Author: "Ariel Darvasi" - Searchworks@Jio Institute Digital Library Search Results

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116 results on '"Ariel Darvasi"'

1. Using brain cell-type-specific protein interactomes to interpret neurodevelopmental genetic signals in schizophrenia

Author: Yu-Han H. Hsu, Greta Pintacuda, Ruize Liu, Eugeniu Nacu, April Kim, Kalliopi Tsafou, Natalie Petrossian, William Crotty, Jung Min Suh, Jackson Riseman, Jacqueline M. Martin, Julia C. Biagini, Daya Mena, Joshua K.T. Ching, Edyta Malolepsza, Taibo Li, Tarjinder Singh, Tian Ge, Shawn B. Egri, Benjamin Tanenbaum, Caroline R. Stanclift, Annie M. Apffel, Steven A. Carr, Monica Schenone, Jake Jaffe, Nadine Fornelos, Hailiang Huang, Kevin C. Eggan, Kasper Lage, 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, Tune H. Pers, Ingrid Agartz, Esben Agerbo, Margot Albus, Madeline Alexander, Farooq Amin, Silviu A. Bacanu, Martin Begemann, Richard A. Belliveau, Jr., 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. Chan, Eric Y.H. Chen, Wei Cheng, Eric FC. 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, 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, 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, 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 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, 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, Shengying Qin, Akira Sawa, Rene Kahn, Kyung Sue Hong, Wenzhao Shi, Ming Tsuang, Masanari Itokawa, Gang Feng, Stephen J. Glatt, Xiancang Ma, Jinsong Tang, Yunfeng Ruan, Feng Zhu, Yasue Horiuchi, Byung Dae Lee, Eun-Jeong Joo, Woojae Myung, Kyooseob Ha, Hong-Hee Won, Ji Hyung Baek, Young Chul Chung, Sung-Wan Kim, Agung Kusumawardhani, Wei J. Chen, Hai-Gwo Hwu, Akitoyo Hishimoto, Ikuo Otsuka, Ichiro Sora, Tomoko Toyota, Takeo Yoshikawa, Hiroshi Kunugi, Kotaro Hattori, Sayuri Ishiwata, Shusuke Numata, Tetsuro Ohmori, Makoto Arai, Yuji Ozeki, Kumiko Fujii, Se Joo Kim, Heon-Jeong Lee, Yong Min Ahn, Se Hyun Kim, Kazufumi Akiyama, Kazutaka Shimoda, and Makoto Kinoshita
Subjects: Molecular interaction, Developmental neuroscience, Cellular neuroscience, Proteomics, Science
Abstract: Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.
Published: 2023
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2. The time and place of European admixture in Ashkenazi Jewish history.

Author: James Xue, Todd Lencz, Ariel Darvasi, Itsik Pe'er, and Shai Carmi
Subjects: Genetics, QH426-470
Abstract: The Ashkenazi Jewish (AJ) population is important in genetics due to its high rate of Mendelian disorders. AJ appeared in Europe in the 10th century, and their ancestry is thought to comprise European (EU) and Middle-Eastern (ME) components. However, both the time and place of admixture are subject to debate. Here, we attempt to characterize the AJ admixture history using a careful application of new and existing methods on a large AJ sample. Our main approach was based on local ancestry inference, in which we first classified each AJ genomic segment as EU or ME, and then compared allele frequencies along the EU segments to those of different EU populations. The contribution of each EU source was also estimated using GLOBETROTTER and haplotype sharing. The time of admixture was inferred based on multiple statistics, including ME segment lengths, the total EU ancestry per chromosome, and the correlation of ancestries along the chromosome. The major source of EU ancestry in AJ was found to be Southern Europe (≈60-80% of EU ancestry), with the rest being likely Eastern European. The inferred admixture time was ≈30 generations ago, but multiple lines of evidence suggest that it represents an average over two or more events, pre- and post-dating the founder event experienced by AJ in late medieval times. The time of the pre-bottleneck admixture event, which was likely Southern European, was estimated to ≈25-50 generations ago.
Published: 2017
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3. A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci.

Author: Eimear E Kenny, Itsik Pe'er, Amir Karban, Laurie Ozelius, Adele A Mitchell, Sok Meng Ng, Monica Erazo, Harry Ostrer, Clara Abraham, Maria T Abreu, Gil Atzmon, Nir Barzilai, Steven R Brant, Susan Bressman, Edward R Burns, Yehuda Chowers, Lorraine N Clark, Ariel Darvasi, Dana Doheny, Richard H Duerr, Rami Eliakim, Nir Giladi, Peter K Gregersen, Hakon Hakonarson, Michelle R Jones, Karen Marder, Dermot P B McGovern, Jennifer Mulle, Avi Orr-Urtreger, Deborah D Proctor, Ann Pulver, Jerome I Rotter, Mark S Silverberg, Thomas Ullman, Stephen T Warren, Matti Waterman, Wei Zhang, Aviv Bergman, Lloyd Mayer, Seymour Katz, Robert J Desnick, Judy H Cho, and Inga Peter
Subjects: Genetics, QH426-470
Abstract: Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p
Published: 2012
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4. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women.

Author: Sagiv Shifman, Martina Johannesson, Michal Bronstein, Sam X Chen, David A Collier, Nicholas J Craddock, Kenneth S Kendler, Tao Li, Michael O'Donovan, F Anthony O'Neill, Michael J Owen, Dermot Walsh, Daniel R Weinberger, Cuie Sun, Jonathan Flint, and Ariel Darvasi
Subjects: Genetics, QH426-470
Abstract: Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p = 2.9 x 10(-5) in women), with a significant gene-sex effect (p = 1.8 x 10(-4)). We studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p = 2.1 x 10(-3) in women; p = 4.2 x 10(-3) for gene-sex interaction). Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p = 8.8 x 10(-7); p = 1.6 x 10(-5) for gene-sex interaction). The female-specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease.
Published: 2008
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5. Identifying alternative hyper-splicing signatures in MG-thymoma by exon arrays.

Author: Lilach Soreq, Adi Gilboa-Geffen, Sonia Berrih-Aknin, Paul Lacoste, Ariel Darvasi, Eyal Soreq, Hagai Bergman, and Hermona Soreq
Subjects: Medicine, Science
Abstract: BACKGROUND: The vast majority of human genes (>70%) are alternatively spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing signatures specific to particular tumor types are still lacking. Here, we report the use of Affymetrix Human Exon Arrays to spot hyper-splicing events characteristic of myasthenia gravis (MG)-thymoma, thymic tumors which develop in patients with MG and discriminate them from colon cancer changes. METHODOLOGY/PRINCIPAL FINDINGS: We combined GO term to parent threshold-based and threshold-independent ad-hoc functional statistics with in-depth analysis of key modified transcripts to highlight various exon-specific changes. These denote alternative splicing in MG-thymoma tumors compared to healthy human thymus and to in-house and Affymetrix datasets from colon cancer and healthy tissues. By using both global and specific, term-to-parent Gene Ontology (GO) statistical comparisons, our functional integrative ad-hoc method allowed the detection of disease-relevant splicing events. CONCLUSIONS/SIGNIFICANCE: Hyper-spliced transcripts spanned several categories, including the tumorogenic ERBB4 tyrosine kinase receptor and the connective tissue growth factor CTGF, as well as the immune function-related histocompatibility gene HLA-DRB1 and interleukin (IL)19, two muscle-specific collagens and one myosin heavy chain gene; intriguingly, a putative new exon was discovered in the MG-involved acetylcholinesterase ACHE gene. Corresponding changes in spliceosome composition were indicated by co-decreases in the splicing factors ASF/SF(2) and SC35. Parallel tumor-associated changes occurred in colon cancer as well, but the majority of the apparent hyper-splicing events were particular to MG-thymoma and could be validated by Fluorescent In-Situ Hybridization (FISH), Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and mass spectrometry (MS) followed by peptide sequencing. Our findings demonstrate a particular alternative hyper-splicing signature for transcripts over-expressed in MG-thymoma, supporting the hypothesis that alternative hyper-splicing contributes to shaping the biological functions of these and other specialized tumors and opening new venues for the development of diagnosis and treatment approaches.
Published: 2008
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6. 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

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

8. Novel Ultra-Rare Exonic Variants Identified in a Founder Population Implicate Cadherins in Schizophrenia

Author: Lorraine N. Clark, Tom Maniatis, Harry Ostrer, Raiyan R. Khan, Nir Barzilai, Shai Carmi, Joseph Vijai, Laurie J. Ozelius, Max Lam, Danny Ben-Avraham, Susan B. Bressman, Anil K. Malhotra, Judy H. Cho, Ariel Darvasi, Erin Flaherty, Kenneth Offit, Steven M. Lipkin, Jin Yu, Robert J. Klein, Todd Lencz, Itsik Pe'er, Zeynep H. Gümüş, Gil Atzmon, and Inga Peter
Subjects: 0301 basic medicine, Male, Population, Protocadherin, Genome-wide association study, Biology, 03 medical and health sciences, Negative selection, 0302 clinical medicine, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, education, Gene, Loss function, Genetic association, Genetics, education.field_of_study, Genetic heterogeneity, General Neuroscience, Exons, Cadherins, medicine.disease, Founder Effect, 030104 developmental biology, Schizophrenia, Jews, Mutation, Female, 030217 neurology & neurosurgery, Founder effect
Abstract: IMPORTANCE Schizophrenia is a serious mental illness with high heritability. While common genetic variants account for a portion of the heritability, identification of rare variants associated with the disorder has proven challenging. OBJECTIVE To identify genes and gene sets associated with schizophrenia in a founder population (Ashkenazi Jewish), and to determine the relative power of this population for rare variant discovery. DESIGN, SETTING, AND PARTICIPANTS Data on exonic variants were extracted from whole genome sequences drawn from 786 patients with schizophrenia and 463 healthy control subjects, all drawn from the Ashkenazi Jewish population. Variants observed in two large publicly available datasets (total n≈153,000, excluding neuropsychiatric patients) were filtered out, and novel ultra-rare variants (URVs) were compared in cases and controls. MAIN OUTCOMES AND MEASURES The number of novel URVs and genes carrying them were compared across cases and controls. Genes in which only cases or only controls carried novel, functional URVs were examined using gene set analyses. RESULTS Cases had a higher frequency of novel missense or loss of function (MisLoF) variants compared to controls, as well as a greater number of genes impacted by MisLoF variants. Characterizing 141 “case-only” genes (in which ≥ 3 AJ cases in our dataset had MisLoF URVs with none found in our AJ controls), we replicated prior findings of both enrichment for synaptic gene sets, as well as specific genes such as SETD1A and TRIO. Additionally, we identified cadherins as a novel gene set associated with schizophrenia including a recurrent mutation in PCDHA3. Several genes associated with autism and other neurodevelopmental disorders including CACNA1E, ASXL3, SETBP1, and WDFY3, were also identified in our case-only gene list, as was TSC2, which is linked to tuberous sclerosis. Modeling the effects of purifying selection demonstrated that deleterious rare variants are greatly over-represented in a founder population with a tight bottleneck and rapidly expanding census, resulting in enhanced power for rare variant association studies. CONCLUSIONS AND RELEVANCE Identification of cell adhesion genes in the cadherin/protocadherin family is consistent with evidence from large-scale GWAS in schizophrenia, helps specify the synaptic abnormalities that may be central to the disorder, and suggests novel potential treatment strategies (e.g., inhibition of protein kinase C). Study of founder populations may serve as a cost-effective way to rapidly increase gene discovery in schizophrenia and other complex disorders.
Published: 2020

9. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Author: Patricia T. Michie, Franziska Degenhardt, Brandon Wormley, Paola Giusti-Rodríguez, Mark J. Daly, Raquelle I. Mesholam-Gately, Ingrid Melle, Sibylle G. Schwab, Andrew McQuillin, Benjamin M. Neale, Joshua L. Roffman, Abraham Reichenberg, Pamela Sklar, Diana O. Perkins, Jennifer L. Moran, Donald W. Black, Per Hoffmann, A. Hofman, Hailiang Huang, John L. Waddington, Giulio Genovese, Aaron R. Wolen, Deborah L. Levy, David Curtis, Digby Quested, Carlos N. Pato, Nicholas John Craddock, Stephanie Williams, Kung Yee Liang, Zhouzhi Wang, Tracey L. Petryshen, Ann E. Pulver, Randy L. Buckner, Stephan Ripke, Roel A. Ophoff, Danielle Posthuma, Lili Milani, Jacques Mallet, Menachem Fromer, Christian R. Marshall, Jaana Suvisaari, Jana Strohmaier, Richard Bruggeman, Marcella Rietschel, Ayman H. Fanous, Andrew M. McIntosh, James T.R. Walters, Dimitris Dikeos, Panos Roussos, Veikko Salomaa, Aiden Corvin, Carin J. Meijer, Tiina Paunio, Assen Jablensky, Sarah E. Bergen, Nancy G. Buccola, Annelie Nordin, Wolfgang Maier, Srdjan Djurovic, Naomi R. Wray, Aniket Shetty, Joel Eriksson, Dan Rujescu, Jouko Lönnqvist, Brian Kelly, Wenting Wu, Alexander Richards, Frans Henskens, Rich Belliveau, Bryan J. Mowry, Elodie Drapeau, Andreas J. Forstner, Silviu Alin Bacanu, Jubao Duan, Tõnu Esko, Bernard Lerer, Carmel M. Loughland, Olli Pietiläinen, Michael Conlon O'Donovan, Shaun M. Purcell, Michael Gill, Thomas G. Schulze, Douglas S. Greer, Stephen W. Scherer, Eli A. Stahl, Markus M. Nöthen, Guiqing Cai, William M. Brandler, Kristin K. Nicodemus, Dominique Campion, David A. Collier, Farooq Amin, Joel N. Hirschhorn, Robin M. Murray, Timothy G. Dinan, Mark Reimers, Murray J. Cairns, Rodney J. Scott, Aarno Palotie, Robert Freedman, Nelson B. Freimer, Joshua R. Atkins, Gary Donohoe, Ann Olincy, Jonathan Sebat, Colm McDonald, Srinivas Thirumalai, John Powell, Jo Knight, Vahram Haroutunian, Dieter B. Wildenauer, Tim B. Bigdeli, Lieuwe de Haan, Peter Eichhammer, James J. Crowley, Lynn E. DeLisi, Ulrich Schall, Rolf Adolfsson, Marcelo Bertalan, Thomas Hansen, Eric Strengman, Michael Davidson, Dheeraj Malhotra, Manuel Mattheisen, Jeffrey A. Lieberman, Benedicto Crespo-Facorro, Stephanie Godard, Edward M. Scolnick, Jonathan Pimm, Bertram Müller-Myhsok, Qingqin Li, Michele T. Pato, Wiepke Cahn, Christos Pantelis, Ingrid Agartz, Brendan Bulik-Sullivan, Madhusudan Gujral, Martilias S. Farrell, Brady J. Maher, Laurent Essioux, Karin V Fuentes Fajarado, Andres Metspalu, Stephanie H. Witt, Patrick F. Sullivan, Mark Weiser, Younes Mokrab, Kai How Farh, Line Olsen, Dermot Walsh, Peter Holmans, Hugh Gurling, Joseph I. Friedman, Andrew Pocklington, Daniel P. Howrigan, Lude Franke, Tune H. Pers, Larry J. Seidman, Pablo V. Gejman, Dalila Pinto, Michael John Owen, Inez Myin-Germeys, Steven A. McCarroll, Wei Cheng, Jackie Goldstein, C. Robert Cloninger, Elliot S. Gershon, Deborah A. Nertney, Thomas Werge, Noa Carrera, Kieran C. Murphy, Rita M. Cantor, Ariel Darvasi, Mark Hansen, Annette M. Hartmann, Ole A. Andreassen, Bradley T. Webb, Henrik B. Rasmussen, David Cohen, Elvira Bramon, Erik G. Jönsson, Vaughan J. Carr, Pui Y. Lee, Masashi Ikeda, Daniele Merico, Danny Antaki, Brien P. Riley, Stefan Herms, Igor Nenadic, Bettina Konte, Kimberley D. Chambert, Jurgen Del Favero, George Kirov, Matthew C. Keller, Jacob Gratten, Douglas F. Levinson, Luba Kalaydjieva, Bhooma Thiruvahindrapuram, Alan R. Sanders, Sang-Yun Oh, Alkes L. Price, Vihra Milanova, Juha Veijola, Erik Söderman, Dragan M. Svrakic, David H. Kavanagh, Patrik K. E. Magnusson, Douglas Blackwood, Nakao Iwata, Jim van Os, Jeremy M. Silverman, Elena Parkhomenko, Kenneth L. Davis, Jing Qin Wu, Eadbhard O'Callaghan, Chris C. A. Spencer, Juha Karjalainen, Anna K. Kähler, Clement C. Zai, Nigel Williams, Joseph D. Buxbaum, Jin P. Szatkiewicz, Laura Nisenbaum, Sang Hong Lee, Yunjung Kim, Colm O'Dushlaine, René S. Kahn, Morten Mattingsdal, Inge Joa, Marian L. Hamshere, Frank Dudbridge, Ina Giegling, Sandra Meier, Derek W. Morris, Robert W. McCarley, Douglas M. Ruderfer, Paul Cormican, Lyudmila Georgieva, Sven Cichon, Josef Frank, Jianxin Shi, George N. Papadimitriou, Kenneth S. Kendler, Margot Albus, Enrico Domenici, Claudine Laurent, Francis A. O'Neill, Adam Savitz, Jordan W. Smoller, James L. Kennedy, Peter M. Visscher, Valentina Escott-Price, Christina M. Hultman, T. Scott Stroup, Elizabeth Bevilacqua, James A. Knowles, William Byerley, Paul A. Tooney, Madeline Alexander, Stanley V. Catts, David St Clair, Sophie E. Legge, Gerald Nestadt, Michelle S. Maile, Perceptual and Cognitive Neuroscience (PCN), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Stem Cell Aging Leukemia and Lymphoma (SALL), Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: Hersen en Zenuw Centrum (3), MUMC+: MA Psychiatrie (3), Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, ANS - Complex Trait Genetics, Adult Psychiatry, Other departments, Marshall, Christian R, Howrigan, Daniel P, Merico, Daniele, Thiruvahindrapuram, Bhooma, Lee, S Hong, Sebat, Jonathan, Psychosis Endophenotypes International Consortium, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, CNV, Schizophrenia Working Grp, Psychosis Endophenotypes, Rehabilitation Medicine, and Child and Adolescent Psychiatry / Psychology
Subjects: 0301 basic medicine, Male, 16P11.2, Duplication, Autism, Rearrangement, Genome-wide association study, Copy number variant, Gene, Medical and Health Sciences, 0302 clinical medicine, DUPLICATIONS, Risk Factors, Gene duplication, Genotype, Disorder, Copy-number variation, Genetics, Genetics & Heredity, RISK, copy number variation, REARRANGEMENTS, Biological Sciences, 16p11.2, 3. Good health, Phenotype, Female, Risk, CNVS, Genetic Markers, genetic etiology, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, DNA Copy Number Variations, DISORDERS, CNV, Non-allelic homologous recombination, PHENOTYPES, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, genomics, Journal Article, Humans, Comparative Study, Genetic Predisposition to Disease, AUTISM, Psychosis Endophenotypes International Consortium, MUTATIONS, Case-control study, Odds ratio, R1, GENE, 030104 developmental biology, genetics research, Genetic marker, Genetic Loci, Case-Control Studies, Mutation, Schizophrenia, Human medicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 10(-5)). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination. Refereed/Peer-reviewed
Published: 2017

10. Expanded genetic screening panel for the Ashkenazi Jewish population

Author: Carole Oddoux, Harry Ostrer, Laurie J. Ozelius, Susan Hiraki, Philip Meyer, Itsik Pe'er, Ariel Darvasi, Inga Peter, Nir Barzilai, Lorraine N. Clark, Kinnari Upadhyay, Brett Baskovich, Jin Yu, Judy H. Cho, Shai Carmi, Todd Lencz, and Gil Atzmon
Subjects: 0301 basic medicine, Genetics, education.field_of_study, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Population, Genetic Carrier Screening, Genomics, 030105 genetics & heredity, Carrier testing, Article, Ashkenazi jews, 03 medical and health sciences, medicine, Medical genetics, education, business, Allele frequency, Genetics (clinical), Genetic testing
Abstract: Carrier screening programs that identify the presence of known mutations have been effective for reducing the incidence of autosomal recessive conditions in the Ashkenazi Jewish (AJ) population and other populations. Yet, these programs have not realized their full potential. Furthermore, many known autosomal recessive and dominant conditions are not screened for and the molecular basis of other conditions for which screening might be offered is unknown. Through literature review and annotation of full sequenced genomes from healthy individuals, we expanded the list of mutations. Mutations were identified in a sample of 128 fully sequenced AJ genomes that were filtered through clinical databases and curated manually for clinical validity and utility using the American College of Medical Genetics and Genomics scoring (ACMG) system. Other known mutations were identified through literature review. A panel of 163 mutations was identified for 76 autosomal recessive, 24 autosomal dominant, and 3 X-linked disorders. Screening for a broader range of disorders not only could further reduce the incidence of autosomal recessive disorders but also could offer the benefits of early or presymptomatic diagnosis. Genet Med 18 5, 522–528.
Published: 2016

11. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Author: Elodie Drapeau, Robert W. McCarley, Jim van Os, Svetlana A. Limborska, Elvira Bramon, Milan Macek, Divya Mehta, Lieuwe de Haan, Christos Pantelis, Inge Joa, Daniel R. Weinberger, Andrew McQuillin, Lynn E. DeLisi, Ulrich Schall, Tõnu Esko, Digby Quested, Jacob Gratten, Gary Donohoe, Kenneth S. Kendler, Derek W. Morris, Ole A. Andreassen, Peter M. Visscher, Valentina Escott-Price, Lyudmila Georgieva, John L. Waddington, Sara Marsal, Naomi R. Wray, Danielle Posthuma, Benedicto Crespo-Facorro, Rita M. Cantor, Ariel Darvasi, Béla Melegh, Jing Qin Wu, Zhihong Zhu, Kieran C. Murphy, Felix C. Tropf, Inez Myin-Germeys, Antonio Julià, Paul A. Tooney, Frans Henskens, C. Robert Cloninger, Bryan J. Mowry, Larry J. Seidman, Bernard Lerer, Andres Metspalu, Carmel M. Loughland, Mark Weiser, Gibran Hemani, Ann Olincy, Joseph D. Buxbaum, Silviu-Alin Bacanu, Srdjan Djurovic, Andrew M. McIntosh, Jian Yang, Patricia T. Michie, Harold Snieder, Richard Bruggeman, John J. McGrath, Nicola Barban, Rodney J. Scott, Nelson B. Freimer, Timothy G. Dinan, Melinda Mills, S. Hong Lee, David Cohen, Andrey Khrunin, Andrew Bakshi, Murray J. Cairns, Patrik K. E. Magnusson, Draga Toncheva, Universidad de Cantabria, Mehta, Divya, Tropf, Felix C, Gratten, Jacob, Bakshi, Andrew, Zhu, Zhihong, Bacanu, Silviu-Alin, Hemani, Gibran, Magnusson, Patrik KE, Barban, Nicola, Esko, Tonu, Metspalu, Andres, Snieder, Harold, Mowry, Bryan J, Kendler, Kenneth S, Yang, Jian, Visscher, Peter M, McGrath, John J, Mills, Melinda C, Wray, Naomi R, Lee, S Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, TwinsUK, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), Psychiatrie & Neuropsychologie, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Adult Psychiatry, Sociology/ICS, Life Course Epidemiology (LCE), Mehta Divya, Tropf Felix C., Gratten Jacob, Bakshi Andrew, Zhu Zhihong, Bacanu Silviu-Alin, Hemani Gibran, Magnusson Patrik K. E., BARBAN N, Esko Tonu, Metspalu Andre, Snieder Harold, Mowry Bryan J., Kendler Kenneth S., Yang Jian, Visscher Peter M., McGrath John J., Mills Melinda C., Wray Naomi R., and Lee S. Hong
Subjects: 0301 basic medicine, Denmark, Genome-wide association study, genetic risk, Cohort Studies, 0302 clinical medicine, Pregnancy, GWAS, genetics, Psychiatry, RISK, PSYCHIATRIC-DISORDERS, BIPOLAR DISORDER, 3. Good health, Psychiatry and Mental health, Birth order, Phenotype, PATERNAL AGE, Schizophrenia, Female, Maternal Age, Cohort study, Adult, medicine.medical_specialty, Offspring, Article, 03 medical and health sciences, PSYCHOSIS, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Alleles, Genetic association, genome-wide association study, business.industry, medicine.disease, de novo mutation, schizophrenia, 030104 developmental biology, maternal age, DE-NOVO MUTATIONS, Birth Order, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Demography, first birth
Abstract: IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. OBJECTIVE: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. DESIGN, SETTING, AND PARTICIPANTS: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18?957 SCZ cases and 22?673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12?247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. MAIN OUTCOMES AND MEASURES: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. RESULTS: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2?=?1.1E-03, P?=?4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers. This research is supported by grants 613602, 1047956, 1078901, 1080157, 1087889, and 1067795 from the Australian National Health and Medical Research Council and by grants DE130100614 and DP160102126 from the Australian Research Council. Primary analyses of the SchizophreniaWorking Group of the Psychiatric Genomics Consortium data were conducted on the Genetic Cluster Computer (http://www .geneticcluster.org) hosted by SURFsara and supported by grant NOW480-05-003 from the Netherlands Scientific Organization, along with a supplement from the Dutch Brain Foundation and the Vrije Universitiet Amsterdam. TwinsUK was funded by theWellcome Trust, by grant FP7/2007-2013 from the European Community’s Seventh Framework Programme, and by support from the National Institute for Health Research–funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust in partnership with King’s College London, and single-nucleotide polymorphism genotyping was performed by theWellcome Trust Sanger Institute and National Eye Institute via the National Institute for Health/Center for Inherited Disease Research. Estonian Genome Center Biobank, University of Tartu, received targeted financing by grant IUT20-60 from the Estonian Research Council, Center of Excellence in Genomics, and University of Tartu, and data analyses were carried out in part in the High Performance Computing Center of the University of Tartu. The Swedish Twin Registry is supported by Karolinska Institutet. Mr Tropf received funding from sciencestarter.de for a research visit to The University of Queensland. The research leading to these results received funding from the European Research Council via an ERC Consolidator Grant SOCIOGENOME (grant 615603 awarded to Dr Mills [http://www.sociogenome.com]).
Published: 2016

12. Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals

Author: Vikas Bansal, Ariel Darvasi, Bernhard O. Boehm, and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: 0301 basic medicine, Adult, Male, Risk, Heterozygote, endocrine system diseases, Adolescent, Genotype, Wolfram syndrome, Endocrinology, Diabetes and Metabolism, Carrier Screening, Mutation, Missense, Type 2 diabetes, 03 medical and health sciences, Young Adult, Ashkenazi Jewish, Gene Frequency, Internal Medicine, medicine, Missense mutation, Humans, Medicine [Science], Age of Onset, Allele frequency, Alleles, Genetic testing, Genetics, Type 1 diabetes, medicine.diagnostic_test, business.industry, Homozygote, nutritional and metabolic diseases, Genetic Variation, Membrane Proteins, Wolfram Syndrome, medicine.disease, Penetrance, Optic Atrophy, 030104 developmental biology, Diabetes Mellitus, Type 1, Phenotype, Diabetes Mellitus, Type 2, Haplotypes, Jews, Female, business
Abstract: Aims/hypothesis Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and opticatrophy and is caused by bi-allelic mutations in the WFS1 gene. In a recent sequencing study, an individual with juvenile-onset diabetes was observed to be homozygous for a rare missense variant (c.1672C>T, p.R558C) in the WFS1 gene. The aim of this study was to performthe genetic characterisation of this variant and to determine whether it is causal for young-onset diabetes and Wolfram syndrome. Methods We analysed the allele frequency of the missense variant in multiple variant databases.We genotyped the variant in 475 individuals with type 1 diabetes and 2237 control individuals of Ashkenazi Jewish ancestry and analysed the phenotypes of homozygotes.We also investigated the association of this variant with risk for type 2 diabetes using genotype and sequence data for type 2 diabetes cases and controls. Results The missense variant demonstrated an allele frequency of 1.4% in individuals of Ashkenazi Jewish ancestry, 60-fold higher than in other populations. Genotyping of this variant in 475 individuals diagnosed with type 1 diabetes identified eight homozygotes compared with none in 2237 control individuals (genotype relative risk 135.3, p = 3.4 × 10−15). The age at diagnosis of diabetes for these eight individuals (17.8 ± 8.3 years) was several times greater than for typical Wolfram syndrome (5 ± 4 years). Further, optic atrophy was observed in only one of the eight individuals, while another individual had theWolfram syndrome-relevant phenotype of neurogenic bladder. Analysis of sequence and genotype data in two case–control cohorts of Ashkenazi ancestry demonstrated that this variant is also associated with an increased risk of type 2 diabetes in heterozygotes (OR 1.81, p = 0.004). Conclusions/interpretation We have identified a low-frequency coding variant in the WFS1 gene that is enriched in Ashkenazi Jewish individuals and causes a mild form ofWolfram syndrome characterised by young-onset diabetes and reduced penetrance for optic atrophy. This variant should be considered for genetic testing in individuals of Ashkenazi ancestry diagnosed with young-onset non-autoimmune diabetes and should be included in Ashkenazi carrier screening panels. MOE (Min. of Education, S’pore) Accepted version
Published: 2018

13. High-depth whole genome sequencing of an Ashkenazi Jewish reference panel: enhancing sensitivity, accuracy, and imputation

Author: Susan Bressman, Harry Ostrer, Jin Yu, Ariel Darvasi, Itsik Pe'er, Laurie J. Ozelius, Gil Atzmon, Lorraine N. Clark, Judy H. Cho, Kenneth Offit, Robert S. Klein, Todd Lencz, Steven M. Lipkin, Inga Peter, Shai Carmi, Zeynep H. Gümüş, Nir Barzilai, Vijai Joseph, Danny Ben-Avraham, and Cameron D. Palmer
Subjects: 0301 basic medicine, Genotype, Population, Genomics, Genome-wide association study, Computational biology, Biology, Genome, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Ashkenazi Jewish, education, Genetics (clinical), Whole genome sequencing, education.field_of_study, Whole Genome Sequencing, Genome, Human, Genetic Variation, Reference Standards, Human genetics, 030104 developmental biology, Haplotypes, Jews, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract: While increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. Here, we sequenced at full-depth (≥ 30×), across two platforms (Illumina X Ten and Complete Genomics, Inc.), a moderately large (n = 738) cohort of samples drawn from the Ashkenazi Jewish population. We developed a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population. Quality control (QC) thresholds for the Illumina X Ten platform were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. QC procedures also identified numerous regions that are poorly mapped using current reference or alternate assemblies. After stringent QC, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels, especially in the range of rare variants that may be most critical to further progress in mapping of complex phenotypes. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.
Published: 2018

14. Genome-wide association study of schizophrenia in Ashkenazi Jews

Author: Paula S. Wolyniec, Inga Peters, Dimitrios Avramopoulos, Ann E. Pulver, Gerald Nestadt, Todd Lencz, Jennifer G. Mulle, Ingo Ruczinski, John A. McGrath, Eimear E. Kenny, Vladimir Vacic, Ariel Darvasi, Stephen T. Warren, Mehdi Pirooznia, and Fernando S. Goes
Subjects: Male, Genome-wide association study, Quantitative trait locus, Polymorphism, Single Nucleotide, Cellular and Molecular Neuroscience, symbols.namesake, Humans, Medicine, Genetic Predisposition to Disease, Israel, Genetics (clinical), Genetic association, Genetics, business.industry, Middle Aged, Heritability, medicine.disease, United States, Ashkenazi jews, Psychiatry and Mental health, Schizophrenia, Case-Control Studies, Jews, Mendelian inheritance, symbols, Female, business, Genome-Wide Association Study, Founder effect
Abstract: Schizophrenia is a common, clinically heterogeneous disorder associated with lifelong morbidity and early mortality. Several genetic variants associated with schizophrenia have been identified, but the majority of the heritability remains unknown. In this study, we report on a case-control sample of Ashkenazi Jews (AJ), a founder population that may provide additional insights into genetic etiology of schizophrenia. We performed a genome-wide association analysis (GWAS) of 592 cases and 505 controls of AJ ancestry ascertained in the US. Subsequently, we performed a meta-analysis with an Israeli AJ sample of 913 cases and 1640 controls, followed by a meta-analysis and polygenic risk scoring using summary results from Psychiatric GWAS Consortium 2 schizophrenia study. The U.S. AJ sample showed strong evidence of polygenic inheritance (pseudo-R2 ∼9.7%) and a SNP-heritability estimate of 0.39 (P = 0.00046). We found no genome-wide significant associations in the U.S. sample or in the combined US/Israeli AJ meta-analysis of 1505 cases and 2145 controls. The strongest AJ specific associations (P-values in 10−6–10−7 range) were in the 22q 11.2 deletion region and included the genes TBX1, GLN1, and COMT. Supportive evidence (meta P
Published: 2015

15. Independent evidence for an association between general cognitive ability and a genetic locus for educational attainment

Author: Ole A. Andreassen, Anil K. Malhotra, Masashi Ikeda, Andrea Christoforou, Jari Lahti, Matthew A. Scult, Bettina Konte, Matthew C. Keller, Gary Donohoe, Dwight Dickinson, Neil Pendleton, Semanti Mukherjee, Stella G. Giakoumaki, Emma Knowles, William Ollier, Dan Rujescu, Joey W. Trampush, Vidar M. Steen, Pamela DeRosse, Stephanie Le Hellard, Saurav Guha, Ingrid Melle, Astri J. Lundervold, Nakao Iwata, Katri Räikkönen, Itsik Pe'er, Aarno Palotie, Elisabeth Widen, Panos Bitsios, Panos Roussos, Ivar Reinvang, Aiden Corvin, Michael A Horan, Johan G. Eriksson, Ina Giegling, Ian J. Deary, Srdjan Djurovic, Derek W. Morris, David C. Liewald, Thomas Espeseth, Todd Lencz, Richard E. Straub, Daniel R. Weinberger, Gail Davies, Ahmad R. Hariri, Majnu John, David C. Glahn, Michael Gill, Ariel Darvasi, Katherine E. Burdick, Antony Payton, John M. Starr, and Kjetil Sundet
Subjects: Genetics, education.field_of_study, Population, Locus (genetics), Genome-wide association study, Cognition, Quantitative trait locus, Educational attainment, Cellular and Molecular Neuroscience, Psychiatry and Mental health, SNP, Psychology, education, Neurocognitive, Genetics (clinical), Clinical psychology
Abstract: Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability (“g”) in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals from a recent GWAS of cognition. A SNP (rs1906252) located at chromosome 6q16.1, previously associated with years of schooling, was significantly associated with g (P = 1.47 × 10−4) in COGENT. The first joint analysis of 43,381 non-overlapping individuals for this a priori-designated locus was strongly significant (P = 4.94 × 10−7), and the second joint analysis of 68,159 non-overlapping individuals was even more robust (P = 1.65 × 10−9). These results provide independent replication, in a large-scale dataset, of a genetic locus associated with cognitive function and education. As sample sizes grow, cognitive GWAS will identify increasing numbers of associated loci, as has been accomplished in other polygenic quantitative traits, which may be relevant to psychiatric illness. © 2015 Wiley Periodicals, Inc.
Published: 2015

16. Common variants of IRF3 conferring risk of schizophrenia

Author: Ming Li, Hong-Yan Jiang, Wen Zhang, Anna Alkelai, Deng-Feng Zhang, Xiufeng Xu, Yong-Gang Yao, Bernard Lerer, Todd Lencz, Li Yu, Ariel Darvasi, and Xiao Li
Subjects: Male, Genotype, Quantitative Trait Loci, Population, Genome-wide association study, Single-nucleotide polymorphism, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, mental disorders, Odds Ratio, Humans, Genetic Predisposition to Disease, Genetic Testing, education, Biological Psychiatry, Genetic association, Genetics, education.field_of_study, Case-control study, Odds ratio, Psychiatry and Mental health, Case-Control Studies, Expression quantitative trait loci, Schizophrenia, Female, Interferon Regulatory Factor-3, Genome-Wide Association Study
Abstract: Schizophrenia is a brain disorder with high heritability. Recent studies have implicated genes involved in the immune response pathway in the pathogenesis of schizophrenia. Interferon regulatory factor 3 (IRF3), a virus-immune-related gene, activates the transcription of several interferon-induced genes, and functionally interacts with several schizophrenia susceptibility genes. To test whether IRF3 is a schizophrenia susceptibility gene, we analyzed the associations of its SNPs with schizophrenia in independent population samples as well as reported data from expression quantitative trait loci (eQTL) in healthy individuals. We observed multiple independent SNPs in IRF3 showing nominally significant associations with schizophrenia (P < 0.05); more intriguingly, a SNP (rs11880923), which is significantly correlated with IRF3 expression in independent samples (P < 0.05), is also consistently associated with schizophrenia across different cohorts and in combined samples (odds ratio = 1.075, Pmeta = 2.08 × 10(-5)), especially in Caucasians (odds ratio = 1.078, Pmeta = 2.46 × 10(-5)). These results suggested that IRF3 is likely a risk gene for schizophrenia, at least in Caucasians. Although the clinical associations of IRF3 with diagnosis did not achieve genome-wide level of statistical significance, the observed odds ratio is comparable with other susceptibility loci identified through large-scale genetic association studies on schizophrenia, which could be regarded simply as small but detectable effects.
Published: 2015

17. 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

18. Facilitating complex DNA mixture interpretation by sequencing highly polymorphic haplotypes

Author: Ariel Darvasi, Lev Voskoboinik, and Uzi Motro
Subjects: 0301 basic medicine, Word error rate, Single-nucleotide polymorphism, Computational biology, Biology, Polymorphism, Single Nucleotide, Pathology and Forensic Medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Genetics, Humans, 030216 legal & forensic medicine, Allele, Alleles, Likelihood Functions, Massive parallel sequencing, Haplotype, Robustness (evolution), DNA, Sequence Analysis, DNA, DNA Fingerprinting, 030104 developmental biology, chemistry, Haplotypes, Minion, Microsatellite Repeats
Abstract: Interpretation of complex DNA mixtures is an ongoing challenge in the field of forensic genetics. Commonly used STR markers are quite polymorphic, enabling very high statistical association between a single source DNA profile from a crime scene and a matching suspect. STR typing of low order mixtures with two and three contributors also commonly produces high statistical association for a contributor, using current interpretation software. However higher order mixtures, with four contributors or more, are more challenging. Shared alleles among the many contributors may complicate the correct assessment of the number of contributors to a mixture and decreases the statistical support for inclusion of contributors. Recently, there is a rising use of massively parallel sequencing for forensic applications, and markers such as SNPs and short haplotypes are receiving more attention. However, these markers are even less polymorphic than autosomal STRs and are not suitable for complex mixture interpretation. We propose to use a different panel of haplotype markers, which contain many SNPs and are very polymorphic. These markers can be sequenced either by standard sequencing technologies or by a new instrument called MinION that sequences DNA as it passes through a nanopore. This instrument is very small and can sequence long stretches of DNA, but suffers from high error rate. We present a method for calling haplotype alleles facing high error rate, and use simulation to test its robustness. We also calculate likelihood ratio (LR) between propositions of contribution and non-contribution for individuals that do, and do not, contribute to various complex DNA mixtures. Our results indicate that the correct alleles can be identified in a mixture, despite the high sequencing error rate, and that contributors get high LR (>109) even in complex mixtures with up to five contributors. Non-contributors receive a very small LR, below 1 in most cases (>98%), which support their exclusion as possible donors to the complex DNA mixtures.
Published: 2017

19. Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood

Author: Guiyan Ni, Gerhard Moser, Naomi R. Wray, S. Hong Lee, 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, 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, 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 Juliá, 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 Chee Keong, 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 Mattingsda, 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 Olinc, Line Olsen, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Sergi Papio, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Milica Pejovic-Milovancevic, Diana O. Perkins, Olli Pietiläinenl, 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. Stah, 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, Peter M. Visscher, 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. McCarrol, 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 Rietsche, 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, APH - Mental Health, ANS - Complex Trait Genetics, Adult Psychiatry, Ni, Guiyan, Moser, Gerhard, Wray, Naomi R, Lee, S Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Clinicum, Department of Psychiatry, and HUS Psychiatry
Subjects: 0301 basic medicine, Linkage disequilibrium, Schizophrenia/genetics, INFORMATION, Restricted maximum likelihood, Inheritance Patterns, linkage disequilibrium score regression, Bioinformatics, Medical and Health Sciences, 3124 Neurology and psychiatry, Linkage Disequilibrium, biasedness, 0302 clinical medicine, Statistics, Databases, Genetic, WIDE ASSOCIATION, Genetics(clinical), PARTITIONING HERITABILITY, Genetics (clinical), Genetics & Heredity, education.field_of_study, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Likelihood Functions, Genome, Body Height/genetics, accuracy, Regression analysis, Single Nucleotide, Biological Sciences, Polymorphism, Single Nucleotide/genetics, genetic correlation, Regression, STATISTICS, genomic restricted maximum likelihood, Mental Health, Phenotype, Regression Analysis, COMPLEX HUMAN TRAITS, Single Nucleotide/genetics, Human, Adult, SUSCEPTIBILITY LOCI, Genotype, SNP heritability, body mass index, genome-wide SNPs, height, schizophrenia, Population, Haplotypes/genetics, Biology, Genetic correlation, Polymorphism, Single Nucleotide, 03 medical and health sciences, Databases, Genetic, ddc:570, Report, Genetics, Humans, Linkage Disequilibrium/genetics, Computer Simulation, Polymorphism, education, linkage disequilibrium score regression (LDSC), Genome, Human, Human Genome, genetic architecture, Genetic architecture, Body Height, Brain Disorders, Inheritance Patterns/genetics, BODY-MASS INDEX, 030104 developmental biology, Haplotypes, Sample size determination, Schizophrenia, 3111 Biomedicine, HUMAN HEIGHT, 030217 neurology & neurosurgery
Abstract: J. Lönnqvist on työryhmän Psychiat Genomics Consortium jäsen. Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on similar to 150,000 individuals give a higher accuracy than LDSC estimates based on similar to 400,000 individuals (from combinedmeta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser.
Published: 2017

20. Age at first birth in women is genetically associated with increased risk of schizophrenia

Author: Fritz Zimprich, Manuel Mattheisen, Edward M. Scolnick, Ayman H. Fanous, Henrik B. Rasmussen, Steven A. McCarroll, Ingrid Agartz, Carmel M. Loughland, Aiden Corvin, Ann Olincy, Anders D. Børglum, F. Anthony O'Neill, T. Scott Stroup, Elizabeth Bevilacqua, Sandra Meier, Ulrich Schall, Jouko Lönnqvist, Jianxin Shi, C. Robert Cloninger, Judit Bene, Veikko Salomaa, George N. Papadimitriou, Milica Pejovic-Milovancevic, Béla Melegh, Kari Stefansson, Brendan Bulik-Sullivan, Janis Klovins, Enrico Domenici, Sibylle G. Schwab, Dai Wang, Assen Jablensky, Mari Nelis, Sang Yun Oh, Peter Holmans, Aaron R. Wolen, Hualin Simon Xi, Eric Strengman, Bryan J. Mowry, Michael Gill, Kung Yee Liang, William Byerley, Rolf Adolfsson, Hugh Gurling, Joseph I. Friedman, Andrew Pocklington, Brien P. Riley, Engilbert Sigurdsson, Benjamin M. Neale, Miaoxin Li, Michael Davidson, Bernard Lerer, Michele T. Pato, Xuebin Zheng, Patrick F. Sullivan, Frans Henskens, Madeline Alexander, Andrew M. McIntosh, Inez Myin-Germeys, Draga Toncheva, Liene Nikitina-Zake, Kenneth S. Kendler, Carin J. Meijer, Robin M. Murray, Richard E. Straub, Ann E. Pulver, Menachem Fromer, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Lyudmila Georgieva, Giulio Genovese, Brion S. Maher, Stanley V. Catts, David St Clair, Robert W. McCarley, David Cohen, Nancy G. Buccola, Dan Rujescu, Carlos N. Pato, Kristin K. Nicodemus, Josef Frank, Claudine Laurent, Dominique Campion, Guiyan Ni, James L. Kennedy, Sena Karachanak-Yankova, Nicholas John Craddock, Peter M. Visscher, Valentina Escott-Price, Jeffrey A. Lieberman, Deborah A. Nertney, Bertram Müller-Myhsok, Marcella Rietschel, Dimitris Dikeos, Stephanie Godard, Stephanie Williams, Andres Metspalu, John L. Waddington, Sophie E. Legge, Roel A. Ophoff, Jonathan Pimm, Richard Bruggeman, Tim B. Bigdeli, Gerald Nestadt, Mark Weiser, Kieran C. Murphy, Eric F.C. Cheung, Kang Sim, Jordan W. Smoller, David J. Kavanagh, Inge Joa, Jens R. Wendland, Thomas G. Schulze, Richard A. Belliveau, Sarah E. Bergen, Ditte Demontis, David Curtis, Todd Lencz, Danielle Posthuma, René S. Kahn, Lili Milani, Randy L. Buckner, Jianjun Liu, Petr Slominsky, Wiepke Cahn, Hana Kuzelova-Ptackova, Sergi Papiol, Tune H. Pers, Stephan Ripke, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Larry J. Seidman, Eli A. Stahl, David A. Collier, Michael Conlon O'Donovan, Svetlana A. Limborska, James T.R. Walters, Farooq Amin, Noa Carrera, Ronald Y.L. Chen, Pablo V. Gejman, Joel N. Hirschhorn, Zita Ausrele Kucinskiene, Michael John Owen, Ina Giegling, Stephanie H. Witt, Timothy G. Dinan, Margot Albus, Wei Cheng, Marian L. Hamshere, Markus M. Nöthen, Thomas Werge, Guiqing Cai, Raquelle I. Mesholam-Gately, Annette M. Hartmann, Ingrid Melle, Ole A. Andreassen, Preben Bo Mortensen, Hannelore Ehrenreich, Tiina Paunio, James A. Knowles, Pak C. Sham, Marion Friedl, Teimuraz Silagadze, Dermot Walsh, Emily H. M. Wong, Igor Nenadic, Matthew C. Keller, John Powell, Naomi R. Wray, Patricia T. Michie, Bradley T. Webb, Lude Franke, Mark Hansen, Masashi Ikeda, Sven Cichon, Elvira Bramon, Frank Dudbridge, Erik G. Jönsson, Annelie Nordin, Wolfgang Maier, Peter Eichhammer, Christian R. Schubert, J. Mallet, Jacob Gratten, Andrey Khrunin, Jacqueline I. Goldstein, Panos Roussos, Pamela Sklar, Diana O. Perkins, Srdjan Djurovic, Phil Lee, Elodie Drapeau, Douglas F. Levinson, Nadine Cohen, Luba Kalaydjieva, Brandon Wormley, Tao Li, Tõnu Esko, Alexander Richards, Srihari Gopal, Jubao Duan, Anil K. Malhotra, Elisabeth Stögmann, Gary Donohoe, Kimberly Chambert, Sara Marsal, Hreinn Stefansson, Jo Knight, Ole Mors, Per Hoffmann, Dieter B. Wildenauer, James J. Crowley, Srinivas Thirumalai, Vahram Haroutunian, A. Hofman, Hailiang Huang, Thomas Hansen, Daniel R. Weinberger, Andrew McQuillin, Vaughan J. Carr, Vaidutis Kučinskas, Jimmy Lee Chee Keong, Digby Quested, Aarno Palotie, Robert Freedman, Hon-Cheong So, Jennifer L. Moran, Donald W. Black, Mark Reimers, Abraham Reichenberg, Jurgen Del Favero, Paola Giusti-Rodríguez, Tracey L. Petryshen, Olli Pietiläinen, Franziska Degenhardt, Laurent Essioux, Esben Agerbo, Qiang Wang, Jana Strohmaier, Siow Ann Chong, Johan G. Eriksson, Martin Begemann, Younes Mokrab, Colm McDonald, Silviu Alin Bacanu, Martilias S. Farrell, Christos Pantelis, Kai How Farh, Line Olsen, Naser Durmishi, Antonio Julià, Stefan Herms, Qingqin S. Li, Bettina Konte, George Kirov, Rodney J. Scott, Nelson B. Freimer, Mads V. Hollegaard, Shaun Purcell, Erik Söderman, Dragan M. Svrakic, Patrik K. E. Magnusson, Douglas Blackwood, Jin P. Szatkiewicz, Sang Hong Lee, Yunjung Kim, Colm O'Dushlaine, Morten Mattingsdal, Jim van Os, Sarah Tosato, Milan Macek, Joshua L. Roffman, Jan Lubinski, Eadbhard O'Callaghan, Juha Karjalainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Joseph D. Buxbaum, Laura Nisenbaum, Eric Y.H. Chen, David M. Hougaard, Jaana Suvisaari, Chris C. A. Spencer, Alan R. Sanders, Alkes L. Price, Vihra Milanova, Juha Veijola, Christian Hammer, Raymond C.K. Chan, Stacy Steinberg, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Kenneth L. Davis, Lieuwe de Haan, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Kučinskas, Vaidutis, Kučinskienė, Zita Aušrelė, Ni, Guiyan, Gratten, Jacob, Wray, Naomi R, Lee, Sang Hong, Germeys, Inez, Complex Trait Genetics, Háskóli Íslands, University of Iceland, Child and Adolescent Psychiatry / Psychology, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, University Management, Department of Psychiatry, Center for Population, Health and Society, Department of Public Health, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: 0301 basic medicine, Multifactorial Inheritance, PATERNAL-AGE, 3124 Neurology and psychiatry, COMMON SNPS, fluids and secretions, 0302 clinical medicine, CHILD, Risk Factors, Pregnancy, 2.1 Biological and endogenous factors, Medicine, Aetiology, Pediatric, PROPORTION, Schizophrenia Working Group of the Psychiatric Genomics Consortium, 0303 health sciences, Multidisciplinary, PSYCHIATRIC-DISORDERS, BIPOLAR DISORDER, Biobank, 3. Good health, AFB, Mental Health, Schizophrenia, Female, Erfðarannsóknir, Psychosocial, TRAITS, schizophrenia, age at birth, AFB, Maternal Age, Adult, age at first birth in women, genetic association, Offspring, Science, Genetic correlation, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Geðklofi, Genetics, age at birth, Humans, Genetic Predisposition to Disease, Bipolar disorder, General, Biology, Genetic association study, 030304 developmental biology, Genetic association, business.industry, Genetic heterogeneity, Prevention, average aged parents, Parturition, SCORE REGRESSION, bacterial infections and mycoses, medicine.disease, Mental health, Brain Disorders, respiratory tract diseases, schizophrenia, Good Health and Well Being, 030104 developmental biology, younger and older parents, DE-NOVO MUTATIONS, ddc:000, Human medicine, business, 030217 neurology & neurosurgery, Demography
Abstract: Publisher's version (útgefin grein), Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is −0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health., This research is supported by the Australian National Health and Medical Research Council (1080157, 1087889, 1103418, 1127440), and the Australian Research Council (DP160102126, FT160100229). This research has been conducted using the UK Biobank Resource. UK Biobank (http://www.ukbiobank.ac.uk) Research Ethics Committee (REC) approval number is 11/NW/0382. Our reference number approved by UK Biobank is 14575.
Published: 2017

21. High-depth whole genome sequencing of a large population-specific reference panel: Enhancing sensitivity, accuracy, and imputation

Author: Shai Carmi, Danny Ben-Avraham, Susan Bressman, Harry Ostrer, Lorraine N. Clark, Gil Atzmon, Robert S. Klein, Zeynep H. Gümüş, Laurie J. Ozelius, Inga Peter, Nir Barzilai, Todd Lencz, Judy H. Cho, Cameron D. Palmer, Jin Yu, Itsik Pe'er, Steven M. Lipkin, Vijai Joseph, Ariel Darvasi, and Kenneth Offit
Subjects: Genetics, Whole genome sequencing, 0303 health sciences, education.field_of_study, Population, Large population, Genomics, Computational biology, Biology, Genome, 03 medical and health sciences, 0302 clinical medicine, False positive paradox, education, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology, Personal genomics
Abstract: BackgroundWhile increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. In the present study, we sequenced at full-depth (≥30x) a moderately large (n=738) cohort of samples drawn from the Ashkenazi Jewish population across two platforms (Illumina X Ten and Complete Genomics, Inc.). We developed and refined a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population.ResultsFor samples sequenced on the Illumina X Ten platform, quality thresholds were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. The Complete Genomics, Inc. platform was more conservative (fewer variants called) compared to the Illumina platform, but also demonstrated relatively greater numbers of false positives that needed to be filtered. Quality control procedures also permitted detection of novel genome reads that are not mapped to current reference or alternate assemblies. After stringent quality control, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.ConclusionsOur primary results demonstrate enhanced accuracy of a population-specific imputation panel relative to cosmopolitan panels, especially in the range of infrequent (
Published: 2017

22. 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

23. Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes

Author: Vladimir Vacic, Mali Gana-Weisz, Eimear E. Kenny, Aviv Bergman, Ariel Darvasi, Nir Giladi, Avi Orr-Urtreger, Inga Peter, Harry Ostrer, Hakon Hakonarson, Alexander Gusev, Todd Lencz, Lorraine N. Clark, Laurie J. Ozelius, Deborah Raymond, Merav Kedmi, Susan B. Bressman, Anat Bar-Shira, Rachel Saunders-Pullman, Helen Mejia-Santana, Anat Mirelman, Tanya Gurevich, Nir Barzilai, Edward R. Burns, Saurav Guha, Karen Marder, Xinmin Liu, Robert J. Desnick, Gil Atzmon, and Itsik Pe'er
Subjects: Male, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Cohort Studies, Ethnicity, Genetics, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Genetics (clinical), Aged, Demography, Genetic association, Association Studies Articles, Haplotype, Chromosome Mapping, Reproducibility of Results, Parkinson Disease, General Medicine, Ashkenazi jews, Haplotypes, Genetic Loci, Cohort, Female, Genealogy and Heraldry, Genome-Wide Association Study, Founder effect
Abstract: The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.
Published: 2014

