabienne Soguel-Dit-Piquard, Cristina Marta Del-Ben, Gabriele Sachs, Elçin Akturan, Manuel Arrojo, Thomas R. Kwapil, Alice Mulè, Eva Mª Díaz Mesa, Federico Chierzi, Köksal Alptekin, Floor J. van der Meer, Pak C. Sham, Jim van Os, Adanna Onyejiaka, Mara Parellada, Bart P. F. Rutten, Jeanne Vilain, Michael John Owen, Sarah Tosato, Haldan Soygür, A.M. Marinaro, Stefania Tognin, Evert Thiery, Cathrin Rohleder, Mary Cannon, Miaoxin Li, F. Markus Leweke, Marc De Hert, Marta Rapado, Maria Gabriella Minenna, Pierre-Michel Llorca, Alexander Richards, Stéphane Jamain, Elles Messchaert, Nadja P. Maric, Semra Ulusoy, Elisa Ira, Peter G. Jones, Paulo Rossi Menezes, Patrick D. McGorry, Bernadette Winklbaur, Stephanie Beards, Nadine Burger, Güvem Gümüş-Akay, Marion Leboyer, James B. Kirkbride, Sinan Guloksuz, Ary Gadelha, E. Bulzacka, Carlos M. Romeo-Casabona, Gülşah Karadayı, Jean-Paul Selten, José Juan Rodríguez Solano, Kathryn Hubbard, Estela Jiménez, Thomas Charpeaud, Nikos C. Stefanis, Lucia Sideli, Miguel Bernardo, Jean-Romain Richard, Ivonne Donegani, Marco Seri, Lucia Valmaggia, Julia Paruch, Catherine van Zelst, Meram Can Saka, Heike Tost, Renata Smieskova, Thomas Marcacci, Nicholas John Craddock, Berna Binnur Akdede, Joachim Klosterkötter, Richard Bruggeman, Charlotte Gayer-Anderson, Sanja Andric, Elena Bonora, Angel Carracedo, Hasan Karadağ, Paula Cristobal, ANS - Amsterdam Neuroscience, Adult Psychiatry, Graduate School, Perceptual and Cognitive Neuroscience (PCN), Maastricht Univ, Kings Coll London, Mondriaan Mental Hlth Trust, Univ Groningen, Cardiff Univ, Cent Inst Mental Hlth, Dokuz Eylul Univ, Istanbul Univ, Ankara Univ, Yale Univ, Middle E Tech Univ, Diskapi YB Res & Training Hosp, Turkish Federat Schizophrenia Assoc, Ataturk Training & Res Hosp, Manisa Mental Hlth Hosp, Univ Complutense, Univ Barcelona, Univ Valencia, Univ Oviedo, Univ Santiago de Compostela, Hosp Virgen de la Luz, Hosp Univ Infanta Leonor Hosp Virgen Torre, Hosp Clin Univ, Hosp Psiquiatr Conxo, Univ Amsterdam, Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Parnassia Psychiat Inst, Rivierduinen Psychiat Inst, Grp Hosp Mondor, Hop Henri Mondor, Univ Paris Est, Fdn Fondamental, CMP B CHU, Univ Auvergne, EPS Maison Blanche, UPC KU Leuven, UPC, Katholieke Univ Leuven, Assoc Sci Res Multiple Births, Univ Ghent, Univ Athens, Med Univ Vienna, Psychiat Univ Clin Basel, Univ Cologne, Univ Hong Kong, Univ Basque Country, Univ Zaragoza, Univ Cambridge, UCL, Royal Coll Surgeons Ireland, Univ Munich, Univ Bologna, Local Hlth Trust, Univ Palermo, P Giaccone Gen Hosp, Univ Melbourne, Universidade de São Paulo (USP), Univ Verona, Copenhagen Univ Hosp, Univ Paris 05, Univ Autonoma Barcelona, St Pere Claver Fundacio Sanitaria, Univ N Carolina, CIBERSAM, Universidade Federal de São Paulo (UNIFESP), Univ Belgrade, van Os J, Rutten BP, Myin-Germeys I, Delespaul P, Viechtbauer W, van Zelst C, Bruggeman R, Reininghaus U, Morgan C, Murray RM, Di Forti M, McGuire P, Valmaggia LR, Kempton MJ, Gayer-Anderson C, Hubbard K, Beards S, Stilo SA, Onyejiaka