Sequencing of DISC1 Pathway Genes Reveals Increased Burden of Rare Missense Variants in Schizophrenia Patients from a Northern Swedish Population

In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence – both genetic and functional – indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P = 0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P = 0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ∼90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.

[1]  B. Childs,et al.  Age at Onset and Causes of Disease , 2015, Perspectives in biology and medicine.

[2]  Vladimir N. Uversky,et al.  The roles of intrinsic disorder in protein interaction networks , 2013 .

[3]  Janet B W Williams.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[4]  B. Puri,et al.  Neurobiology and phenotypic expression in early onset schizophrenia , 2011, Early intervention in psychiatry.

[5]  Christian Schaefer,et al.  Protein secondary structure appears to be robust under in silico evolution while protein disorder appears not to be , 2010, Bioinform..

[6]  R. Vakkalanka,et al.  DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms , 2009, Proceedings of the National Academy of Sciences.

[7]  I. Deary,et al.  DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder , 2009, Molecular Psychiatry.

[8]  Predrag Radivojac,et al.  Influence of Sequence Changes and Environment on Intrinsically Disordered Proteins , 2009, PLoS Comput. Biol..

[9]  C. Korth,et al.  Oligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C. , 2009, Biochemistry.

[10]  L. Kay,et al.  Protein dynamics and conformational disorder in molecular recognition , 2009, Journal of molecular recognition : JMR.

[11]  A Keith Dunker,et al.  Unfoldomics of human diseases: linking protein intrinsic disorder with diseases , 2009, BMC Genomics.

[12]  A Keith Dunker,et al.  Protein disorder in the human diseasome: unfoldomics of human genetic diseases , 2009, BMC Genomics.

[13]  Paul J. Harrison,et al.  DISC-1 Leu607Phe alleles differentially affect centrosomal PCM1 localization and neurotransmitter release , 2009, Molecular Psychiatry.

[14]  Debashis Mukhopadhyay,et al.  The Role of Intrinsically Unstructured Proteins in Neurodegenerative Diseases , 2009, PloS one.

[15]  Suzanne M. Leal,et al.  Discovery of Rare Variants via Sequencing: Implications for the Design of Complex Trait Association Studies , 2009, PLoS genetics.

[16]  Francesco Vallania,et al.  Quantification of rare allelic variants from pooled genomic DNA , 2009, Nature Methods.

[17]  Max Ingman,et al.  SNP frequency estimation using massively parallel sequencing of pooled DNA , 2009, European Journal of Human Genetics.

[18]  Yusuke Nakamura,et al.  Case–control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population , 2009, Journal of Human Genetics.

[19]  Ole A. Andreassen,et al.  Association between a disrupted-in-schizophrenia 1 (DISC1) single nucleotide polymorphism and schizophrenia in a combined Scandinavian case–control sample , 2008, Schizophrenia Research.

[20]  Fabio Sambataro,et al.  Association of the Ser704Cys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding , 2008, The European journal of neuroscience.

[21]  Christopher J. Oldfield,et al.  The unfoldomics decade: an update on intrinsically disordered proteins , 2008, BMC Genomics.

[22]  Akira Sawa,et al.  Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses. , 2008, Archives of general psychiatry.

[23]  W. Bodmer,et al.  Common and rare variants in multifactorial susceptibility to common diseases , 2008, Nature Genetics.

[24]  Christopher J. Oldfield,et al.  Intrinsically disordered proteins in human diseases: introducing the D2 concept. , 2008, Annual review of biophysics.

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

[26]  Jianxin Shi,et al.  No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. , 2008, The American journal of psychiatry.

[27]  Philip M. Kim,et al.  The role of disorder in interaction networks: a structural analysis , 2008, Molecular systems biology.

[28]  L. Heston,et al.  Identification of high risk DISC1 structural variants with a 2% attributable risk for schizophrenia. , 2008, Biochemical and biophysical research communications.