24. A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF

Author: Bruce E. Sands, Peter Legnani, Steven R. Brant, Maria T. Abreu, Robert J. Desnick, Manuel A. Rivas, Todd Lencz, Seth Lipka, Wei Zhang, Clara Abraham, Inga Peter, Beatrice M. Bowen, James F. George, Anthony W. Segal, Jody-Ann Facey, Jacob L. McCauley, Nicole Villaverde, Arthur Mortha, Joanne M. Stempak, Dalin Li, Ellen Scherl, Lisa W. Datta, Ken Y. Hui, Sok Meng Evelyn Ng, Yashoda Sharma, L Phillip Schumm, Mark J. Daly, Romain Remark, Talin Haritunians, Elena R. Schiff, Vincent Plagnol, Sacha Gnjatic, Alexander Gusev, Heriberto Fernandez-Hernandez, Judy H. Cho, Hakon Hakonarson, Ariel Darvasi, Itsik Pe'er, Stephan R. Targan, Alexio M. Muise, Nai Yun Hsu, Adam S. Cheifetz, Gil Atzmon, Mark S. Silverberg, Ling-Shiang Chuang, Dermot P.B. McGovern, Richard H. Duerr, Nir Barzilai, Jerome I. Rotter, Kaida Ning, Miriam Merad, Kent D. Taylor, Seymour Katz, Marla J. Dubinsky, Tramy Luong, Adam P. Levine, Nikolas Pontikos, Subramaniam Kugathasan, Hongyu Zhao, and Adeeb Rahman
Subjects: 0301 basic medicine, Male, medicine.disease_cause, Monocytes, Ethnic Variation, Immune tolerance, Cytokine Receptor Common beta Subunit, 0302 clinical medicine, Crohn Disease, Risk Factors, Granulocyte Colony-Stimulating Factor, Homeostasis, Frameshift Mutation, Mutation, biology, Gastroenterology, Ashkenazi jews, Intestines, Granulocyte macrophage colony-stimulating factor, medicine.anatomical_structure, 030211 gastroenterology & hepatology, Female, medicine.drug, Signal Transduction, Adenomatous polyposis coli, IBD, Clinical Sciences, Article, Frameshift mutation, Paediatrics and Reproductive Medicine, 03 medical and health sciences, medicine, Humans, Lamina propria, Hepatology, Gastroenterology & Hepatology, Macrophage Colony-Stimulating Factor, Monocyte, Risk Factor, Inflammatory Bowel Disease, Neurosciences, Genetic Variation, Granulocyte-Macrophage Colony-Stimulating Factor, digestive system diseases, 030104 developmental biology, Case-Control Studies, Jews, Immunology, biology.protein, Granulocytes
Abstract: Background & Aims Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. Methods We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony-stimulating factor 2–receptor β common subunit gene ( CSF2RB ). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and granulocyte-macrophage colony–stimulating factor–responsive cells were defined by adenomatous polyposis coli (APC) time-of-flight mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and the expression and functions of gene products were compared. Results In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB ( P = 8.52 × 10 -4 ); the finding was validated in the replication cohort (combined P = 3.42 × 10 -6 ). Incubation of intestinal lamina propria leukocytes with granulocyte-macrophage colony–stimulating factor resulted in high levels of phosphorylation of signal transducer and activator of transcription (STAT5) and lesser increases in phosphorylation of extracellular signal–regulated kinase and AK straining transforming (AKT). Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 after stimulation with granulocyte-macrophage colony–stimulating factor, compared with cells transfected with control CSF2RB, indicating a dominant-negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to granulocyte-macrophage colony–stimulating factor and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance. Conclusions In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB . Intestinal monocytes from carriers of this mutation had reduced responses to granulocyte-macrophage colony–stimulating factor, providing an additional mechanism for alterations to the innate immune response in individuals with CD.
Published: 2016

25. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women

Author: Kenneth S. Kendler, Sam X. Chen, Michael Conlon O'Donovan, Nicholas John Craddock, F. Anthony O'Neill, Jonathan Flint, Tao Li, Michal Bronstein, David A. Collier, Martina Johannesson, Daniel R. Weinberger, Ariel Darvasi, Cuie Sun, Dermot Walsh, Sagiv Shifman, and Michael John Owen
Subjects: Male, Cancer Research, Genome-wide association study, 0302 clinical medicine, Gene Frequency, Risk Factors, Homo (Human), Odds Ratio, Genetics(clinical), Genetics (clinical), Genetics, Extracellular Matrix Proteins, Sex Characteristics, 0303 health sciences, Serine Endopeptidases, Rs7341475, Middle Aged, 3. Good health, Schizophrenia, Female, Research Article, Adult, medicine.medical_specialty, lcsh:QH426-470, Cell Adhesion Molecules, Neuronal, Epigenetics of schizophrenia, Nerve Tissue Proteins, Biology, Neurological Disorders, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, Molecular genetics, mental disorders, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Allele, QH426, Molecular Biology, Alleles, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genome, Human, Genetic Variation, Genetics and Genomics, medicine.disease, R1, Introns, Human genetics, lcsh:Genetics, Reelin Protein, Case-Control Studies, Jews, RC0321, 030217 neurology & neurosurgery
Abstract: Sex differences in schizophrenia are well known, but their genetic basis has not been identified. We performed a genome-wide association scan for schizophrenia in an Ashkenazi Jewish population using DNA pooling. We found a female-specific association with rs7341475, a SNP in the fourth intron of the reelin (RELN) gene (p = 2.9 × 10−5 in women), with a significant gene-sex effect (p = 1.8 × 10−4). We studied rs7341475 in four additional populations, totaling 2,274 cases and 4,401 controls. A significant effect was observed only in women, replicating the initial result (p = 2.1 × 10−3 in women; p = 4.2 × 10−3 for gene-sex interaction). Based on all populations the estimated relative risk of women carrying the common genotype is 1.58 (p = 8.8 × 10−7; p = 1.6 × 10−5 for gene-sex interaction). The female-specific association between RELN and schizophrenia is one of the few examples of a replicated sex-specific genetic association in any disease., Author Summary Schizophrenia is a complex mental disease, which includes symptoms of delusions, hallucinations, disorganized speech, aberrant behavior, lack of emotional expression, diminished motivation, and social withdrawal. The cause of schizophrenia is unknown, but there is extensive evidence that genetics play a significant role in its aetiology. We studied the genetic basis of schizophrenia by analyzing around 500,000 genetic variants distributed across the whole human genome in DNA from schizophrenic patients and controls. We analyzed separately the DNA from men and women, and identified a genetic variant that increases the risk of developing schizophrenia in women only. The genetic variant is estimated to increase the risk of schizophrenia for women carrying the risk variant by 1.4-fold. The genetic variant is in a gene called reelin, which is known to play a part in brain development. However, it is still unclear how this genetic variant predisposes to schizophrenia nor why it is specific to women only.
Published: 2016

26. The time and place of European admixture in Ashkenazi Jewish history

Author: Ariel Darvasi, Todd Lencz, Shai Carmi, James Xue, and Itsik Pe'er
Subjects: 0301 basic medicine, Male, Cancer Research, Linkage disequilibrium, Heredity, Population genetics, Linkage Disequilibrium, Geographical Locations, 0302 clinical medicine, Ethnicities, Ashkenazi Jewish, 10. No inequality, Mendelian disorders, Genetics (clinical), media_common, High rate, Genetics, 0303 health sciences, education.field_of_study, Geography, Chromosome Biology, Simulation and Modeling, Genomics, Genealogy, Ashkenazi jews, Eastern european, Europe, Genetic Mapping, Female, Research Article, Gene Flow, lcsh:QH426-470, Population, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, White People, Chromosomes, 03 medical and health sciences, media_common.cataloged_instance, Humans, European union, education, Molecular Biology, Allele frequency, Ecology, Evolution, Behavior and Systematics, Historical Geography, 030304 developmental biology, Evolutionary Biology, Population Biology, Haplotype, Biology and Life Sciences, Cell Biology, lcsh:Genetics, 030104 developmental biology, Genetics, Population, Haplotypes, Jews, People and Places, Earth Sciences, Population Groupings, 030217 neurology & neurosurgery, Population Genetics, Founder effect
Abstract: The Ashkenazi Jewish (AJ) population is important in genetics due to its high rate of Mendelian disorders. AJ appeared in Europe in the 10th century, and their ancestry is thought to comprise European (EU) and Middle-Eastern (ME) components. However, both the time and place of admixture are subject to debate. Here, we attempt to characterize the AJ admixture history using a careful application of new and existing methods on a large AJ sample. Our main approach was based on local ancestry inference, in which we first classified each AJ genomic segment as EU or ME, and then compared allele frequencies along the EU segments to those of different EU populations. The contribution of each EU source was also estimated using GLOBETROTTER and haplotype sharing. The time of admixture was inferred based on multiple statistics, including ME segment lengths, the total EU ancestry per chromosome, and the correlation of ancestries along the chromosome. The major source of EU ancestry in AJ was found to be Southern Europe (≈60–80% of EU ancestry), with the rest being likely Eastern European. The inferred admixture time was ≈30 generations ago, but multiple lines of evidence suggest that it represents an average over two or more events, pre- and post-dating the founder event experienced by AJ in late medieval times. The time of the pre-bottleneck admixture event, which was likely Southern European, was estimated to ≈25–50 generations ago., Author summary The Ashkenazi Jewish population has resided in Europe for much of its 1000-year existence. However, its ethnic and geographic origins are controversial, due to the scarcity of reliable historical records. Previous genetic studies have found links to Middle-Eastern and European ancestries, but the admixture history has not been studied in detail yet, partly due to technical difficulties in disentangling signals from multiple admixture events. Here, we present an in-depth analysis of the sources of European gene flow and the time of admixture events by using multiple new and existing methods and extensive simulations. Our results suggest a model of at least two events of European admixture. One event slightly pre-dated a late medieval founder event and was likely from a Southern European source. Another event post-dated the founder event and likely occurred in Eastern Europe. These results, as well as the methods introduced, will be highly valuable for geneticists and other researchers interested in Ashkenazi Jewish origins.
Published: 2016

27. A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects

Author: Aiden Corvin, Kenneth S. Kendler, Jouko Lönnqvist, Patricia T. Michie, Stephanie H. Witt, Annelie Nordin, Robin M. Murray, Benjamin M. Neale, Dermot Walsh, Peter Holmans, Richard A. Belliveau, Jacques Mallet, Matthew C. Keller, Hugh Gurling, Joseph I. Friedman, Giulio Genovese, Andrew Pocklington, Lieuwe de Haan, Marcelo Bertalan, Noa Carrera, Brian Kelly, Lude Franke, Carlos N. Pato, Inez Myin-Germeys, Brandon Wormley, Nicholas John Craddock, Sven Cichon, Manuel Mattheisen, Annette M. Hartmann, Ole A. Andreassen, Masashi Ikeda, Madhusudan Gujral, Edward M. Scolnick, Jeffrey A. Lieberman, Elodie Drapeau, Deborah A. Nertney, Richard Bruggeman, Bertram Müller-Myhsok, Raquelle I. Mesholam-Gately, Ingrid Melle, Jacob Gratten, Ingrid Agartz, Frans Henskens, Stephanie Godard, Andres Metspalu, Mark Weiser, Johan G. Eriksson, Christian R. Marshall, Preben Bo Mortensen, Tõnu Esko, Sarah E. Bergen, Ina Giegling, Carmel M. Loughland, Stephen W. Scherer, Panos Roussos, Colm McDonald, Douglas F. Levinson, David Cohen, Martilias S. Farrell, James J. Crowley, Sibylle G. Schwab, Stephanie Williams, Henrik B. Rasmussen, Wei Cheng, Ann Olincy, Anders D. Børglum, Andreas J. Forstner, Wenting Wu, Benedicto Crespo-Facorro, David J. Kavanagh, Aniket Shetty, Thomas Werge, Daniel P. Howrigan, Gary Donohoe, Stephan Ripke, Jo Knight, Michael Conlon O'Donovan, Erik Söderman, Luba Kalaydjieva, Silviu Alin Bacanu, Dragan M. Svrakic, Brion S. Maher, Alexander Richards, Digby Quested, Eadbhard O' Callaghan, René S. Kahn, Lili Milani, Karin V. Fuentes Fajarado, Mark Hansen, Douglas S. Greer, Sandra Meier, S. Hong Lee, Markus M. Nöthen, Brendan Bulik-Sullivan, Guiqing Cai, Lynn E. DeLisi, Thomas Hansen, Bernard Lerer, Jubao Duan, James T.R. Walters, Ulrich Schall, Ole Mors, Kai-How Farh, Randy L. Buckner, Andrew M. McIntosh, Kung-Yee Liang, Olli Pietiläinen, Colm O. Dushlaine, Paola Giusti-Rodríguez, Srdjan Djurovic, Jaana Suvisaari, Carin J. Meijer, Christos Pantelis, Peter Eichhammer, Nancy G. Buccola, Kristin K. Nicodemus, Phil Lee, Zhouzhi Wang, Dominique Campion, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Dan Rujescu, Joshua R. Atkins, Naomi R. Wray, Michael Davidson, Michele T. Pato, Brien P. Riley, Tim B. Bigdeli, Patrik K. E. Magnusson, Aaron R. Wolen, Srinivas Thirumalai, Vahram Haroutunian, Joshua L. Roffman, Tiina Paunio, K Kähler Anna, Thomas G. Schulze, Assen Jablensky, Andrew McQuillin, Kimberley D. Chambert, John Powell, Douglas Blackwood, Ditte Demontis, Daniele Merico, Stefan Herms, Tune H. Pers, Bryan J. Mowry, Eric Strengman, Larry J. Seidman, Pablo V. Gejman, Laura Nisenbaum, Bettina Konte, Jennifer L. Moran, Donald W. Black, Michael Gill, Line Olsen, Aarno Palotie, Robert Freedman, Dalila Pinto, Abraham Reichenberg, Qingqin S. Li, Ann E. Pulver, Mark Reimers, Jurgen Del Favero, Murray J. Cairns, Patrick F. Sullivan, Deborah L. Levy, John L. Waddington, Menachem Fromer, Marcella Rietschel, Jonathan Sebat, Rolf Adolfsson, George Kirov, Veikko Salomaa, David Curtis, Rodney J. Scott, Jin P. Szatkiewicz, Jacqueline I. Goldstein, Tracey L. Petryshen, Nelson B. Freimer, Mads V. Hollegaard, Franziska Degenhardt, David M. Hougaard, Dimitris Dikeos, Pamela Sklar, Diana O. Perkins, Shaun Purcell, Yunjung Kim, Laurent Essioux, Dheeraj Malhotra, Wolfgang Maier, Eli A. Stahl, Per Hoffmann, David A. Collier, Farooq Amin, Juha Karjalainen, William M. Brandler, Clement C. Zai, A. Hofman, Nigel Williams, Hailiang Huang, Joseph D. Buxbaum, Danielle Posthuma, Kieran C. Murphy, Jonathan Pimm, Bradley T. Webb, Joel N. Hirschhorn, Elvira Bramon, Timothy G. Dinan, Jana Strohmaier, Wiepke Cahn, Erik G. Jönsson, F. Anthony O’ Neill, Dieter B. Wildenauer, Michael John Owen, Igor Nenadic, Vaughan J. Carr, Esben Agerbo, Younes Mokrab, Morten Mattingsdal, Elliot S. Gershon, Danny Antaki, Jim van Os, Bhooma Thiruvahindrapuram, Alan R. Sanders, Sang-Yun Oh, Alkes L. Price, Vihra Milanova, Juha Veijola, Chris C. A. Spencer, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Kenneth L. Davis, Jing Qin Wu, Robert W. McCarley, Steven A. McCarroll, Derek W. Morris, Douglas M. Ruderfer, Josef Frank, C. Robert Cloninger, George N. Papadimitriou, Paul Cormican, Lyudmila Georgieva, Enrico Domenici, Claudine Laurent, James L. Kennedy, Frank Dudbridge, Peter M. Visscher, Valentina Escott-Price, Inge Joa, Marian L. Hamshere, Jianxin Shi, Margot Albus, Jordan W. Smoller, Adam Savitz, T. Scott Stroup, Elizabeth Bevilacqua, James A. Knowles, William Byerley, Madeline Alexander, Stanley V. Catts, David St Clair, Sophie E. Legge, Roel A. Ophoff, Gerald Nestadt, Paul A. Tooney, and Ayman H. Fanous
Subjects: Genetics, 0303 health sciences, Genomics, Biology, medicine.disease, Genome, Phenotype, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, Cohort, Etiology, medicine, Copy-number variation, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e −15 ), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e −6 ). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e −11 ) and neurobehavioral phenotypes in mouse (OR = 1.18, P=7.3e −5 ). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).
Published: 2016

