A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects: CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium

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).

C. Spencer | K. Davis | P. Visscher | N. Wray | M. Daly | D. Pinto | S. Scherer | J. Sebat | D. Rujescu | S. Cichon | O. Pietiläinen | T. Hansen | I. Giegling | A. Hartmann | J. Lonnqvist | J. Suvisaari | T. Paunio | E. Bramon | R. Murray | S. Djurovic | I. Melle | N. Freimer | O. Andreassen | R. Ophoff | M. Rietschel | T. Werge | M. Nöthen | D. Collier | D. Clair | G. Kirov | J. Lieberman | T. Schulze | M. Gill | N. Craddock | M. Owen | M. O’Donovan | L. DeLisi | P. Sullivan | D. Levy | D. Merico | C. Marshall | Zhouzhi Wang | J. Buxbaum | R. Cantor | S. Mccarroll | V. Salomaa | M. Bertalan | Jianxin Shi | J. Hirschhorn | R. Buckner | J. Os | B. Neale | M. Hamshere | P. Holmans | A. Price | J. Waddington | R. Kahn | W. Cahn | S. Purcell | R. McCarley | W. Maier | V. Haroutunian | J. Smoller | I. Agartz | J. Roffman | A. McIntosh | J. Mallet | M. Cairns | R. Scott | P. Tooney | A. Palotie | A. Metspalu | T. Esko | L. Milani | P. Sklar | D. Blackwood | A. Corvin | C. Hultman | A. McQuillin | C. Pato | D. Ruderfer | D. Morris | C. O'Dushlaine | E. Scolnick | N. Williams | V. Milanova | J. Pimm | S. Thirumalai | D. Quested | D. Curtis | M. Pato | A. Fanous | J. Knowles | M. Fromer | J. Friedman | P. Michie | Yunjung Kim | C. Pantelis | K. Kendler | D. Posthuma | L. Seidman | T. Stroup | D. Perkins | E. Stahl | D. Levinson | J. Powell | M. Keller | I. Nenadić | E. Gershon | G. Papadimitriou | J. Karjalainen | P. Magnusson | T. Pers | J. Eriksson | L. Franke | J. Crowley | A. Pocklington | S. Bacanu | F. Henskens | C. Mcdonald | M. Davidson | R. Mesholam-Gately | B. Crespo-Facorro | O. Mors | Wei Cheng | K. Murphy | J. Veijola | C. R. Cloninger | P. Mortensen | A. Børglum | D. Hougaard | H. Rasmussen | M. Mattheisen | E. Strengman | E. Jönsson | D. Campion | B. Müller-Myhsok | F. Dudbridge | B. Lerer | J. Kennedy | J. Goldstein | D. Howrigan | S. Ripke | Qingqin S. Li | J. Moran | D. Antaki | Madhusudan Gujral | B. Riley | T. Dinan | S. Lee | B. Thiruvahindrapuram | E. Parkhomenko | F. O’Neill | B. Webb | D. Walsh | E. Domenici | I. Myin-Germeys | G. Nestadt | E. Drapeau | Kai-How Farh | B. Maher | J. Szatkiewicz | B. Bulik-Sullivan | G. Genovese | L. Essioux | A. Jablensky | Phil H. Lee | M. Ikeda | G. Donohoe | M. Mattingsdal | A. Reichenberg | M. Farrell | J. Duan | A. Sanders | P. Gejman | P. Hoffmann | A. Darvasi | T. Petryshen | A. Pulver | A. Kähler | Sarah L Bergen | Stephanie Williams | P. Cormican | A. Richards | J. Walters | C. Laurent | B. Mowry | S. Schwab | D. Wildenauer | M. Albus | M. Alexander | D. Cohen | D. Dikeos | P. Eichhammer | S. Godard | M. Hansen | K. Liang | D. Nertney | J. Silverman | B. Wormley | L. Kalaydjieva | D. Demontis | E. Agerbo | R. Belliveau | M. Hollegaard | Hailiang Huang | P. Roussos | D. Black | Sang-Yun Oh | V. Escott-Price | D. Svrakic | A. Olincy | L. Haan | N. Carrera | S. Legge | S. Witt | F. Degenhardt | A. Forstner | J. Atkins | S. Herms | J. Wu | V. Carr | C. Loughland | U. Schall | W. Byerley | M. Weiser | M. Reimers | S. Meier | N. Iwata | T. Bigdeli | P. Giusti-Rodríguez | Douglas S Greer | Wenting Wu | E. Söderman | E. O'callaghan | L. Nisenbaum | K. Nicodemus | R. Freedman | J. Strohmaier | H. Gurling | F. Amin | R. Bruggeman | N. Buccola | J. Frank | L. Georgieva | B. Konte | L. Olsen | Elizabeth Bevilacqua | Guiqing Cai | S. Catts | K. Chambert | J. Gratten | A. Hofman | I. Joa | D. Kavanagh | C. Meijer | Y. Mokrab | A. Nordin | A. Wolen | C. Zai | R. Adolfsson | J. Knight | A. Savitz | W. Brandler | B. Kelly | Aniket Shetty | Dheeraj Malholtra | K. V. F. Fajarado | J. D. Favero | Danny Antaki | S. Williams | C. O’Dushlaine | K. Farh | J. Eriksson | C. Cloninger | Paola Giusti-Rodríguez | R. Murray | J. Eriksson | Annelie Nordin | R. Scott | Marcelo Bertalan | R. Scott | A. Price | Madeline Alexander | J. Walters | Elodie Drapeau | C. Spencer | J. Kennedy | R. Scott | J. Powell | M. Hansen | Douglas S. Greer | Karin V. Fuentes Fajarado | I. Myin‐Germeys

