Rare Genetic Variations Linked to Schizophrenia

Summary: A new study reveals several regions of the genome where mutations increase schizophrenia risk between four- and 60-fold.

Source: UCSD.

Genome-wide scan of more than 41,000 people reveals ‘copy number variants’ that carry a significant risk for psychiatric illness.

Many of the genetic variations that increase risk for schizophrenia are rare, making it difficult to study their role in the disease. To overcome this, the Psychiatric Genomics Consortium, an international team led by Jonathan Sebat, PhD, at University of California San Diego School of Medicine, analyzed the genomes of more than 41,000 people in the largest genome-wide study of its kind to date. Their study, published November 21 in Nature Genetics, reveals several regions of the genome where mutations increase schizophrenia risk between four- and 60-fold.

These mutations, known as copy number variants, are deletions or duplications of the DNA sequence. A copy number variant may affect dozens of genes, or it can disrupt or duplicate a single gene. This type of variation can cause significant alterations to the genome and lead to psychiatric disorders, said Sebat, who is a professor and chief of the Beyster Center for Genomics of Neuropsychiatric Diseases at UC San Diego School of Medicine. Sebat and other researchers previously discovered that relatively large copy number variants occur more frequently in schizophrenia than in the general population.

In this latest study, Sebat teamed up with more than 260 researchers from around the world, part of the Psychiatric Genomics Consortium, to analyze the genomes of 21,094 people with schizophrenia and 20,227 people without schizophrenia. They found eight locations in the genome with copy number variants associated with schizophrenia risk. Only a small fraction of cases (1.4 percent) carried these variants. The researchers also found that these copy number variants occurred more frequently in genes involved in the function of synapses, the connections between brain cells that transmit chemical messages.

a dna strand

The findings support the idea that strain leads to inner-directed deviant behavior such as gambling or substance abuse, as well as to negative emotions such as depression and anger. Neurosciencenews image is for illustrative purposes only.

With its large sample size, this study had the power to find copy number variants with large effects that occur in more than 0.1 percent of schizophrenia cases. However, the researchers said they are still missing many variants. More analyses will be needed to detect risk variants with smaller effects, or ultra-rare variants.

“This study represents a milestone that demonstrates what large collaborations in psychiatric genetics can accomplish,” Sebat said. “We’re confident that applying this same approach to a lot of new data will help us discover additional genomic variations and identify specific genes that play a role in schizophrenia and other psychiatric conditions.”

About this genetics research article

Funding: Funding provided by NIH.