28. Genetic architecture of prostate cancer in the Ashkenazi Jewish population

Author: William D. Foulkes, Kenneth Offit, Saurav Guha, Todd Lencz, Tomas Kirchhoff, David J. Gallagher, Robert J. Klein, Joseph Vijai, Ariel Darvasi, and N Hamel
Subjects: Male, Cancer Research, Linkage disequilibrium, Genotype, Population, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, Humans, Genetic Predisposition to Disease, education, Allele frequency, Genetics, education.field_of_study, Genetic heterogeneity, Haplotype, Prostatic Neoplasms, Genetics and Genomics, prostate cancer, Ashkenazi jews, Oncology, association studies, Case-Control Studies, Jews, SNPs, Genome-Wide Association Study
Abstract: Recent studies have identified numerous single nucleotide polymorphisms (SNPs) that modify an individual's risk of developing prostate cancer (Amundadottir et al, 2006; Eeles et al, 2008; Gudmundsson et al, 2007a; Gudmundsson et al, 2008; Gudmundsson et al, 2007b; Haiman et al, 2007; Robbins et al, 2007; Thomas et al, 2008). Although some investigators have considered the possibility of heterogeneity between ethnic groups, where a SNP shows a different effect on prostate cancer risk depending on the population being studied, these studies only considered ethnic groups with different continents of ancestral origins (Haiman et al, 2007; Waters et al, 2009; Yamada et al, 2009; Hooker et al, 2010; Zheng et al, 2010). As alleles of numerous SNPs are known to vary in frequency across Europe (Bersaglieri et al, 2004), and population substructure is consistently observed in Americans with ancestry from different locations in Europe (Price et al, 2008; Tian et al, 2008), there is a possibility that prostate cancer risk alleles may have different effects in different populations of European ancestry. Ashkenazi Jews are Jews whose ancestors come primarily from central and eastern Europe; the majority of North American Jews and a large proportion of Israeli Jews are of Ashkenazi ancestry. The global linkage disequilibrium (LD) profiles of the Ashkenazi Jewish (AJ) population do not seem to differ significantly from that of other populations of European ancestry. However, it has been suggested that there may be significant local differences in allele frequencies and haplotype structure between the Ashkenazi population and other European populations, including at loci associated with common cancer (Gold et al, 2008; Olshen et al, 2008; Price et al, 2008; Tian et al, 2008). Therefore, examination of known prostate cancer risk SNPs in the AJ population provides a unique opportunity to test for genetic heterogeneity at these loci among individuals of European ancestry. Here, we report the results of a case–control association study in the AJ population of 29 previously identified prostate cancer SNPs. Our data argue against the hypothesis that risk alleles for prostate cancer generally have different effects in the Ashkenazi and non-Ashkenazi European ancestry populations.
Published: 2011

29. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2

Author: Anna-Karin Persson, Martin Michaelis, Anne Minert, Kaj Fried, Merav Abitbul-Yarkoni, Anne Pisanté, Ariel Darvasi, Ze'ev Seltzer, Mathias Gebauer, Erez Shabo, Tina Elahipanah, Marshall Devor, Jonathan Nissenbaum, Ruslan Dorfman, Michael Tal, Benjamin Yakir, Hagai Y. Shpigler, Yan Lu, and Sonia delCanho
Subjects: Genotype, Quantitative Trait Loci, Mice, Inbred Strains, Quantitative trait locus, Bioinformatics, Cohort Studies, Mice, Chromosome 15, Genetics, medicine, Genetic predisposition, Animals, Humans, Genetic Predisposition to Disease, Genetics (clinical), Polymorphism, Genetic, biology, CACNG2, Research, Chronic pain, Nerve injury, medicine.disease, biology.organism_classification, Phenotype, Spinal Nerves, Neuropathic pain, biology.protein, Neuralgia, Female, Calcium Channels, medicine.symptom, Stargazer
Abstract: Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes for stargazin, a protein intimately involved in the trafficking of glutamatergic AMPA receptors. The protein might also be a Ca2+ channel subunit. CACNG2 has previously been implicated in epilepsy. Initially, using two fine-mapping strategies in a mouse model (recombinant progeny testing [RPT] and recombinant inbred segregation test [RIST]), we mapped a pain-related quantitative trait locus (QTL) (Pain1) into a 4.2-Mb interval on chromosome 15. This interval includes 155 genes. Subsequently, bioinformatics and whole-genome microarray expression analysis were used to narrow the list of candidates and ultimately to pinpoint Cacng2 as a likely candidate. Analysis of stargazer mice, a Cacng2 hypomorphic mutant, provided electrophysiological and behavioral evidence for the gene's functional role in pain processing. Finally, we showed that human CACNG2 polymorphisms are associated with chronic pain in a cohort of cancer patients who underwent breast surgery. Our findings provide novel information on the genetic basis of neuropathic pain and new insights into pain physiology that may ultimately enable better treatments.
Published: 2010

30. Correlational Analysis for Identifying Genes whose Regulation Contributes to Chronic Neuropathic Pain

Author: Suzana Jordan, Ariel Darvasi, Anke M. Schulte, Anna-Karin Persson, Kaj Fried, Christiane Metz-Weidmann, Hans-Christoph Schneider, Xiao-Jun Xu, Mathias Gebauer, Marshall Devor, Danping Ding-Pfennigdorff, Zsuzsanna Wiesenfeld-Hallin, and Jonas Thun
Subjects: Candidate gene, Pain medicine, TRPM Cation Channels, In situ hybridization, Sodium Channels, Mice, Cellular and Molecular Neuroscience, Species Specificity, Dorsal root ganglion, Ganglia, Spinal, lcsh:Pathology, medicine, Animals, RNA, Messenger, NAV1.9 Voltage-Gated Sodium Channel, Regulation of gene expression, Microarray analysis techniques, business.industry, Research, Gene Expression Profiling, Neuropeptides, Gene expression profiling, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Gene Expression Regulation, Neuropathic pain, Neuralgia, Molecular Medicine, business, Neuroscience, lcsh:RB1-214
Abstract: Background Nerve injury-triggered hyperexcitability in primary sensory neurons is considered a major source of chronic neuropathic pain. The hyperexcitability, in turn, is thought to be related to transcriptional switching in afferent cell somata. Analysis using expression microarrays has revealed that many genes are regulated in the dorsal root ganglion (DRG) following axotomy. But which contribute to pain phenotype versus other nerve injury-evoked processes such as nerve regeneration? Using the L5 spinal nerve ligation model of neuropathy we examined differential changes in gene expression in the L5 (and L4) DRGs in five mouse strains with contrasting susceptibility to neuropathic pain. We sought genes for which the degree of regulation correlates with strain-specific pain phenotype. Results In an initial experiment six candidate genes previously identified as important in pain physiology were selected for in situ hybridization to DRG sections. Among these, regulation of the Na+ channel α subunit Scn11a correlated with levels of spontaneous pain behavior, and regulation of the cool receptor Trpm8 correlated with heat hypersensibility. In a larger scale experiment, mRNA extracted from individual mouse DRGs was processed on Affymetrix whole-genome expression microarrays. Overall, 2552 ± 477 transcripts were significantly regulated in the axotomized L5DRG 3 days postoperatively. However, in only a small fraction of these was the degree of regulation correlated with pain behavior across strains. Very few genes in the “uninjured” L4DRG showed altered expression (24 ± 28). Conclusion Correlational analysis based on in situ hybridization provided evidence that differential regulation of Scn11a and Trpm8 contributes to across-strain variability in pain phenotype. This does not, of course, constitute evidence that the others are unrelated to pain. Correlational analysis based on microarray data yielded a larger “look-up table” of genes whose regulation likely contributes to pain variability. While this list is enriched in genes of potential importance for pain physiology, and is relatively free of the bias inherent in the candidate gene approach, additional steps are required to clarify which transcripts on the list are in fact of functional importance.
Published: 2009

31. Sex-specific variability and a ‘cage effect’ independently mask a neuropathic pain quantitative trait locus detected in a whole genome scan

Author: Benjamin Yakir, Ariel Darvasi, Anne Minert, Marshall Devor, Anne Pisanté, Amit Gilad, Pnina Raber, Jonathan Nissenbaum, and Michal Arbilly
Subjects: Genetics, Chromosome 15, General Neuroscience, Strain (biology), Genetic variation, Threshold of pain, Genome Scan, Quantitative trait locus, Biology, Autotomy, Sex characteristics
Abstract: Sex and environment may dramatically affect genetic studies, and thus should be carefully considered. Beginning with two inbred mouse strains with contrasting phenotype in the neuroma model of neuropathic pain (autotomy), we established a backcross population on which we conducted a genome-wide scan. The backcross population was partially maintained in small social groups and partially in isolation. The genome scan detected one previously reported quantitative trait locus (QTL) on chromosome 15 (pain1), but no additional QTLs were found. Interestingly, group caging introduced phenotypic noise large enough to completely mask the genetic effect of the chromosome 15 QTL. The reason appears to be that group-caging animals from the low-autotomy strain together with animals from the high-autotomy strain dramatically increases autotomy in the otherwise low-autotomy mice (males or females). The converse, suppression of pain behaviour in the high-autotomy strain when caged with the low-autotomy strain was also observed, but only in females. Even in isolated mice, the genetic effect of the chromosome 15 QTL was significant only in females. To determine why, we evaluated autotomy levels of females in 12 different inbred stains of mice and compared them to previously reported levels for males. Strikingly larger environmental variation was observed in males than in females for this pain phenotype. The high baseline variance in males can explain the difficulty in detecting the genetic effect, which was readily seen in females. Our study emphasizes the importance of sex and environment in the genetic analysis of pain.
Published: 2007

32. An Integrated in Silico Gene Mapping Strategy in Inbred Mice

Author: Christopher Mader, Mohammad Fallahi, Alessandra C. L. Cervino, Nicholas F. Tsinoremas, and Ariel Darvasi
Subjects: Genetics, Candidate gene, Genome, Models, Genetic, In silico, Strain (biology), Quantitative Trait Loci, Chromosome Mapping, Mice, Inbred Strains, Investigations, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Mice, Haplotypes, Gene mapping, Databases, Genetic, Animals, SNP, Computer Simulation, Gene, Algorithms
Abstract: In recent years in silico analysis of common laboratory mice has been introduced and subsequently applied, in slightly different ways, as a methodology for gene mapping. Previously we have demonstrated some limitation of the methodology due to sporadic genetic correlations across the genome. Here, we revisit the three main aspects that affect in silico analysis. First, we report on the use of marker maps: we compared our existing 20,000 SNP map to the newly released 140,000 SNP map. Second, we investigated the effect of varying strain numbers on power to map QTL. Third, we introduced a novel statistical approach: a cladistic analysis, which is well suited for mouse genetics and has increased flexibility over existing in silico approaches. We have found that in our examples of complex traits, in silico analysis by itself does fail to uniquely identify quantitative trait gene (QTG)-containing regions. However, when combined with additional information, it may significantly help to prioritize candidate genes. We therefore recommend using an integrated work flow that uses other genomic information such as linkage regions, regions of shared ancestry, and gene expression information to obtain a list of candidate genes from the genome.
Published: 2007