A, Bourque F, Modinos G, Tognin S, Calem M, O'Donovan MC, Owen MJ, Holmans P, Williams N, Craddock N, Richards A, Humphreys I, Meyer-Lindenberg A, Leweke FM, Tost H, Akdeniz C, Rohleder C, Bumb JM, Schwarz E, Alptekin K, Üçok A, Saka MC, Atbaşoğlu EC, Gülöksüz S, Gumus-Akay G, Cihan B, Karadağ H, Soygür H, Cankurtaran EŞ, Ulusoy S, Akdede B, Binbay T, Ayer A, Noyan H, Karadayı G, Akturan E, Ulaş H, Arango C, Parellada M, Bernardo M, Sanjuán J, Bobes J, Arrojo M, Santos JL, Cuadrado P, Rodríguez Solano JJ, Carracedo A, García Bernardo E, Roldán L, López G, Cabrera B, Cruz S, Díaz Mesa EM, Pouso M, Jiménez E, Sánchez T, Rapado M, González E, Martínez C, Sánchez E, Olmeda MS, de Haan L, Velthorst E, van der Gaag M, Selten JP, van Dam D, van der Ven E, van der Meer F, Messchaert E, Kraan T, Burger N, Leboyer M, Szoke A, Schürhoff F, Llorca PM, Jamain S, Tortelli A, Frijda F, Vilain J, Galliot AM, Baudin G, Ferchiou A, Richard JR, Bulzacka E, Charpeaud T, Tronche AM, De Hert M, van Winkel R, Decoster J, Derom C, Thiery E, Stefanis NC, Sachs G, Aschauer H, Lasser I, Winklbaur B, Schlögelhofer M, Riecher-Rössler A, Borgwardt S, Walter A, Harrisberger F, Smieskova R, Rapp C, Ittig S, Soguel-dit-Piquard F, Studerus E, Klosterkötter J, Ruhrmann S, Paruch J, Julkowski D, Hilboll D, Sham PC, Cherny SS, Chen EY, Campbell DD, Li M, Romeo-Casabona CM, Emaldi Cirión A, Urruela Mora A, Jones P, Kirkbride J, Cannon M, Rujescu D, Tarricone I, Berardi D, Bonora E, Seri M, Marcacci T, Chiri L, Chierzi F, Storbini V, Braca M, Minenna MG, Donegani I, Fioritti A, La Barbera D, La Cascia CE, Mulè A, Sideli L, Sartorio R, Ferraro L, Tripoli G, Seminerio F, Marinaro AM, McGorry P, Nelson B, Amminger GP, Pantelis C, Menezes PR, Del-Ben CM, Gallo Tenan SH, Shuhama R, Ruggeri M, Tosato S, Lasalvia A, Bonetto C, Ira E, Nordentoft M, Krebs MO, Barrantes-Vidal N, Cristóbal P, Kwapil TR, Brietzke E, Bressan RA, Gadelha A, Maric NP, Andric S, Mihaljevic M, Mirjanic T, Clinical Psychology, EMGO+ - Mental Health, Van Os, J., Rutten, B., Myin Germeys, I., Delespaul, P., Viechtbauer, W., Van Zelst, C., Bruggeman, R., Reininghaus, U., Morgan, C., Murray, R., Di Forti, M., Mcguire, P., Valmaggia, L., Kempton, M., Gayer Anderson, C., Hubbard, K., Beards, S., Stilo, S., Onyejiaka, A., Bourque, F., Modinos, G., Tognin, S., Calem, M., O'Donovan, M., Owen, M., Holmans, P., Williams, N., Craddock, N., Richards, A., Humphreys, I., Meyer Lindenberg, A., Leweke, F., Tost, H., Akdeniz, C., Rohleder, C., Bumb, J., Schwarz, E., Alptekin, K., Üçok, A., Saka, M., Atbagoǧlu, E., Gülöksüz, S., Gumus Akay, G., Cihan, B., Karadaǧ, H., Soygür, H., Cankurtaran, E., Ulusoy, S., Akdede, B., Binbay, T., Ayer, A., Noyan, H., Karadayi, G., Akturan, E., Ulaş, H., Arango, C., Parellada, M., Bernardo, M., Sanjuán, J., Bobes, J., Arrojo, M., Santos, J., Cuadrado, P., Solano, J., Carracedo, A., Bernardo, E., Roldán, L., López, G., Cabrera, B., Cruz, S., Mesa, E., Pouso, M., Jiménez, E., Sánchez, T., Rapado, M., González, E., Martínez, C., Sánchez, E., Olmeda, M., De