[1]  P. Sullivan,et al.  Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. , 2003, Archives of general psychiatry.

[2]  E. Roeder,et al.  Clinical characterization of int22h1/int22h2-mediated Xq28 duplication/deletion: new cases and literature review , 2015, BMC Medical Genetics.

[3]  Fikret Erdogan,et al.  Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. , 2007, Human molecular genetics.

[4]  G. Raymond,et al.  Distal Xq28 microdeletions: Clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature , 2014, American journal of medical genetics. Part A.

[5]  M C O'Donovan,et al.  Copy number variation in schizophrenia in Sweden , 2014, Molecular Psychiatry.

[6]  Gary D. Bader,et al.  GeneMANIA Prediction Server 2013 Update , 2013, Nucleic Acids Res..

[7]  M. Gill,et al.  Cosegregation of schizophrenia with Becker muscular dystrophy: susceptibility locus for schizophrenia at Xp21 or an effect of the dystrophin gene in the brain? , 1993, Journal of medical genetics.

[8]  Joseph A. Gogos,et al.  Strong association of de novo copy number mutations with sporadic schizophrenia , 2008, Nature Genetics.

[9]  P. Visscher,et al.  Rare chromosomal deletions and duplications increase risk of schizophrenia , 2008, Nature.

[10]  G. Kirov,et al.  Analysis of copy number variations at 15 schizophrenia-associated loci , 2014, The British journal of psychiatry : the journal of mental science.

[11]  J. Sebat,et al.  Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia , 2011, Nature.

[12]  Jessica R. Wolff,et al.  Microduplications of 16p11.2 are Associated with Schizophrenia , 2009, Nature Genetics.

[13]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[14]  D. Cutler,et al.  Microdeletions of 3q29 confer high risk for schizophrenia. , 2010, American journal of human genetics.

[15]  P. Stankiewicz,et al.  Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions , 2011, Journal of Medical Genetics.

[16]  Mark J Daly,et al.  Analysis of high-resolution HapMap of DTNBP1 (Dysbindin) suggests no consistency between reported common variant associations and schizophrenia. , 2006, American journal of human genetics.