[29]  T Varilo,et al.  Association of DISC1 with autism and Asperger syndrome , 2008, Molecular Psychiatry.

[30]  Alcino J. Silva,et al.  Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice , 2007, Proceedings of the National Academy of Sciences.

[31]  A. Tuulio-Henriksson,et al.  Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments. , 2007, Human molecular genetics.

[32]  Xin Duan,et al.  Disrupted-In-Schizophrenia 1 Regulates Integration of Newly Generated Neurons in the Adult Brain , 2007, Cell.

[33]  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.

[34]  Lin He,et al.  Case-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population. , 2007, Journal of psychiatric research.

[35]  Fei Wang,et al.  Positive association of the Disrupted‐in‐Schizophrenia‐1 gene (DISC1) with schizophrenia in the Chinese han population , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[36]  M. King,et al.  Schizophrenia: a common disease caused by multiple rare alleles , 2007, British Journal of Psychiatry.

[37]  P Shaw,et al.  Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories , 2007, Molecular Psychiatry.

[38]  Lippincott-Schwartz,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S8 Table S1 Movies S1 to S3 a " Silent " Polymorphism in the Mdr1 Gene Changes Substrate Specificity Corrected 30 November 2007; See Last Page , 2022 .

[39]  K. Kaibuchi,et al.  DISC1 Regulates Neurotrophin-Induced Axon Elongation via Interaction with Grb2 , 2007, The Journal of Neuroscience.

[40]  K. Kaibuchi,et al.  DISC1 Regulates the Transport of the NUDEL/LIS1/14-3-3ε Complex through Kinesin-1 , 2007, The Journal of Neuroscience.

[41]  K. Shokat,et al.  Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure , 2006, Science.

[42]  P. Zandi,et al.  Differential Expression of Disrupted-in-Schizophrenia (DISC1) in Bipolar Disorder , 2006, Biological Psychiatry.

[43]  Takahisa Taguchi,et al.  Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. , 2006, Human molecular genetics.

[44]  Sarah A. J. Reading,et al.  Neurobiology of Schizophrenia , 2006, Neuron.

[45]  A. Dunker,et al.  Abundance of intrinsic disorder in protein associated with cardiovascular disease. , 2006, Biochemistry.

[46]  T. Akiyama,et al.  Corrigendum to “A functional link between Disrupted-In-Schizophrenia 1 and the eukaryotic translation initiation factor 3” [Biochem. Biophys. Res. Commun. 338 (2005) 771–776] , 2006 .

[47]  D. Porteous,et al.  Disrupted in schizophrenia 1: building brains and memories. , 2006, Trends in molecular medicine.

[48]  A Keith Dunker,et al.  Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Daniel R Weinberger,et al.  Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs. , 2006, Human molecular genetics.

[50]  T. Akiyama,et al.  A functional link between Disrupted-In-Schizophrenia 1 and the eukaryotic translation initiation factor 3. , 2005, Biochemical and biophysical research communications.

[51]  Christopher A. Ross,et al.  A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development , 2005, Nature Cell Biology.

[52]  Tyrone D. Cannon,et al.  A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia , 2005, Molecular Psychiatry.

[53]  I. Deary,et al.  Association between genotype at an exonic SNP in DISC1 and normal cognitive aging , 2005, Neuroscience Letters.

[54]  Jennifer E. Chubb,et al.  DISC1 and PDE4B Are Interacting Genetic Factors in Schizophrenia That Regulate cAMP Signaling , 2005, Science.

[55]  A. Addington,et al.  Dysbindin (DTNBP1, 6p22.3) is Associated with Childhood-Onset Psychosis and Endophenotypes Measured by the Premorbid Adjustment Scale (PAS) , 2005, Journal of autism and developmental disorders.

[56]  Tyrone D. Cannon,et al.  Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. , 2005, Archives of general psychiatry.

[57]  G. Kirov,et al.  Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13. , 2005, Archives of general psychiatry.