Haan, L., Velthorst, E., Van Der Gaag, M., Selten, J., Van Dam, D., Van Der Ven, E., Van Der Meer, F., Messchaert, E., Kraan, T., Burger, N., Leboyer, M., Szoke, A., Schürhoff, F., Llorca, P., Jamain, S., Tortelli, A., Frijda, F., Vilain, J., Galliot, A., Baudin, G., Ferchiou, A., Richard, J., Bulzacka, E., Charpeaud, T., Tronche, A., De Hert, M., Van Winkel, R., Decoster, J., Derom, C., Thiery, E., Stefanis, N., Sachs, G., Aschauer, H., Lasser, I., Winklbaur, B., Schlögelhofer, M., Riecher Rössler, A., Borgwardt, S., Walter, A., Harrisberger, F., Smieskova, R., Rapp, C., Ittig, S., Soguel Dit Piquard, F., Studerus, E., Klosterkötter, J., Ruhrmann, S., Paruch, J., Julkowski, D., Hilboll, D., Sham, P., Cherny, S., Chen, E., Campbell, D., Li, M., Romeo Casabona, C., Cirión, A., Mora, A., Jones, P., Kirkbride, J., Cannon, M., Rujescu, D., Tarricone, I., Berardi, D., Bonora, E., Seri, M., Marcacci, T., Chiri, L., Chierzi, F., Storbini, V., Braca, M., Minenna, M., Donegani, I., Fioritti, A., LA BARBERA, D., LA CASCIA, C., Mulè, A., Sideli, L., Sartorio, C., Ferraro, L., Tripoli, G., Seminerio, F., Marinaro, A., Mcgorry, P., Nelson, B., Amminger, G., Pantelis, C., Menezes, P., Del Ben, C., Tenan, S., Shuhama, R., Ruggeri, M., Tosato, S., Lasalvia, A., Bonetto, C., Ira, E., Nordentoft, M., Krebs, M., Barrantes Vidal, N., Cristóbal, P., Kwapil, T., Brietzke, E., Bressan, R., Gadelha, A., Maric, N., Andric, S., Mihaljevic, M., Mirjanic, T., Psychiatrie & Neuropsychologie, Promovendi MHN, and RS: MHeNs - R2 - Mental Health
Subjects: URBANICITY, Schizophrenia (object-oriented programming), CHILDHOOD, Genome-wide association study, VARIANTS, Social Environment, psychosi, 03 medical and health sciences, 0302 clinical medicine, PSYCHOSIS, epidemiology, gene-environment interaction, genetics, psychosis, schizophrenia, SDG 3 - Good Health and Well-being, RISK-FACTOR, Settore M-PSI/08 - Psicologia Clinica, Genetic variation, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Gene, Settore MED/25 - Psichiatria, METAANALYSIS, Scale (chemistry), Psychosis, Genetic variants, Environment and Schizophrenia Invited, CANNABIS USE, 3. Good health, 030227 psychiatry, Psychiatry and Mental health, Evolutionary biology, Identification (biology), Schizophrenic Psychology, Population Risk, genetic, Psychology, FOLLOW-UP, 030217 neurology & neurosurgery, FUTURE-DIRECTIONS, Clinical psychology
Abstract: European Community Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G x E), however, so far, thorough replication of findings is rare and G x E research still faces several conceptual and methodological challenges. in this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G x E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G x E in schizophrenia. While such investigations are now well underway, new challenges emerge for G x E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype. Maastricht Univ, Med Ctr, Dept Psychiat & Neuropsychol, Sch Mental Hlth & Neurosci,South Limburg Mental H, NL-6200 MD Maastricht, Netherlands Kings