33. Mice congenic for a locus that determines phenotype in the neuroma model of neuropathic pain

Author: Pnina Raber, Ariel Darvasi, Marshall Devor, and Sonia del Canho
Subjects: Male, Quantitative Trait Loci, Congenic, Mice, Inbred Strains, Locus (genetics), Selective breeding, Mice, Mice, Congenic, Neuroma, Sex Factors, Developmental Neuroscience, Peripheral Nervous System Neoplasms, medicine, Animals, Selection, Genetic, Gene, Genetics, business.industry, Chronic pain, Chromosome Mapping, medicine.disease, Phenotype, Disease Models, Animal, Animals, Newborn, Neurology, Neuropathic pain, Neuralgia, Female, business, Neuroscience
Abstract: A common strategy for identifying physiological processes responsible for pain is to compare animal strains that show high versus low pain phenotype. However, this approach yields only weak inference because most strains differ from one another at a large number of genetic loci. We undertook a congenic breeding program aimed at transposing the gene(s) that confers dominant (low) pain phenotype in the neuroma model of neuropathic pain from mice of the C58/J strain onto a genetic background that normally expresses high pain phenotype (C3H/HeN). Successful transposition, and the observation of equal numbers of phenotypically high and low offspring in each of 11 generations of selective breeding, provides evidence that the trait is largely controlled by a single gene (or linked cluster) of major effect.
Published: 2006

34. A complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia

Author: Michal Bronstein, Ariel Darvasi, Ruth Navon, Avraham Weizman, Benjamin Yakir, Mao-Liang Chen, Chia-Hsiang Chen, Anat Levit, and Sagiv Shifman
Subjects: Male, Psychosis, Linkage disequilibrium, Chromosomes, Human, Pair 22, Population, Biology, Catechol O-Methyltransferase, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Cohort Studies, Genetics, medicine, Animals, Humans, SNP, Genetic Predisposition to Disease, education, Gene, Alleles, Genetics (clinical), Clozapine, Genetic association, education.field_of_study, Membrane Glycoproteins, Brain, Membrane Proteins, medicine.disease, Rats, Gene Expression Regulation, Platelet Glycoprotein GPIb-IX Complex, Schizophrenia, Case-Control Studies, Jews, Female, Chromosome Deletion, Antipsychotic Agents, medicine.drug
Abstract: Several lines of evidence have established the presence of an association between a 3-Mb deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs.
Published: 2006

35. Further tests of the association between schizophrenia and single nucleotide polymorphism markers at the catechol-O-methyltransferase locus in an Askenazi Jewish population using microsatellite markers

Author: Anne Pisanté, Anat Horowitz, Nehama Rivlin, Ariel Darvasi, and Sagiv Shifman
Subjects: Genetic Markers, Linkage disequilibrium, Population, Single-nucleotide polymorphism, Locus (genetics), Biology, Catechol O-Methyltransferase, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Genetics, Humans, Polymorphic Microsatellite Marker, education, Genotyping, Biological Psychiatry, Genetics (clinical), DNA Primers, Genetic association, education.field_of_study, Base Sequence, Psychiatry and Mental health, Jews, Schizophrenia, Microsatellite, Microsatellite Repeats
Abstract: Association studies are now primarily being conducted with single nucleotide polymorphisms because they are present everywhere in the genome and can be genotyped in "high throughput" formats. Microsatellite markers have a higher degree of polymorphism than single nucleotide polymorphisms and have been widely used in both linkage and association studies of disease. Polymorphic microsatellite markers with several alleles can readily detect linkage disequilibrium but at any given locus there may be differences between single nucleotide polymorphisms and microsatellites in their power to detect linkage disequilibrium because of the evolutionary history of the locus, especially the rate at which both the single nucleotide polymorphisms and microsatellite polymorphisms have mutated and the number of disease mutations and their history. In the current study, we examined the efficiency of microsatellite markers in association analysis by looking at all existent microsatellite markers in the catechol-O-methyltransferase gene region and by genotyping these microsatellites in a large cohort of schizophrenia patients and healthy controls, a subset of a sample where catechol-O-methyltransferase and schizophrenia were found to be associated. We also estimated the levels of linkage disequilibrium between these microsatellites and the previously reported single nucleotide polymorphisms (within the catechol-O-methyltransferase gene) found to be associated with schizophrenia. A modest allelic association of P=0.041 was found between schizophrenia and the microsatellite marker D22S944, which was not significant, however, when corrected for all microsatellites tested. Nevertheless, significant linkage disequilibrium was found between this marker and the three single nucleotide polymorphisms within the catechol-O-methyltransferase gene that displayed association with the disease in the previously published research on this sample. Significant linkage disequilibrium was also observed between microsatellites up to approximately 300 kb distant from those single nucleotide polymorphisms. Although significant, the extent of linkage disequilibrium in terms of r2 was small (in the order of 0.01).
Published: 2005

36. COMT: A common susceptibility gene in bipolar disorder and schizophrenia

Author: Eilat Shinar, Moshe Kotler, Anne Pisanté, Avraham Weizman, Benjamin Yakir, Michal Bronstein, Rael D. Strous, Richard Schiffer, Marnina Swartz-Vanetik, Baruch Spivak, Leon Karp, Haim Y. Knobler, Naomi B. Zak, Sagiv Shifman, Ariel Darvasi, Ilya Reznik, Nimrod Grisaru, and Meira Sternfeld
Subjects: Genetics, Psychosis, Catechol-O-methyl transferase, business.industry, fungi, Haplotype, medicine.disease, behavioral disciplines and activities, Ashkenazi jews, Cellular and Molecular Neuroscience, Psychiatry and Mental health, nervous system, Schizophrenia, mental disorders, medicine, Bipolar disorder, business, Allele frequency, Genetics (clinical), Psychiatric genetics
Abstract: A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits.
Published: 2004

37. The Collaborative Cross, a community resource for the genetic analysis of complex traits

Author: Linda D. Siracusa, Bastien Llamas, Lisa M. Tarantino, William Valdar, Aldons J. Lusis, Siming Shou, Fuad A. Iraqi, Dabao Zhang, Alexander V. Osadchuk, Frank Lammert, Heinz Himmelbauer, Boris Ivandic, Zonghua Qi, Daniel R. Prows, Willam D. Beavis, Kari J. Buck, Pedro R. Lowenstein, Ariel Darvasi, Fei Zou, Leena Peltonen-Palotie, J. M. Lassalle, James M. Cheverud, Roger H. Reeves, Karen L. Svenson, Howard K. Gershenfeld, Molly A. Bogue, Hans-Willem Snoeck, Nancy L. Hayes, John C. Roder, Karl J. Jepsen, Guy Mittleman, Robert Hitzemann, Howard J. Jacob, Jiri Forejt, Juan F. Medrano, Craig Heller, Richard Mott, Joe M. Angel, Gerald de Haan, Fernando Pardo-Manuel de Villena, Michal Pravenec, Grant Morahan, Kenneth F. Manly, Beverly Paigen, Weikuan Gu, Steve Whatley, Glenn D. Rosen, Kent W. Hunter, Gerd Kempermann, Christina Kendziorski, Margit Burmeister, Jing Gu, Hui-Chen Hsu, Hooman Allayee, Steven J. Clapcote, R. Frank Kooy, Christian F. Deschepper, Linda A. Toth, Rebecca W. Doerge, Ritsert C. Jansen, Ralph S. Marcucio, Steven J. Garlow, John C. Crabbe, Elissa J. Chesler, Beth Bennett, André Bleich, Nengjun Yi, Tom Wiltshire, Kazuhiro Shimomura, Roger D. Cox, Wim E. Crusio, Lu Lu, Hiroki Nagase, Joseph H. Nadeau, Doug Matthews, Leonard C. Schalkwyk, Jeremy L. Peirce, Dabney K. Johnson, Richard S. Nowakowski, Jackson Beatty, Terry Gordon, Beverly A. Mock, Eric E. Schadt, David C. Airey, Wade H. Berrettini, Charles R. Farber, Mikko J. Sillanpää, Xavier Montagutelli, Gary A. Churchill, Jimmy L. Spearow, Daniel Gaile, Darla R. Miller, Huei Ju Pan, Grier P. Page, Melloni N. Cook, Malak Kotb, Thomas E. Johnson, Min Zhang, Karl W. Broman, Hartmut Geiger, David G. Morris, Ze'ev Seltzer, Craig H Warden, Alan D. Attie, Edward S. Buckler, Abraham A. Palmer, Robert W. Williams, David W. Threadgill, John K. Belknap, Jeffrey S. Mogil, Daniel Pomp, Kenneth Paigen, Bruce F. O'Hara, Faculty of Science and Engineering, Groningen Biomolecular Sciences and Biotechnology, Bioinformatics, Faculteit Medische Wetenschappen/UMCG, and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Mice, Inbred Strains, Disease, Breeding, Biology, Community Networks, Genetic analysis, 03 medical and health sciences, Human health, 0302 clinical medicine, Databases, Genetic, Genetics, Animals, Humans, Systems genetics, Crosses, Genetic, 030304 developmental biology, Recombination, Genetic, 0303 health sciences, ENVIRONMENT, business.industry, STRAINS, Health services research, Data science, Biotechnology, MICE, Community resource, Trait, Health Resources, Health Services Research, business, 030217 neurology & neurosurgery
Abstract: The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact potygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.
Published: 2004

38. Population-based gene discovery in psychiatric diseases

Author: Ariel Darvasi, Anne Pisanté-Shalom, and Naomi B. Zak
Subjects: Genetics, education.field_of_study, medicine.medical_specialty, General Neuroscience, Population, Haplotype, Single-nucleotide polymorphism, Biology, medicine.disease, Schizophrenia, Pharmacogenomics, medicine, Pharmacology (medical), Neurology (clinical), education, Psychiatry, Genotyping, Gene, Genetic association
Abstract: There is strong evidence that psychiatric disorders, such as schizophrenia and bipolar, have a significant genetic component. Yet, despite many attempts, the susceptibility genes that predispose to these illnesses have not been revealed. We describe an approach to the discovery of genes involved in such complex diseases. The prospect of gene discovery is optimized by considering elements, such as the applicability of a family- versus population-based paradigm, sample size and use of an isolated population. We suggest that a high level of statistical significance can be achieved by efficient scanning of a dense map of polymorphisms followed by intensive genotyping of informative variations and haplotype analysis.
Published: 2003

39. Peak morphological diversity in an ecotone unveiled in the chukar partridge by a novel Estimator in a Dependent Sample (EDS)

Author: Imanuel Noy-Meir, Rachel Nissani, Ariel Darvasi, Salit Kark, Uriel N. Safriel, and Tapan Mukerji
Subjects: Genetic diversity, Phenotypic plasticity, Ecology, Range (biology), media_common.quotation_subject, Ecotone, respiratory system, Biology, Biodiversity hotspot, Divergence, Genetic algorithm, Animal Science and Zoology, human activities, Ecology, Evolution, Behavior and Systematics, Diversity (politics), media_common
Abstract: 1. Areas of environmental transition (i.e. ecotones) have recently been shown to play an important role in the maintenance of genetic diversity, divergence and in speciation processes. We test the hypothesis that ecotone populations maintain high phenotypic diversity compared to other populations across the distribution range.
Published: 2002

40. [Untitled]

Author: Ralph McGinnis, Sagiv Shifman, and Ariel Darvasi
Subjects: Genetics, Linkage disequilibrium, Biology, Population stratification, Power (physics), Sample size determination, Relative risk, Statistics, Allele, Association (psychology), Allele frequency, Genetics (clinical), Ecology, Evolution, Behavior and Systematics
Abstract: Sample size required for the TDT and the case-control designs was studied for marker-based genome-wide scans for disease association. The influence of various parameters on sample size required to attain a given level of power was analyzed in detail. Small genotypic relative risks, low levels of linkage disequilibrium, and departure from equal frequencies for the disease allele and associated marker allele, significantly and similarly increase sample size required by either the TDT or case-control design. Under the case-control paradigm, we show that the optimal strategy will often be to collect many more control individuals than disease cases with the optimal ratio depending on the relative cost of acquiring cases as compared to controls. For the TDT, the number of required simplex families is virtually equal to the number of cases required for similar power in case-control studies with an equal number of cases and controls. The case-control approach may therefore prove to be more economical and expeditious than the TDT design for diseases in which the cost and time required to collect simplex families is much greater than that needed to acquire isolated disease cases. Nevertheless, possible population stratification needs to be addressed when the case-control design is applied.
Published: 2002

41. SNP-microarrays can accurately identify the presence of an individual in complex forensic DNA mixtures

Author: Lev Voskoboinik, Sheri B. Ayers, Ariel Darvasi, and Aaron K. LeFebvre
Subjects: Genetics, Forensic Genetics, Likelihood Functions, Microarray, Homozygote, Single-nucleotide polymorphism, Computational biology, DNA, Biology, Polymorphism, Single Nucleotide, Statistical power, Pathology and Forensic Medicine, Forensic dna, SNP, Humans, DNA microarray, Mass disaster, Alleles, SNP array
Abstract: Common forensic and mass disaster scenarios present DNA evidence that comprises a mixture of several contributors. Identifying the presence of an individual in such mixtures has proven difficult. In the current study, we evaluate the practical usefulness of currently available "off-the-shelf" SNP microarrays for such purposes. We found that a set of 3000 SNPs specifically selected for this purpose can accurately identify the presence of an individual in complex DNA mixtures of various compositions. For example, individuals contributing as little as 5% to a complex DNA mixture can be robustly identified even if the starting DNA amount was as little as 5.0ng and had undergone whole-genome amplification (WGA) prior to SNP analysis. The work presented in this study represents proof-of-principle that our previously proposed approach, can work with real "forensic-type" samples. Furthermore, in the absence of a low-density focused forensic SNP microarray, the use of standard, currently available high-density SNP microarrays can be similarly used and even increase statistical power due to the larger amount of available information.
Published: 2014

42. Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins

Author: Kenneth Offit, Christine Van Broeckhoven, Guy Froyen, Itsik Pe'er, Shai Carmi, Semanti Mukherjee, Saurav Guha, Gil Atzmon, Todd Lencz, Ken Y. Hui, Inga Peter, Xinmin Liu, Ariel Darvasi, Ethan Kochav, Tinu Thomas, Kinnari Upadhyay, Judy H. Cho, Fillan Grady, Danny Ben-Avraham, Nir Barzilai, Marc Cruts, Lorraine N. Clark, Diether Lambrechts, Harry Ostrer, James Xue, Joseph Vijai, Laurie J. Ozelius, B. Monica Bowen, Philip Van Damme, Stéphane Plaisance, Susan B. Bressman, and Herwig Van Marck
Subjects: Adult, Male, Demographic history, Population, General Physics and Astronomy, Genomics, Biology, Identity by descent, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, White People, Article, Gene Frequency, Humans, education, Allele frequency, Aged, Genetics, Aged, 80 and over, education.field_of_study, Multidisciplinary, Genome, Genetic Variation, General Chemistry, Sequence Analysis, DNA, Middle Aged, Ashkenazi jews, Healthy Volunteers, Genetics, Population, Jews, Female, Metagenomics, Genetic isolate, Engineering sciences. Technology, Imputation (genetics)
Abstract: The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈12–25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum., Ashkenazi Jews are a genetically isolated population with distinct patterns of genetic diversity. Here, the authors sequence the genomes of 128 Ashkenazi Jewish individuals and use the sequence information to provide insight into the population's European and Middle Eastern origins.
Published: 2014

43. Excess of homozygosity in the major histocompatibility complex in schizophrenia

Author: Anil K. Malhotra, Todd Lencz, Ariel Darvasi, Semanti Mukherjee, Masashi Ikeda, Nakao Iwata, Itsik Pe'er, and Saurav Guha
Subjects: Genotype, Ubiquitin-Protein Ligases, Population, Genome-wide association study, Runs of Homozygosity, Major histocompatibility complex, Major Histocompatibility Complex, Tripartite Motif Proteins, Asian People, Japan, Histocompatibility Antigens, MHC class I, Genetics, Humans, Allele, education, Molecular Biology, Genetics (clinical), education.field_of_study, biology, HLA-A Antigens, Homozygote, Association Studies Articles, Intracellular Signaling Peptides and Proteins, General Medicine, Ashkenazi jews, Histocompatibility, DNA-Binding Proteins, Case-Control Studies, biology.protein, Schizophrenia, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) in schizophrenia have focused on additive allelic effects to identify disease risk loci. In order to examine potential recessive effects, we applied a novel approach to identify regions of excess homozygosity in an ethnically homogenous cohort: 904 schizophrenia cases and 1640 controls drawn from the Ashkenazi Jewish (AJ) population. Genome-wide examination of runs of homozygosity identified an excess in cases localized to the major histocompatibility complex (MHC). To refine this signal, we used the recently developed GERMLINE algorithm to identify chromosomal segments shared identical-by-descent (IBD) and compared homozygosity at such segments in cases and controls. We found a significant excess of homozygosity in schizophrenia cases compared with controls in the MHC (P-value = 0.003). An independent replication cohort of 548 schizophrenia cases from Japan and 542 matched healthy controls demonstrated similar effects. The strongest case-control recessive effects (P = 8.81 × 10(-8)) were localized to a 53-kb region near HLA-A, in a segment encompassing three poorly annotated genes, TRIM10, TRIM15 and TRIM40. At the same time, an adjacent segment in the Class I MHC demonstrated clear additive effects on schizophrenia risk, demonstrating the complexity of association in the MHC and the ability of our IBD approach to refine localization of broad signals derived from conventional GWAS. In sum, homozygosity in the classical MHC region appears to convey significant risk for schizophrenia, consistent with the ecological literature suggesting that homozygosity at the MHC locus may be associated with vulnerability to disease.
Published: 2014

44. 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

45. Experimental strategies for the genetic dissection of complex traits in animal models

Author: Ariel Darvasi
Subjects: Genetic dissection, Models, Genetic, ved/biology, ved/biology.organism_classification_rank.species, Chromosome Mapping, food and beverages, Computational biology, Biology, Quantitative trait locus, Qtl analysis, Mice, Quantitative Trait, Heritable, Gene mapping, Chromosome (genetic algorithm), Research Design, Genetics, Trait, Animals, Humans, Model organism, Function (biology)
Abstract: Current success in detecting complex trait loci in general, and quantitative trait loci (QTLs) using model organisms in particular, has attracted major biological and biomedical interest. The potential ability to identify genes and their function provides opportunities for new diagnostics and treatments of complex genetic diseases. Despite the success in gene mapping, however, cloning of complex trait loci or QTLs is not straightforward. A major obstacle lies in achieving fine mapping resolution for the detected loci. Compared to the rapid development of sophisticated statistical and molecular tools, development and analysis of experimental designs for various stages in QTL mapping experiments have barely been considered. In this study, novel and existing experimental strategies for QTL analysis are presented and evaluated.
Published: 1998

46. An integrative approach for the identification of quantitative trait loci

Author: Anne Pisanté, Ariel Darvasi, Michal Arbilly, and Marshall Devor
Subjects: Genetics, Candidate gene, Gene Expression Profiling, Quantitative Trait Loci, Chromosome Mapping, Computational Biology, Genomics, General Medicine, Computational biology, Quantitative trait locus, Biology, Genetic architecture, Mice, Gene mapping, Family-based QTL mapping, Inclusive composite interval mapping, Trait, Animals, Animal Science and Zoology, Association mapping
Abstract: The genetic dissection of complex traits is one of the most difficult and most important challenges facing science today. We discuss here an integrative approach to quantitative trait loci (QTL) mapping in mice. This approach makes use of the wealth of genetic tools available in mice, as well as the recent advances in genome sequence data already available for a number of inbred mouse strains. We have developed mapping strategies that allow a stepwise narrowing of a QTL mapping interval, prioritizing candidate genes for further analysis with the potential of identifying the most probable candidate gene for the given trait. This approach integrates traditional mapping tools, fine mapping tools, sequence-based analysis, bioinformatics and gene expression.
Published: 2006

47. Inheritance and Mapping of Compact (Cmpt), a New Mutation Causing Hypermuscularity in Mice

Author: Géza Müller, Morris Soller, László Varga, Miklós Sass, Gyula Szabó, and Ariel Darvasi
Subjects: Male, Genetics, Genetic Linkage, Muscles, Haplotype, Chromosome Mapping, Investigations, Biology, Phenotype, Mice, Mutant Strains, Protein content, Mice, Fixation (population genetics), Genetic linkage, Mutation, New mutation, Animals, Female, Gene, Dominance (genetics)
Abstract: During selection for protein content in mice at the Technical University of Berlin, individuals showing high protein content and a compact exterior were noted. Animals showing this “Compact” phenotype were separated to form a new line. The present investigations were carried out on a Hungarian subpopulation of this line, selected for maximum expression of the Compact phenotype, and apparently at fixation for the relevant genes. Fertility and viability of the Compact subpopulation was normal. As compared to normal mice, carcass percentage values for male and female Compact mice were 9.4 and 6.8% greater, respectively; and the muscle:bone weight ratio in males was 1.61-fold greater. The Compact phenotype showed variable expressivity and was of intermediate dominance in males, but almost fully recessive in females. The hypothesis that a single gene is solely responsible for the Compact phenotype was rejected by maximum likelihood analysis. Linkage mapping using selective DNA pooling located a single locus (denoted Cmpt) strongly associated with the Compact phenotype on mouse chromosome 1. Fine mapping, using individual selective genotyping and haplotype analysis, located Cmpt to the region between D1Mit375 and D1Mit21, approximately one third of the way to D1Mit21.
Published: 1997

48. [Untitled]

Author: Morris Soller and Ariel Darvasi
Subjects: Genetics, Infinite number, Inclusive composite interval mapping, Statistics, food and beverages, Map Location, Quantitative trait locus, Explained variation, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Confidence interval, Mathematics
Abstract: "Resolving power" is defined as the 95% confidence interval for quantitative trait locus (QTL) map location that would be obtained when scoring an infinite number of markers in a given constellation of a marker-QTL mapping experiment. Resolving power can serve as a close estimate of the confidence interval of QTL map location, as well as a guide to the lower efficient limit of marker spacing in an initial marker-QTL mapping experiment. In the present study, an extensive series of simulations was carried out to provide estimates of resolving power, for backcross (BC) and F2 designs, over a wide range of experimental sizes and of gene effects and dominance at the QTL. From the simulation results, the remarkably simple expressions, 3000/(mNd2) (where m = 1 for BC and m = 2 for F2; N = population size, and d = allele substitution effect) and 530/Nv (in terms of v, the proportion of variance explained), were obtained for estimating resolving power. These expressions can provide a convenient guide to planning marker spacing in BC and F2 marker-QTL linkage experiments and for placing confidence intervals about QTL map location obtained in such experiments.
Published: 1997

49. Genome-wide association study implicates NDST3 in schizophrenia and bipolar disorder

Author: Pamela DeRosse, Anne Pisanté, John M. Kane, David Goldman, Peter K. Gregersen, Chunling Zhang, Judith A. Badner, Marcella Rietschel, Masashi Ikeda, Todd Lencz, Markus M. Nöthen, Annette Lee, Qiaoping Yuan, Anil K. Malhotra, Andrew T. A. Cheng, Itsik Pe'er, Ariel Darvasi, Majnu John, Jeffrey A. Rosenfeld, Colin A. Hodgkinson, Sven Cichon, Saurav Guha, Lijun Cheng, Chunyu Liu, Semanti Mukherjee, and Nakao Iwata
Subjects: medicine.medical_specialty, Bipolar Disorder, General Physics and Astronomy, Locus (genetics), Genome-wide association study, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Prevalence of mental disorders, mental disorders, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Psychiatry, Psychiatric genetics, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Psychiatric Disease, Genome, Human, business.industry, General Chemistry, Odds ratio, medicine.disease, 3. Good health, Gene Expression Regulation, Jews, Schizophrenia, Human genome, Sulfotransferases, business, 030217 neurology & neurosurgery
Abstract: Schizophrenia and bipolar disorder are major psychiatric disorders with high heritability and overlapping genetic variance. Here we perform a genome-wide association study in an ethnically homogeneous cohort of 904 schizophrenia cases and 1,640 controls drawn from the Ashkenazi Jewish population. We identify a novel genome-wide significant risk locus at chromosome 4q26, demonstrating the potential advantages of this founder population for gene discovery. The top single-nucleotide polymorphism (SNP; rs11098403) demonstrates consistent effects across 11 replication and extension cohorts, totalling 23, 191 samples across multiple ethnicities, regardless of diagnosis (schizophrenia or bipolar disorder), resulting in Pmeta=9.49 × 10−12 (odds ratio (OR)=1.13, 95% confidence interval (CI): 1.08–1.17) across both disorders and Pmeta=2.67 × 10−8 (OR=1.15, 95% CI: 1.08–1.21) for schizophrenia alone. In addition, this intergenic SNP significantly predicts postmortem cerebellar gene expression of NDST3, which encodes an enzyme critical to heparan sulphate metabolism. Heparan sulphate binding is critical to neurite outgrowth, axon formation and synaptic processes thought to be aberrant in these disorders., Schizophrenia and bipolar disorder are important psychiatric disorders with overlapping genetic components. Here, the authors identify and replicate a genome-wide significant risk locus for the two disorders, and suggest a role for NDST3 in severe psychiatric disease.
Published: 2013

50. High rate of disease-related copy number variations in childhood onset schizophrenia

Author: Matthew W. State, T M Andersen, Ariel Darvasi, Yohan Lee, Saurav Guha, N Gotay, Peter Gochman, Hakon Hakonarson, J. Glessner, A. A. Anvari, Kwangmi Ahn, Todd Lencz, Judith L. Rapoport, Yin Yao Shugart, and Stephen Sanders
Subjects: Proband, Male, Pediatrics, Genotyping Techniques, Autism, Medical and Health Sciences, Intellectual disability, 2.1 Biological and endogenous factors, Copy-number variation, Aetiology, Child, Sequence Deletion, Genetics, Pediatric, Psychiatry, education.field_of_study, neurodevelopment, Genetic Pleiotropy, Single Nucleotide, Biological Sciences, Serious Mental Illness, Psychiatry and Mental health, Mental Health, Autism spectrum disorder, Schizophrenia, Female, Psychology, Adult, medicine.medical_specialty, Child Development Disorders, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Population, CNV, Polymorphism, Single Nucleotide, Article, Cellular and Molecular Neuroscience, Clinical Research, mental disorders, medicine, Humans, Polymorphism, education, Molecular Biology, Childhood schizophrenia, Pervasive, Prevention, Siblings, Human Genome, Psychology and Cognitive Sciences, Neurosciences, medicine.disease, Childhood, Brain Disorders, schizophrenia, Child Development Disorders, Pervasive, Schizophrenia, Childhood
Abstract: Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P=0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P
Published: 2013

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