Source: Heather Buschman – UCSD
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects” by CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, Christian R Marshall, Daniel P Howrigan, Daniele Merico, Bhooma Thiruvahindrapuram, Wenting Wu, Douglas S Greer, Danny Antaki, Aniket Shetty, Peter A Holmans, Dalila Pinto, Madhusudan Gujral, William M Brandler, Dheeraj Malhotra, Zhouzhi Wang, Karin V Fuentes Fajarado, Michelle S Maile, Stephan Ripke, Ingrid Agartz, Margot Albus, Madeline Alexander, Farooq Amin, Joshua Atkins, Silviu A Bacanu, Richard A Belliveau Jr, Sarah E Bergen, Marcelo Bertalan, Elizabeth Bevilacqua, Tim B Bigdeli, Donald W Black, Richard Bruggeman, Nancy G Buccola, Randy L Buckner, Brendan Bulik-Sullivan, William Byerley, Wiepke Cahn, Guiqing Cai, Murray J Cairns, Dominique Campion, Rita M Cantor, Vaughan J Carr, Noa Carrera, Stanley V Catts, Kimberley D Chambert, Wei Cheng, C Robert Cloninger, David Cohen, Paul Cormican, Nick Craddock, Benedicto Crespo-Facorro, James J Crowley, David Curtis, Michael Davidson, Kenneth L Davis, Franziska Degenhardt, Jurgen Del Favero, Lynn E DeLisi, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H Fanous, Kai-How Farh, Martilias S Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B Freimer, Joseph I Friedman, Andreas J Forstner, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Elliot S Gershon, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I Goldstein, Jacob Gratten, Lieuwe de Haan, Marian L Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M Hartmann, Frans A Henskens, Stefan Herms, Joel N Hirschhorn, Per Hoffmann, Andrea Hofman, Hailiang Huang, Masashi Ikeda, Inge Joa, Brandon K Wormley, Sang-Yun Oh, Alan R Sanders, Jim Van Os, Igor Nenadic, Shaun M Purcell, Thomas G Schulze, Christina M Hultman, Younes Mokrab, Bettina Konte, Sibylle G Schwab, Luba Kalaydjieva, Assen V Jablensky, Jana Strohmaier, Sophie E Legge, Tõnu Esko, Paul A Tooney, Eric Strengman, Alkes Price, Naomi R Wray, T Scott Stroup, Chris C A Spencer, Stephanie H Witt, Panos Roussos, Roel A Ophoff, Diana O Perkins, Abraham Reichenberg, Mark A Reimers, Claudine Laurent, S Hong Lee, Ole A Andreassen, Dan Rujescu, Michael J Owen, Juha Veijola, Ulrich Schall, Edward M Scolnick, Annelie Nordin, Bertram Müller-Myhsok, Mark J Daly, Andrew McQuillin, George N Papadimitriou, Dragan M Svrakic, Colm O’Dushlaine, Ann Olincy, Peter M Visscher, Erik G Jönsson, Douglas H R Blackwood, David Kavanagh, Manuel Mattheisen, Markus M Nöthen, Adam Savitz, Tune H Pers, Ann E Pulver, James A Knowles, Sandra Meier, Brien P Riley, Jonathan Pimm, Henrik B Rasmussen, Enrico Domenici, Robert W McCarley, Carlos N Pato, Dermot Walsh, Tiina Paunio, David A Collier, Qingqin S Li, Michele T Pato, Jeremy M Silverman, Brian J Kelly, Raquelle I Mesholam-Gately, Sven Cichon, Bernard Lerer, Digby Quested, Stephen W Scherer, Aaron R Wolen, Andres Metspalu, John Powell, Mark Weiser, Nakao Iwata, Pamela Sklar, Eadbhard O’Callaghan, Patrik K E Magnusson, Olli Pietiläinen, Jianxin Shi, Phil Lee, Colm McDonald, Jing Qin Wu, Alexander L Richards, Jaana Suvisaari, Gerald Nestadt, Joseph D Buxbaum, Morten Mattingsdal, Bradley T Webb, Jacques Mallet, Rodney J Scott, Michael C O’Donovan, Steven A McCarroll, George Kirov, James L Kennedy, Stephanie Williams, Elvira Bramon, James T R Walters, Douglas M Ruderfer, Christos Pantelis, Elena Parkhomenko, Juha Karjalainen, Yunjung Kim, Kenneth S Kendler, Nigel M Williams, Michael Gill, Lili Milani, Eli A Stahl, Anna K Kähler, Hugh Gurling, Erik Söderman, Rolf Adolfsson, Pablo V Gejman, Derek W Morris, René S Kahn, Line Olsen, Robin M Murray, Aiden Corvin, Inez Myin-Germeys, Jonathan Sebat, Andrew J Pocklington, Tracey L Petryshen, Clement C Zai, Andrew M McIntosh, Srinivas Thirumalai, Thomas Werge, Matthew C Keller, Patricia T Michie, Dieter B Wildenauer, Brion S Maher, Kristin K Nicodemus, Benjamin M Neale, Carmel M Loughland, Jouko Lönnqvist, Kung-Yee Liang, Ariel Darvasi, Vihra Milanova, Jin P Szatkiewicz, Deborah A Nertney, Jo Knight, Veikko Salomaa, Marcella Rietschel, Deborah L Levy, Patrick F Sullivan, Larry J Seidman, David St Clair, Douglas F Levinson, Danielle Posthuma, Carin J Meijer, Ingrid Melle, Jordan W Smoller, John Waddington, Jennifer L Moran, F Anthony O’Neill, Joshua L Roffman, Laura Nisenbaum, Aarno Palotie, Bryan J Mowry, Wolfgang Maier, Jeffrey Lieberman & Kieran C Murphy in Nature Genetics. Published online November 21 2016 doi:10.1038/ng.3725

Cite This NeuroscienceNews.com Article
UCSD. “Rare Genetic Variations Linked to Schizophrenia.” NeuroscienceNews. NeuroscienceNews, 22 November 2016.
<http://neurosciencenews.com/genetics-schizophrenia-neuroscience-5574/>.
UCSD. (2016, November 22). Rare Genetic Variations Linked to Schizophrenia. NeuroscienceNews. Retrieved November 22, 2016 from http://neurosciencenews.com/genetics-schizophrenia-neuroscience-5574/
UCSD. “Rare Genetic Variations Linked to Schizophrenia.” http://neurosciencenews.com/genetics-schizophrenia-neuroscience-5574/ (accessed November 22, 2016).

Abstract

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

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 × 10−15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 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.

“Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects” by CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, Christian R Marshall, Daniel P Howrigan, Daniele Merico, Bhooma Thiruvahindrapuram, Wenting Wu, Douglas S Greer, Danny Antaki, Aniket Shetty, Peter A Holmans, Dalila Pinto, Madhusudan Gujral, William M Brandler, Dheeraj Malhotra, Zhouzhi Wang, Karin V Fuentes Fajarado, Michelle S Maile, Stephan Ripke, Ingrid Agartz, Margot Albus, Madeline Alexander, Farooq Amin, Joshua Atkins, Silviu A Bacanu, Richard A Belliveau Jr, Sarah E Bergen, Marcelo Bertalan, Elizabeth Bevilacqua, Tim B Bigdeli, Donald W Black, Richard Bruggeman, Nancy G Buccola, Randy L Buckner, Brendan Bulik-Sullivan, William Byerley, Wiepke Cahn, Guiqing Cai, Murray J Cairns, Dominique Campion, Rita M Cantor, Vaughan J Carr, Noa Carrera, Stanley V Catts, Kimberley D Chambert, Wei Cheng, C Robert Cloninger, David Cohen, Paul Cormican, Nick Craddock, Benedicto Crespo-Facorro, James J Crowley, David Curtis, Michael Davidson, Kenneth L Davis, Franziska Degenhardt, Jurgen Del Favero, Lynn E DeLisi, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H Fanous, Kai-How Farh, Martilias S Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B Freimer, Joseph I Friedman, Andreas J Forstner, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Elliot S Gershon, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I Goldstein, Jacob Gratten, Lieuwe de Haan, Marian L Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M Hartmann, Frans A Henskens, Stefan Herms, Joel N Hirschhorn, Per Hoffmann, Andrea Hofman, Hailiang Huang, Masashi Ikeda, Inge Joa, Brandon K Wormley, Sang-Yun Oh, Alan R Sanders, Jim Van Os, Igor Nenadic, Shaun M Purcell, Thomas G Schulze, Christina M Hultman, Younes Mokrab, Bettina Konte, Sibylle G Schwab, Luba Kalaydjieva, Assen V Jablensky, Jana Strohmaier, Sophie E Legge, Tõnu Esko, Paul A Tooney, Eric Strengman, Alkes Price, Naomi R Wray, T Scott Stroup, Chris C A Spencer, Stephanie H Witt, Panos Roussos, Roel A Ophoff, Diana O Perkins, Abraham Reichenberg, Mark A Reimers, Claudine Laurent, S Hong Lee, Ole A Andreassen, Dan Rujescu, Michael J Owen, Juha Veijola, Ulrich Schall, Edward M Scolnick, Annelie Nordin, Bertram Müller-Myhsok, Mark J Daly, Andrew McQuillin, George N Papadimitriou, Dragan M Svrakic, Colm O’Dushlaine, Ann Olincy, Peter M Visscher, Erik G Jönsson, Douglas H R Blackwood, David Kavanagh, Manuel Mattheisen, Markus M Nöthen, Adam Savitz, Tune H Pers, Ann E Pulver, James A Knowles, Sandra Meier, Brien P Riley, Jonathan Pimm, Henrik B Rasmussen, Enrico Domenici, Robert W McCarley, Carlos N Pato, Dermot Walsh, Tiina Paunio, David A Collier, Qingqin S Li, Michele T Pato, Jeremy M Silverman, Brian J Kelly, Raquelle I Mesholam-Gately, Sven Cichon, Bernard Lerer, Digby Quested, Stephen W Scherer, Aaron R Wolen, Andres Metspalu, John Powell, Mark Weiser, Nakao Iwata, Pamela Sklar, Eadbhard O’Callaghan, Patrik K E Magnusson, Olli Pietiläinen, Jianxin Shi, Phil Lee, Colm McDonald, Jing Qin Wu, Alexander L Richards, Jaana Suvisaari, Gerald Nestadt, Joseph D Buxbaum, Morten Mattingsdal, Bradley T Webb, Jacques Mallet, Rodney J Scott, Michael C O’Donovan, Steven A McCarroll, George Kirov, James L Kennedy, Stephanie Williams, Elvira Bramon, James T R Walters, Douglas M Ruderfer, Christos Pantelis, Elena Parkhomenko, Juha Karjalainen, Yunjung Kim, Kenneth S Kendler, Nigel M Williams, Michael Gill, Lili Milani, Eli A Stahl, Anna K Kähler, Hugh Gurling, Erik Söderman, Rolf Adolfsson, Pablo V Gejman, Derek W Morris, René S Kahn, Line Olsen, Robin M Murray, Aiden Corvin, Inez Myin-Germeys, Jonathan Sebat, Andrew J Pocklington, Tracey L Petryshen, Clement C Zai, Andrew M McIntosh, Srinivas Thirumalai, Thomas Werge, Matthew C Keller, Patricia T Michie, Dieter B Wildenauer, Brion S Maher, Kristin K Nicodemus, Benjamin M Neale, Carmel M Loughland, Jouko Lönnqvist, Kung-Yee Liang, Ariel Darvasi, Vihra Milanova, Jin P Szatkiewicz, Deborah A Nertney, Jo Knight, Veikko Salomaa, Marcella Rietschel, Deborah L Levy, Patrick F Sullivan, Larry J Seidman, David St Clair, Douglas F Levinson, Danielle Posthuma, Carin J Meijer, Ingrid Melle, Jordan W Smoller, John Waddington, Jennifer L Moran, F Anthony O’Neill, Joshua L Roffman, Laura Nisenbaum, Aarno Palotie, Bryan J Mowry, Wolfgang Maier, Jeffrey Lieberman & Kieran C Murphy in Nature Genetics. Published online November 21 2016 doi:10.1038/ng.3725

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