Coll London, Inst Psychiat, Dept Psychosis Studies, London WC2R 2LS, England Mondriaan Mental Hlth Trust, Maastricht, Heerlen, Netherlands Univ Groningen, Univ Med Ctr Groningen, Rob Giel Clin Res, Univ Ctr Psychiat, Groningen, Netherlands Kings Coll London, Inst Psychiat, Dept Hlth Serv & Populat Res, London WC2R 2LS, England Kings Coll London, Inst Psychiat, Dept Psychol, London WC2R 2LS, England Cardiff Univ, MRC, Ctr Neuropsychiat Genet, Cardiff CF10 3AX, S Glam, Wales Cent Inst Mental Hlth, Dept Psychiat & Psychotherapy, Mannheim, Germany Dokuz Eylul Univ, Sch Med, Dept Psychiat, Konak, Turkey Istanbul Univ, Istanbul Fac Med, Dept Psychiat, Psychot Disorders Res Unit, Istanbul, Turkey Ankara Univ, Sch Med, Dept Psychiat, Cebeci Hosp, TR-06100 Ankara, Turkey Ankara Univ, Brain Res Ctr, TR-06100 Ankara, Turkey Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA Middle E Tech Univ, Dept Psychol, TR-06531 Ankara, Turkey Diskapi YB Res & Training Hosp, Ankara, Turkey Turkish Federat Schizophrenia Assoc, Ankara, Turkey Ataturk Training & Res Hosp, Psychiat Clin, Ankara, Turkey Manisa Mental Hlth Hosp, Manisa, Turkey Istanbul Univ, Expt Med Res Inst, Dept Adv Neurol Sci, Istanbul Fac Med, Istanbul, Turkey Univ Complutense, IiSGM CIBERSAM, Dept Child & Adolescent Psychiat, Hosp Gen Univ Gregorio Maranon,Sch Med, E-28040 Madrid, Spain Univ Barcelona, Dept Psychiat, Hosp Clin, IDIBAPS,Ctr Invest Biomed Red Salud Mental CIBERS, Barcelona, Spain Univ Valencia, Sch Med, Dept Psychiat, Ctr Invest Biomed Red Salud Mental CIBERSAM, Valencia, Spain Univ Oviedo, Sch Med, Dept Med,Psychiat Area, Ctr Invest Biomed Red Salud Mental CIBERSAM, Oviedo, Spain Univ Santiago de Compostela, Dept Mental Hlth & Drug Addit Assistance, Hlth Serv Galicia,Psychiat Genet Grp IDIS, Hosp Clin,Ctr Invest Biomedica Red Salud Mental C, Santiago de Compostela 15706, Spain Hosp Virgen de la Luz, Serv Psiquiat, Dept Psychiat, Cuenca, Spain Hosp Univ Infanta Leonor Hosp Virgen Torre, Villa de Vallecas Mental Hlth Ctr, Villa de Vallecas Mental Hlth Dept, Madrid, Spain Hosp Univ Infanta Leonor Hosp Virgen Torre, Puente de Vallecas Mental Hlth Dept, Ctr Salud Mental Puente Vallecas, Madrid, Spain Hosp Clin Univ, Fdn Publ Galega Med Xenomica, Santiago de Compostela, Spain Univ Complutense, Sch Med, Hosp Gen Univ Gregorio Maranon, Dept Psychiat, E-28040 Madrid, Spain Hosp Psiquiatr Conxo, Santiago de Compostela, Spain Univ Amsterdam, Acad Med Ctr, Early Psychosis Sect, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands Vrije Univ Amsterdam, Dept Clin Psychol, Amsterdam, Netherlands EMGO Inst Hlth & Care Res, Amsterdam, Netherlands Parnassia Psychiat Inst, Dept Psychosis Res, the Hague, Netherlands Rivierduinen Psychiat Inst, Leiden, Netherlands Grp Hosp Mondor, AP HP, Creteil, France Hop Henri Mondor, INSERM, U955, Equipe 15, F-94010 Creteil, France Univ Paris Est, Fac Med, Creteil, France Fdn Fondamental, Creteil, France CMP B CHU, F-63003 Clermont Ferrand 1, France Univ Auvergne, EA 7280, Clermont Ferrand, France EPS Maison