[en] 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 approximately 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Moens, Lotte N.
De Rijk, Peter
Reumers, Joke
Van den Bossche, Maarten J. A.
Glassee, Wim
De Zutter, Sonia
Lenaerts, An-Sofie
Nordin, Annelie
Nilsson, Lars-Goran
Medina Castello, Ignacio
Norrback, Karl-Fredrik
Goossens, Dirk
Van Steen, Kristel ; Université de Liège - ULiège > Dép. d'électric., électron. et informat. (Inst.Montefiore) > Bioinformatique
Shih RA, Belmonte PL, Zandi PP, (2004) A review of the evidence from family, twin and adoption studies for a genetic contribution to adult psychiatric disorders. Int Rev Psychiatry 16: 260-283.
Williams HJ, Owen MJ, O'Donovan MC, (2009) New findings from genetic association studies of schizophrenia. J Hum Genet 54: 9-14.
Sanders AR, Duan J, Levinson DF, Shi J, He D, et al. (2008) No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. Am J Psychiatry 165: 497-506.
Betcheva ET, Mushiroda T, Takahashi A, Kubo M, Karachanak SK, et al. (2009) 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. J Hum Genet 54: 98-107.
St Clair D, Blackwood D, Muir W, Carothers A, Walker M, et al. (1990) Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336: 13-16.
Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, et al. (2005) Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci U S A 102: 8627-8632.
Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, et al. (2005) Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry 62: 1205-1213.
Curtis D, Kalsi G, Brynjolfsson J, McInnis M, O'Neill J, et al. (2003) 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. Psychiatr Genet 13: 77-84.
Ekelund J, Hennah W, Hiekkalinna T, Parker A, Meyer J, et al. (2004) Replication of 1q42 linkage in Finnish schizophrenia pedigrees. Mol Psychiatry 9: 1037-1041.
Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, et al. (2001) Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 10: 1611-1617.
Hamshere ML, Bennett P, Williams N, Segurado R, Cardno A, et al. (2005) Genomewide linkage scan in schizoaffective disorder: significant evidence for linkage at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19p13. Arch Gen Psychiatry 62: 1081-1088.
Hennah W, Thomson P, McQuillin A, Bass N, Loukola A, et al. (2009) DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry 14: 865-873.
Hwu HG, Liu CM, Fann CS, Ou-Yang WC, Lee SF, (2003) Linkage of schizophrenia with chromosome 1q loci in Taiwanese families. Mol Psychiatry 8: 445-452.
Macgregor S, Visscher PM, Knott SA, Thomson P, Porteous DJ, et al. (2004) A genome scan and follow-up study identify a bipolar disorder susceptibility locus on chromosome 1q42. Mol Psychiatry 9: 1083-1090.
Thomson PA, Harris SE, Starr JM, Whalley LJ, Porteous DJ, et al. (2005) Association between genotype at an exonic SNP in DISC1 and normal cognitive aging. Neurosci Lett 389: 41-45.
Chen QY, Chen Q, Feng GY, Lindpaintner K, Wang LJ, et al. (2007) Case-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population. J Psychiatr Res 41: 428-434.
Maeda K, Nwulia E, Chang J, Balkissoon R, Ishizuka K, et al. (2006) Differential expression of disrupted-in-schizophrenia (DISC1) in bipolar disorder. Biol Psychiatry 60: 929-935.
Palo OM, Antila M, Silander K, Hennah W, Kilpinen H, et al. (2007) Association of distinct allelic haplotypes of DISC1 with psychotic and bipolar spectrum disorders and with underlying cognitive impairments. Hum Mol Genet 16: 2517-2528.
Qu M, Tang F, Yue W, Ruan Y, Lu T, et al. (2007) Positive association of the Disrupted-in-Schizophrenia-1 gene (DISC1) with schizophrenia in the Chinese Han population. Am J Med Genet B Neuropsychiatr Genet 144B: 266-270.
Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, et al. (2003) Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 12: 3151-3159.
Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, et al. (2008) Family-based association study of lithium-related and other candidate genes in bipolar disorder. Arch Gen Psychiatry 65: 53-61.
Saetre P, Agartz I, De Franciscis A, Lundmark P, Djurovic S, et al. (2008) Association between a disrupted-in-schizophrenia 1 (DISC1) single nucleotide polymorphism and schizophrenia in a combined Scandinavian case-control sample. Schizophr Res 106: 237-241.
Kilpinen H, Ylisaukko-Oja T, Hennah W, Palo OM, Varilo T, et al. (2008) Association of DISC1 with autism and Asperger syndrome. Mol Psychiatry 13: 187-196.
Hashimoto R, Numakawa T, Ohnishi T, Kumamaru E, Yagasaki Y, et al. (2006) Impact of the DISC1 Ser704Cys polymorphism on risk for major depression, brain morphology and ERK signaling. Hum Mol Genet 15: 3024-3033.
Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, et al. (2005) DISC1 and neurocognitive function in schizophrenia. Neuroreport 16: 1399-1402.
Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, et al. (2005) A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia. Mol Psychiatry 10: 1097-1103.
Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, et al. (2007) Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A 104: 18280-18285.
Austin CP, Ky B, Ma L, Morris JA, Shughrue PJ, (2004) Expression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development. Neuroscience 124: 3-10.
Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, et al. (2007) Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell 130: 1146-1158.
Harrison PJ, (2004) The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology (Berl) 174: 151-162.
James R, Adams RR, Christie S, Buchanan SR, Porteous DJ, et al. (2004) Disrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria. Mol Cell Neurosci 26: 112-122.
Lipska BK, Peters T, Hyde TM, Halim N, Horowitz C, et al. (2006) Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs. Hum Mol Genet 15: 1245-1258.
Ozeki Y, Tomoda T, Kleiderlein J, Kamiya A, Bord L, et al. (2003) Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci U S A 100: 289-294.
Schurov IL, Handford EJ, Brandon NJ, Whiting PJ, (2004) Expression of disrupted in schizophrenia 1 (DISC1) protein in the adult and developing mouse brain indicates its role in neurodevelopment. Mol Psychiatry 9: 1100-1110.
Porteous DJ, Millar JK, (2006) Disrupted in schizophrenia 1: building brains and memories. Trends Mol Med 12: 255-261.
Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK, (2008) The DISC locus in psychiatric illness. Mol Psychiatry 13: 36-64.
Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, et al. (2005) A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol 7: 1167-1178.
Miyoshi K, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Katayama T, et al. (2004) DISC1 localizes to the centrosome by binding to kendrin. Biochem Biophys Res Commun 317: 1195-1199.
Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K, et al. (2003) Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth. Mol Psychiatry 8: 685-694.
Brandon NJ, Handford EJ, Schurov I, Rain JC, Pelling M, et al. (2004) Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders. Mol Cell Neurosci 25: 42-55.
Kamiya A, Tan PL, Kubo K, Engelhard C, Ishizuka K, et al. (2008) Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4: a candidate for psychiatric illnesses. Arch Gen Psychiatry 65: 996-1006.
Millar JK, Pickard BS, Mackie S, James R, Christie S, et al. (2005) DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310: 1187-1191.
Morris JA, Kandpal G, Ma L, Austin CP, (2003) 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. Hum Mol Genet 12: 1591-1608.
Ogawa F, Kasai M, Akiyama T, (2005) A functional link between Disrupted-In-Schizophrenia 1 and the eukaryotic translation initiation factor 3. Biochem Biophys Res Commun 338: 771-776.
Shinoda T, Taya S, Tsuboi D, Hikita T, Matsuzawa R, et al. (2007) DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. J Neurosci 27: 4-14.
Taya S, Shinoda T, Tsuboi D, Asaki J, Nagai K, et al. (2007) DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci 27: 15-26.
Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, et al. (2007) Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry 12: 74-86.
Millar JK, Christie S, Porteous DJ, (2003) Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun 311: 1019-1025.
Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT, (2006) Neurobiology of schizophrenia. Neuron 52: 139-153.
McClellan JM, Susser E, King MC, (2007) Schizophrenia: a common disease caused by multiple rare alleles. Br J Psychiatry 190: 194-199.
Bodmer W, Bonilla C, (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40: 695-701.
Ingman M, Gyllensten U, (2009) SNP frequency estimation using massively parallel sequencing of pooled DNA. Eur J Hum Genet 17: 383-386.
Druley TE, Vallania FL, Wegner DJ, Varley KE, Knowles OL, et al. (2009) Quantification of rare allelic variants from pooled genomic DNA. Nat Methods 6: 263-265.
Hennah W, Thomson P, Peltonen L, Porteous D, (2006) Genes and schizophrenia: beyond schizophrenia: the role of DISC1 in major mental illness. Schizophr Bull 32: 409-416.
Nakata K, Lipska BK, Hyde TM, Ye T, Newburn EN, et al. (2009) DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms. Proc Natl Acad Sci U S A 106: 15873-15878.
Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, et al. (2006) Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314: 1930-1933.
D'Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, et al. (1999) Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci U S A 96: 5598-5603.
Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, et al. (2007) A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 315: 525-528.
Song W, Li W, Feng J, Heston LL, Scaringe WA, et al. (2008) Identification of high risk DISC1 structural variants with a 2% attributable risk for schizophrenia. Biochem Biophys Res Commun 367: 700-706.
Childs B, Scriver CR, (1986) Age at onset and causes of disease. Perspect Biol Med 29: 437-460.
Addington AM, Gornick M, Duckworth J, Sporn A, Gogtay N, et al. (2005) GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol Psychiatry 10: 581-588.
Addington AM, Gornick M, Sporn AL, Gogtay N, Greenstein D, et al. (2004) Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified. Biol Psychiatry 55: 976-980.