[58]  L. Peltonen,et al.  Genes and schizophrenia: beyond schizophrenia: the role of DISC1 in major mental illness. , 2005, Schizophrenia bulletin.

[59]  David Goldman,et al.  DISC1 and neurocognitive function in schizophrenia , 2005, Neuroreport.

[60]  A. Meyer-Lindenberg,et al.  Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[61]  A. Addington,et al.  GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss , 2005, Molecular Psychiatry.

[62]  G. Abecasis,et al.  A note on exact tests of Hardy-Weinberg equilibrium. , 2005, American journal of human genetics.

[63]  H. Dyson,et al.  Intrinsically unstructured proteins and their functions , 2005, Nature Reviews Molecular Cell Biology.

[64]  C. Austin,et al.  Expression of disrupted-in-schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development , 2004, Neuroscience.

[65]  N. Brandon,et al.  Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment , 2004, Molecular Psychiatry.

[66]  P. Visscher,et al.  A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42 , 2004, Molecular Psychiatry.

[67]  W Hennah,et al.  Replication of 1q42 linkage in Finnish schizophrenia pedigrees , 2004, Molecular Psychiatry.

[68]  P. Zandi,et al.  A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders , 2004, International review of psychiatry.

[69]  L. Nyberg,et al.  Betula: A Prospective Cohort Study on Memory, Health and Aging , 2004 .

[70]  Deanna Greenstein,et al.  Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified , 2004, Biological Psychiatry.

[71]  M. Tohyama,et al.  DISC1 localizes to the centrosome by binding to kendrin. , 2004, Biochemical and biophysical research communications.

[72]  R James,et al.  Disrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria , 2004, Molecular and Cellular Neuroscience.

[73]  Paul J. Harrison.  The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications , 2004, Psychopharmacology.

[74]  J. Rain,et al.  Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders , 2004, Molecular and Cellular Neuroscience.

[75]  Leena Peltonen,et al.  Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. , 2003, Human molecular genetics.

[76]  Sheila Christie,et al.  Yeast two-hybrid screens implicate DISC1 in brain development and function. , 2003, Biochemical and biophysical research communications.

[77]  Christopher P Austin,et al.  DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. , 2003, Human molecular genetics.

[78]  H. Pétursson,et al.  Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23‐q24, and suggests the presence of additional loci on 1p and 1q , 2003, Psychiatric genetics.

[79]  S. Snyder,et al.  Disrupted-in-Schizophrenia-1 (DISC-1): Mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[80]  L. Iakoucheva,et al.  Intrinsic disorder in cell-signaling and cancer-associated proteins. , 2002, Journal of molecular biology.

[81]  Zoran Obradovic,et al.  The protein trinity—linking function and disorder , 2001, Nature Biotechnology.

[82]  J S Sinsheimer,et al.  Chromosome 1 loci in Finnish schizophrenia families. , 2001, Human molecular genetics.

[83]  G. Schellenberg,et al.  Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[84]  D. Clair,et al.  Association within a family of a balanced autosomal translocation with major mental illness , 1990, The Lancet.

[85]  M. Owen,et al.  New findings from genetic association studies of schizophrenia , 2009, Journal of Human Genetics.

[86]  P. Buckley.  Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia , 2009 .

[87]  Jennifer E. Chubb,et al.  The DISC locus in psychiatric illness , 2008, Molecular Psychiatry.

[88]  S. Purcell,et al.  Family-based association study of lithium-related and other candidate genes in bipolar disorder. , 2008, Archives of general psychiatry.

[89]  K. Kaibuchi,et al.  DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. , 2007, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[90]  K Mizuguchi,et al.  Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia , 2007, Molecular Psychiatry.

[91]  H. Hwu,et al.  Linkage of schizophrenia with chromosome 1q loci in Taiwanese families , 2003, Molecular Psychiatry.

[92]  M Tohyama,et al.  Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth , 2003, Molecular Psychiatry.

[93]  A Keith Dunker,et al.  Intrinsic disorder and protein function. , 2002, Biochemistry.