Blanche, Paris, France UPC KU Leuven, Dept Neurosci, UPC, Kortenberg, Belgium UPC, Dept Neurosci, Res Grp Psychiat, Leuven, Belgium Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Dept Human Genet, Leuven, Belgium Assoc Sci Res Multiple Births, Ghent, Belgium Univ Ghent, Dept Neurol, Ghent Univ Hosp, B-9000 Ghent, Belgium Univ Athens, Sch Med, Eginit Hosp, Athens 11528, Greece Med Univ Vienna, Dept Psychiat & Psychotherapy, Vienna, Austria Psychiat Univ Clin Basel, Ctr Gender Res & Early Detect, Basel, Switzerland Psychiat Univ Clin Basel, Diagnost & Crisis Intervent Ctr, Basel, Switzerland Univ Cologne, Dept Psychiat & Psychotherapy, D-50931 Cologne, Germany Univ Hong Kong, Li Ka Shing Fac Med, Ctr Genom Sci, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, Li Ka Shing Fac Med, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, Queen Mary Hosp, Li Ka Shing Fac Med, State Key Lab Brain & Cognit Sci, Hong Kong, Hong Kong, Peoples R China Univ Hong Kong, Queen Mary Hosp, Li Ka Shing Fac Med, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China Univ Basque Country, Univ Deusto, Interuniv Chair Law & Human Genome Prov Govt Bisk, Bilbao, Bizkaia, Spain Univ Zaragoza, Zaragoza, Spain Univ Cambridge, Dept Psychiat, Cambridge, England UCL, Div Psychiat, London, England Royal Coll Surgeons Ireland, Beaumont Hosp, Educ & Res Ctr, Dept Psychiat, Dublin 9, Ireland Univ Munich, Dept Psychiat, Div Mol & Clin Neurobiol, Munich, Germany Univ Bologna, Alma Mater Studiorium, Psychiat Unit, Dept Med & Surg Sci, Bologna, Italy Univ Bologna, Alma Mater Studiorium, Genet Unit, Dept Med & Surg Sci, Bologna, Italy Local Hlth Trust, Dept Mental Hlth & Pathol Addict, Bologna, Italy Univ Palermo, Sect Psychiat, Dept Expt Biomed & Clin Neurosci, Palermo, Italy P Giaccone Gen Hosp, Unit Psychiat, Palermo, Italy Univ Melbourne, Ctr Youth Mental Hlth, Parkville, Vic 3052, Australia Univ Melbourne, Melbourne Neuropsychiat Ctr, Carlton, Vic, Australia Univ São Paulo, Fac Med, Dept Med Prevent, BR-01246903 São Paulo, Brazil Univ São Paulo, Nucleo Pesquina Saude Mental Populac, São Paulo, Brazil Univ São Paulo, Fac Med Ribeirao Preto, Dept Neurociencias & Ciencias Comportamento, BR-14049 Ribeirao Preto, Brazil Univ Verona, Sect Psychiat, Dept Publ Hlth & Community Med, I-37100 Verona, Italy Copenhagen Univ Hosp, Res Unit, Mental Hlth Ctr Copenhagen, Copenhagen, Denmark Univ Paris 05, Fac Med, Serv Hosp Univ, Hop St Anne, Paris, France Univ Autonoma Barcelona, Dept Psicol Clin & Salut, E-08193 Barcelona, Spain St Pere Claver Fundacio Sanitaria, Dept Salut Mental, Barcelona, Spain Univ N Carolina, Dept Psychol, Greensboro, NC 27412 USA CIBERSAM, Spanish Mental Hlth Res Network, Barcelona, Spain Universidade Federal de São Paulo, Dept Psychiat, PRISMA Early Intervent Program, São Paulo, Brazil Univ Belgrade, Sch Med, Beograd, Serbia Universidade Federal de São Paulo, Dept Psychiat, PRISMA Early Intervent Program, São Paulo, Brazil European Community: HEALTH-F2-2009-241909 Web of Science
Published: 2014
Full Text: View/download PDF

