Strong association of de novo copy number mutations with sporadic schizophrenia

Schizophrenia is an etiologically heterogeneous psychiatric disease, which exists in familial and nonfamilial (sporadic) forms. Here, we examine the possibility that rare de novo copy number (CN) mutations with relatively high penetrance contribute to the genetic component of schizophrenia. We carried out a whole-genome scan and implemented a number of steps for finding and confirming CN mutations. Confirmed de novo mutations were significantly associated with schizophrenia (P = 0.00078) and were collectively ∼8 times more frequent in sporadic (but not familial) cases with schizophrenia than in unaffected controls. In comparison, rare inherited CN mutations were only modestly enriched in sporadic cases. Our results suggest that rare de novo germline mutations contribute to schizophrenia vulnerability in sporadic cases and that rare genetic lesions at many different loci can account, at least in part, for the genetic heterogeneity of this disease.

[1]  Kenny Q. Ye,et al.  Strong Association of De Novo Copy Number Mutations with Autism , 2007, Science.

[2]  D. Cerretti,et al.  Specification of Distinct Dopaminergic Neural Pathways: Roles of the Eph Family Receptor EphB1 and Ligand Ephrin-B2 , 1999, The Journal of Neuroscience.

[3]  D. Blackwood,et al.  Chromosomal abnormalities and mental illness , 2003, Molecular Psychiatry.

[4]  A. Wittinghofer,et al.  Characterisation of PDZ-GEFs, a family of guanine nucleotide exchange factors specific for Rap1 and Rap2. , 2003, Biochimica et biophysica acta.

[5]  Maria Karayiorgou,et al.  Schizophrenia genetics: uncovering positional candidate genes , 2006, European Journal of Human Genetics.

[6]  C. Li,et al.  Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  P. Sullivan,et al.  Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia. , 2006, Human molecular genetics.

[8]  D. Conrad,et al.  Global variation in copy number in the human genome , 2006, Nature.

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

[10]  Paul Pavlidis,et al.  Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model , 2008, Nature Genetics.

[11]  G. Abecasis,et al.  Genetic variation in the 22q11 locus and susceptibility to schizophrenia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Housman,et al.  Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. , 1994, The Journal of nervous and mental disease.

[13]  L. Silengo,et al.  Defective Neurogenesis in Citron Kinase Knockout Mice by Altered Cytokinesis and Massive Apoptosis , 2000, Neuron.

[14]  Leena Peltonen,et al.  Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. , 2003, American journal of human genetics.

[15]  G. Hannon,et al.  miRNAs on the move: miRNA biogenesis and the RNAi machinery. , 2004, Current opinion in cell biology.

[16]  J. Shields,et al.  A polygenic theory of schizophrenia. , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Karayiorgou,et al.  Identification of an interstitial deletion in an adult female with schizophrenia, mental retardation, and dysmorphic features: further support for a putative schizophrenia-susceptibility locus at 5q21-23.1. , 1997, American journal of human genetics.

[18]  M. Dalva,et al.  Intracellular and Trans-Synaptic Regulation of Glutamatergic Synaptogenesis by EphB Receptors , 2006, The Journal of Neuroscience.

[19]  F. McMahon,et al.  Evidence of association between bipolar disorder and Citron on chromosome 12q24 , 2005, Molecular Psychiatry.

[20]  Gonçalo R Abecasis,et al.  Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1. , 2004, American journal of human genetics.

[21]  J. Pritchard,et al.  The allelic architecture of human disease genes: common disease-common variant...or not? , 2002, Human molecular genetics.

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

[23]  J. Lupski,et al.  Genomic rearrangements and sporadic disease , 2007, Nature Genetics.

[24]  R. Shprintzen,et al.  Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Thomas Bourgeron,et al.  Mapping autism risk loci using genetic linkage and chromosomal rearrangements , 2007, Nature Genetics.

[26]  M. Owen,et al.  High rates of schizophrenia in adults with velo-cardio-facial syndrome (VCFS) , 1999, Schizophrenia Research.

[27]  K. Fujisawa,et al.  Citron, a Rho-Target, Interacts with PSD-95/SAP-90 at Glutamatergic Synapses in the Thalamus , 1999, The Journal of Neuroscience.

[28]  M. Karayiorgou,et al.  Assessment of the frequency of the 22q11 deletion in Afrikaner schizophrenic patients , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[29]  D. Pinto,et al.  Structural variation of chromosomes in autism spectrum disorder. , 2008, American journal of human genetics.