[17]  S Purcell,et al.  De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia , 2011, Molecular Psychiatry.

[18]  Andreas Buja,et al.  Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism , 2011, Proceedings of the National Academy of Sciences.

[19]  R. Shprintzen,et al.  Late-onset psychosis in the velo-cardio-facial syndrome. , 1992, American journal of medical genetics.

[20]  J. Sebat,et al.  Implication of a rare deletion at distal 16p11.2 in schizophrenia. , 2013, JAMA psychiatry.

[21]  Urvashi Surti,et al.  Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. , 2010, American journal of human genetics.

[22]  Thomas W. Mühleisen,et al.  Large recurrent microdeletions associated with schizophrenia , 2008, Nature.

[23]  Jianxin Shi,et al.  Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. , 2011, The American journal of psychiatry.

[24]  Randy L. Buckner,et al.  Individual Differences in Amygdala-Medial Prefrontal Anatomy Link Negative Affect, Impaired Social Functioning, and Polygenic Depression Risk , 2012, The Journal of Neuroscience.

[25]  M. Schwartz,et al.  Large genomic rearrangements in MECP2 , 2005, Human mutation.

[26]  Gary D Bader,et al.  Functional impact of global rare copy number variation in autism spectrum disorders , 2010, Nature.

[27]  Cathleen K. Yoshida,et al.  Increased female autosomal burden of rare copy number variants in human populations and in autism families , 2015, Molecular Psychiatry.

[28]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[29]  Willy C. Shih,et al.  Danish National Advanced Technology Foundation , 2012 .

[30]  J. Sebat,et al.  CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics , 2012, Cell.

[31]  J. Witte,et al.  The contribution of genetic variants to disease depends on the ruler , 2014, Nature Reviews Genetics.

[32]  D. Conrad,et al.  Reciprocal Duplication of the Williams-Beuren Syndrome Deletion on Chromosome 7q11.23 Is Associated with Schizophrenia , 2014, Biological Psychiatry.

[33]  Joseph T. Glessner,et al.  PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. , 2007, Genome research.

[34]  G. Kirov,et al.  Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia , 2015, Neuron.

[35]  H. Peeters,et al.  Microduplication 22q11.2: a description of the clinical, developmental and behavioral characteristics during childhood. , 2012, Genetic counseling.

[36]  R. Straub,et al.  Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. , 2002, American journal of human genetics.

[37]  Joshua M. Korn,et al.  Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs , 2008, Nature Genetics.

[38]  Elvira Bramon,et al.  Disruption of the neurexin 1 gene is associated with schizophrenia. , 2009, Human molecular genetics.

[39]  G. Kirov,et al.  Evidence that duplications of 22q11.2 protect against schizophrenia , 2013, Molecular Psychiatry.

[40]  E. Banks,et al.  De novo mutations in schizophrenia implicate synaptic networks , 2014, Nature.

[41]  R. Handsaker,et al.  Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder , 2012, Molecular Psychiatry.

[42]  J. Sebat,et al.  High Frequencies of De Novo CNVs in Bipolar Disorder and Schizophrenia , 2011, Neuron.

[43]  J. Lupski.  Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. , 1998, Trends in genetics : TIG.

[44]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[45]  A. Reymond,et al.  KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant , 2012, Nature.

[46]  Joshua M. Korn,et al.  Accurately Assessing the Risk of Schizophrenia Conferred by Rare Copy-Number Variation Affecting Genes with Brain Function , 2010, PLoS genetics.

[47]  D. Rujescu,et al.  Duplications in RB1CC1 are associated with schizophrenia; identification in large European sample sets , 2013, Translational Psychiatry.

[48]  A. Singleton,et al.  Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia , 2008, Science.

[49]  H. Stefánsson,et al.  Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness. , 2011, The American journal of psychiatry.