25. Common Variants on Xq28 Conferring Risk of Schizophrenia in Han Chinese

Author: Basil Paul, Maria-Mercè Garcia-Barceló, Ronald R. L. Chen, Stacey S. Cherny, Grainne M. McAlonan, Man-Ting So, Tomy C. K. Hui, Amy W. Butler, Siu-Chung Choi, Eric F.C. Cheung, Shaun Purcell, Pak C. Sham, Miaoxin Li, Tao Li, Quang Wang, Hon-Cheong So, Raymond C.K. Chan, Emily H. M. Wong, Eric Y.H. Chen, and Hei-Man Wu
Subjects: Male, Candidate gene, China, Methyl-CpG-Binding Protein 2, Schizophrenia (object-oriented programming), Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Asian People, Humans, Genetic Predisposition to Disease, Copy-number variation, education, Alleles, Genetic association, Genetics, education.field_of_study, Chromosomes, Human, X, GTPase-Activating Proteins, Case-control study, Genetic Variation, Regular Article, Psychiatry and Mental health, Logistic Models, Case-Control Studies, Schizophrenia, Female, Carbohydrate Epimerases, Carrier Proteins, Genome-Wide Association Study
Abstract: Schizophrenia is a highly heritable, severe psychiatric disorder affecting approximately 1% of the world population. A substantial portion of heritability is still unexplained and the pathophysiology of schizophrenia remains to be elucidated. To identify more schizophrenia susceptibility loci, we performed a genome-wide association study (GWAS) on 498 patients with schizophrenia and 2025 controls from the Han Chinese population, and a follow-up study on 1027 cases and 1005 controls. In the follow-up study, we included 384 single nucleotide polymorphisms (SNPs) which were selected from the top hits in our GWAS (130 SNPs) and from previously implicated loci for schizophrenia based on the SZGene database, NHGRI GWAS Catalog, copy number variation studies, GWAS meta-analysis results from the international Psychiatric Genomics Consortium (PGC) and candidate genes from plausible biological pathways (254 SNPs). Within the chromosomal region Xq28, SNP rs2269372 in RENBP achieved genome-wide significance with a combined P value of 3.98×10-8 (OR of allele A = 1.31). SNPs with suggestive P values were identified within 2 genes that have been previously implicated in schizophrenia, MECP2 (rs2734647, P combined = 8.78×10-7, OR = 1.28; rs2239464, P combined = 6.71×10-6, OR = 1.26) and ARHGAP4 (rs2269368, P combined = 4.74×10-7, OR = 1.25). In addition, the patient sample in our follow-up study showed a significantly greater burden for pre-defined risk alleles based on the SNPs selected than the controls. This indicates the existence of schizophrenia susceptibility loci among the SNPs we selected. This also further supports multigenic inheritance in schizophrenia. Our findings identified a new schizophrenia susceptibility locus on Xq28, which harbor the genes RENBP, MECP2, and ARHGAP4. © 2014 The Author.
Published: 2013

26. Uncovering the total heritability explained by all true susceptibility variants in a genome-wide association study

Author: Pak C. Sham, Miaoxin Li, and Hon-Cheong So
Subjects: Male, Risk, Genotype, Epidemiology, Population, Statistics as Topic, Normal Distribution, Genome-wide association study, Computational biology, Quantitative trait locus, Biology, Genetic correlation, Crohn Disease, Missing heritability problem, Humans, Computer Simulation, Genetic Predisposition to Disease, education, Genetics (clinical), Triglycerides, Genetic association, Genetics, education.field_of_study, Molecular Epidemiology, Models, Statistical, Genetic Variation, Heritability, Genetic architecture, Lipoproteins, LDL, Female, Lipoproteins, HDL, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have become increasingly popular recently and contributed to the discovery of many susceptibility variants. However, a large proportion of the heritability still remained unexplained. This observation raises queries regarding the ability of GWAS to uncover the genetic basis of complex diseases. In this study, we propose a simple and fast statistical framework to estimate the total heritability explained by all true susceptibility variants in a GWAS. It is expected that many true risk variants will not be detected in a GWAS due to limited power. The proposed framework aims at recovering the "hidden" heritability. Importantly, only the summary z-statistics are required as input and no raw genotype data are needed. The strategy is to recover the true effect sizes from the observed z-statistics. The methodology does not rely on any distributional assumptions of the effect sizes of variants. Both binary and quantitative traits can be handled and covariates may be included. Population-based or family-based designs are allowed as long as the summary statistics are available. Simulations were conducted and showed satisfactory performance of the proposed approach. Application to real data (Crohn's disease, HDL, LDL, and triglycerides) reveals that at least around 10-20% of variance in liability or phenotype can be explained by GWAS panels. This translates to around 10-40% of the total heritability for the studied traits.
Published: 2010

27. IGG3: a tool to rapidly integrate large genotype datasets for whole-genome imputation and individual-level meta-analysis