Addington AM, Gornick MC, Shaw P, Seal J, Gogtay N, et al. (2007) Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories. Mol Psychiatry 12: 195-205.
Gornick MC, Addington AM, Sporn A, Gogtay N, Greenstein D, et al. (2005) Dysbindin (DTNBP1, 6p22.3) is associated with childhood-onset psychosis and endophenotypes measured by the Premorbid Adjustment Scale (PAS). J Autism Dev Disord 35: 831-838.
Vyas NS, Patel NH, Puri BK, (2011) Neurobiology and phenotypic expression in early onset schizophrenia. Early Interv Psychiatry 5: 3-14.
Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, et al. (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320: 539-543.
Dunker AK, Brown CJ, Lawson JD, Iakoucheva LM, Obradovic Z, (2002) Intrinsic disorder and protein function. Biochemistry 41: 6573-6582.
Dunker AK, Obradovic Z, (2001) The protein trinity--linking function and disorder. Nat Biotechnol 19: 805-806.
Dyson HJ, Wright PE, (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6: 197-208.
Cheng Y, LeGall T, Oldfield CJ, Dunker AK, Uversky VN, (2006) Abundance of intrinsic disorder in protein associated with cardiovascular disease. Biochemistry 45: 10448-10460.
Iakoucheva LM, Brown CJ, Lawson JD, Obradovic Z, Dunker AK, (2002) Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 323: 573-584.
Midic U, Oldfield CJ, Dunker AK, Obradovic Z, Uversky VN, (2009) Protein disorder in the human diseasome: unfoldomics of human genetic diseases. BMC Genomics 10 (Suppl 1): S12.
Raychaudhuri S, Dey S, Bhattacharyya NP, Mukhopadhyay D, (2009) The role of intrinsically unstructured proteins in neurodegenerative diseases. PLoS One 4: e5566.
Uversky VN, Oldfield CJ, Dunker AK, (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys 37: 215-246.
Uversky VN, Oldfield CJ, Midic U, Xie H, Xue B, et al. (2009) Unfoldomics of human diseases: linking protein intrinsic disorder with diseases. BMC Genomics 10 (Suppl 1): S7.
Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN, (2005) Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J 272: 5129-5148.
Dunker AK, Oldfield CJ, Meng J, Romero P, Yang JY, et al. (2008) The unfoldomics decade: an update on intrinsically disordered proteins. BMC Genomics 9 (Suppl 2): S1.
Kim PM, Sboner A, Xia Y, Gerstein M, (2008) The role of disorder in interaction networks: a structural analysis. Mol Syst Biol 4: 179.
Romero PR, Zaidi S, Fang YY, Uversky VN, Radivojac P, et al. (2006) Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci U S A 103: 8390-8395.
Mohan A, Uversky VN, Radivojac P, (2009) Influence of sequence changes and environment on intrinsically disordered proteins. PLoS Comput Biol 5: e1000497.
Schaefer C, Schlessinger A, Rost B, (2010) Protein secondary structure appears to be robust under in silico evolution while protein disorder appears not to be. Bioinformatics 26: 625-631.
Di Giorgio A, Blasi G, Sambataro F, Rampino A, Papazacharias A, et al. (2008) Association of the SerCys DISC1 polymorphism with human hippocampal formation gray matter and function during memory encoding. Eur J Neurosci 28: 2129-2136.
Leliveld SR, Hendriks P, Michel M, Sajnani G, Bader V, et al. (2009) Oligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C. Biochemistry 48: 7746-7755.
Eastwood SL, Hodgkinson CA, Harrison PJ, (2009) DISC-1 Leu607Phe alleles differentially affect centrosomal PCM1 localization and neurotransmitter release. Mol Psychiatry 14: 556-557.
Eyre-Walker A, (2010) Evolution in health and medicine Sackler colloquium: Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies. Proc Natl Acad Sci U S A 107 (Suppl 1): 1752-1756.
Mittag T, Kay LE, Forman-Kay JD, (2010) Protein dynamics and conformational disorder in molecular recognition. J Mol Recognit 23: 105-116.
American Psychiatry Association (1994) Diagnostic and Statistical Manual of Mental Disorders. Washington, DC American Psychiatric Press.
Nilsson L-G, Bäckman L, Erngrund K, Nyberg L, Adolfsson R, et al. (1997) The Betula prospective cohort study: memory, health and aging. Aging Neuropsychol Cognition 4: 1-32.
Nilsson L-G, Adolfsson R, Bäckman L, de Frias CM, Molander B, et al. (2004) Betula: A prospective cohort study on memory, health and agin. Aging Neuropsychol Cognition 11: 134-148.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559-575.
Wigginton JE, Cutler DJ, Abecasis GR, (2005) A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet 76: 887-893.
Li B, Leal SM, (2009) Discovery of rare variants via sequencing: implications for the design of complex trait association studies. PLoS Genet 5: e1000481.