Author: Patrick Y. P. Kao, Lin Jiang, Miaoxin Li, You-Qiang Song, and Pak C. Sham
Subjects: Statistics and Probability, Genotype, Computer science, Information Storage and Retrieval, computer.software_genre, Biochemistry, Genome, Meta-Analysis as Topic, Databases, Genetic, Imputation (statistics), International HapMap Project, Molecular Biology, Genetic association, Genomics, Individual level, Computer Science Applications, Computational Mathematics, Computational Theory and Mathematics, Meta-analysis, Data mining, computer, Algorithms, Software, Imputation (genetics), Genome-Wide Association Study, SNP array
Abstract: Summary: There is an urgent and increasing demand for integrating large genotype datasets across genome-wide association studies and HapMap project for whole-genome imputation and individual-level meta-analysis. A new algorithm was developed to efficiently merge raw genotypes across large datasets and implemented in the latest version of IGG, IGG3. In addition, IGG3 can integrate the latest phased and unphased HapMap genotypes and can flexibly generate complete sets of input files for six popular genotype imputation tools. We demonstrated the efficiency of IGG3 by simulation tests, which could rapidly merge genotypes in tens of thousands of large genotype chips (e.g. Affymetrix Genome-Wide Human SNP Array 6.0 and Illumina Human1m-duo) and in HapMap III project on an ordinary desktop computer. Availability: http://bioinfo.hku.hk/iggweb (version 3.0). Contacts: songy@hkucc.hku.hk; limx54@yahoo.com Supplementary information: Supplementary data are available at Bioinformatics online.
Published: 2009
Full Text: View/download PDF

28. A Knowledge-Based Weighting Framework to Boost the Power of Genome-Wide Association Studies

Author: You-Qiang Song, Pak C. Sham, Miaoxin Li, and Stacey S. Cherny
Subjects: lcsh:Medicine, Genome-wide association study, Single-nucleotide polymorphism, Genomics, Alzheimer Disease - genetics, Computational biology, Genetics and Genomics/Complex Traits, Biology, Polymorphism, Single Nucleotide, Deep sequencing, Computational Biology/Molecular Genetics, Alzheimer Disease, Genetics and Genomics/Population Genetics, Humans, Computer Simulation, Genetic Predisposition to Disease, Genetics and Genomics/Genomics, lcsh:Science, Genetics and Genomics/Genetics of Disease, Statistic, Genetic association, Genetics, Binding Sites, Models, Statistical, Multidisciplinary, Models, Genetic, Genome, Human, lcsh:R, Computational Biology, Genetics and Genomics/Bioinformatics, Replication (computing), Weighting, MicroRNAs, Computational Biology - methods, lcsh:Q, Computational Biology/Population Genetics, Software, Research Article, Computational Biology/Genomics, Genome-Wide Association Study
Abstract: Background: We are moving to second-wave analysis of genome-wide association studies (GWAS), characterized by comprehensive bioinformatical and statistical evaluation of genetic associations. Existing biological knowledge is very valuable for GWAS, which may help improve their detection power particularly for disease susceptibility loci of moderate effect size. However, a challenging question is how to utilize available resources that are very heterogeneous to quantitatively evaluate the statistic significances. Methodology/Principal Findings: We present a novel knowledge-based weighting framework to boost power of the GWAS and insightfully strengthen their explorative performance for follow-up replication and deep sequencing. Built upon diverse integrated biological knowledge, this framework directly models both the prior functional information and the association significances emerging from GWAS to optimally highlight single nucleotide polymorphisms (SNPs) for subsequent replication. In the theoretical calculation and computer simulation, it shows great potential to achieve extra over 15% power to identify an association signal of moderate strength or to use hundreds of whole-genome subjects fewer to approach similar power. In a case study on late-onset Alzheimer disease (LOAD) for a proof of principle, it highlighted some genes, which showed positive association with LOAD in previous independent studies, and two important LOAD related pathways. These genes and pathways could be originally ignored due to involved SNPs only having moderate association significance. Conclusions/Significance: With user-friendly implementation in an open-source Java package, this powerful framework will provide an important complementary solution to identify more true susceptibility loci with modest or even small effect size in current GWAS for complex diseases. © 2010 Li et al., published_or_final_version
Published: 2010
Full Text: View/download PDF

29. GATES: A Rapid and Powerful Gene-Based Association Test Using Extended Simes Procedure

Author: Hongsheng Gui, Pak C. Sham, Miaoxin Li, and Johnny S. H. Kwan
Subjects: Genome-wide association study, Single-nucleotide polymorphism, Computational biology, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, Statistical power, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Crohn Disease, Databases, Genetic, Genetics, Humans, SNP, Computer Simulation, SIMes, Genetics(clinical), p-value, Crohn Disease - genetics, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Reproducibility of Results, Polymorphism, Single Nucleotide - genetics, chemistry, Genetic Association Studies - methods, 030217 neurology & neurosurgery, Genome-Wide Association Study, Type I and type II errors
Abstract: The gene has been proposed as an attractive unit of analysis for association studies, but a simple yet valid, powerful, and sufficiently fast method of evaluating the statistical significance of all genes in large, genome-wide datasets has been lacking. Here we propose the use of an extended Simes test that integrates functional information and association evidence to combine the p values of the single nucleotide polymorphisms within a gene to obtain an overall p value for the association of the entire gene. Our computer simulations demonstrate that this test is more powerful than the SNP-based test, offers effective control of the type 1 error rate regardless of gene size and linkage-disequilibrium pattern among markers, and does not need permutation or simulation to evaluate empirical significance. Its statistical power in simulated data is at least comparable, and often superior, to that of several alternative gene-based tests. When applied to real genome-wide association study (GWAS) datasets on Crohn disease, the test detected more significant genes than SNP-based tests and alternative gene-based tests. The proposed test, implemented in an open-source package, has the potential to identify additional novel disease-susceptibility genes for complex diseases from large GWAS datasets. © 2011 The American Society of Human Genetics., link_to_OA_fulltext
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources

Refine your results

29 results on '"Miaoxin Li"'

1. DESE: estimating driver tissues by selective expression of genes associated with complex diseases or traits

2. Powerful and robust inference of complex phenotypes' causal genes with dependent expression quantitative loci by a median-based Mendelian randomization

3. Genome-Wide Association Study Identifies New Risk Loci for Progression of Schistosomiasis Among the Chinese Population

4. Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders

5. A conditional gene-based association framework integrating isoform-level eQTL data reveals new susceptibility genes for schizophrenia

6. Hippocampal transcriptome-wide association study and neurobiological pathway analysis for Alzheimer’s disease

7. A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts

8. Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma

9. A powerful approach reveals numerous expression quantitative trait haplotypes in multiple tissues

10. Estimating driver-tissues by robust selective expression of genes associated with complex diseases or traits

11. FAPI: Fast and accurate P-value Imputation for genome-wide association study

12. A powerful conditional gene-based association approach implicated functionally important genes for schizophrenia

13. Knowledge-Based Genetic Association Study of Hepatitis B Virus Related Hepatocellular Carcinoma in Chinese Populations

14. Modeling Linkage Disequilibrium Increases Accuracy of Polygenic Risk Scores

15. Sharing of Genes and Pathways Across Complex Phenotypes: A Multilevel Genome-Wide Analysis

16. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

17. cepip: context-dependent epigenomic weighting for prioritization of regulatory variants and disease-associated genes

18. Genetic overlap between epilepsy and schizophrenia: Evidence from cross phenotype analysis in Hong Kong Chinese population

19. HYST: A Hybrid Set-Based Test for Genome-wide Association Studies, with Application to Protein-Protein Interaction-Based Association Analysis

20. Evaluating the effective numbers of independent tests and significant p-value thresholds in commercial genotyping arrays and public imputation reference datasets

21. Increased co-expression of genes harboring the damaging de novo mutations in Chinese schizophrenic patients during prenatal development

22. MGAS: a powerful tool for multivariate gene-based genome-wide association analysis

23. Biological insights from 108 schizophrenia-associated genetic loci

24. Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations

25. Common Variants on Xq28 Conferring Risk of Schizophrenia in Han Chinese

26. Uncovering the total heritability explained by all true susceptibility variants in a genome-wide association study

27. IGG3: a tool to rapidly integrate large genotype datasets for whole-genome imputation and individual-level meta-analysis

28. A Knowledge-Based Weighting Framework to Boost the Power of Genome-Wide Association Studies

29. GATES: A Rapid and Powerful Gene-Based Association Test Using Extended Simes Procedure

Catalog

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

29 results on '"Miaoxin Li"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources