Sequencing of DISC1 pathway genes reveals increased burden of rare missense variants in schizophrenia patients from a northern Swedish population

• Published in: PloS one Vol. 6; no. 8; p. e23450
• Main Authors: 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-Göran, Medina Castello, Ignacio, Norrback, Karl-Fredrik, Goossens, Dirk, Van Steen, Kristel, Adolfsson, Rolf, Del-Favero, Jurgen
• Format: Journal Article Web Resource
• Language: English
• Published: United States Public Library of Science 11.08.2011; Public Library of Science (PLoS)
• Subjects: Adult; Age of Onset; Aging; Analysis; Biology; Biotechnology; Case-Control Studies; Cognition & reasoning; Computational Biology; Development and progression; DISC1; Disc1 protein; Disease; Disorders; DNA Mutational Analysis; Etiology; Frameshift Mutation - genetics; Gene Frequency - genetics; Gene sequencing; Genes; Genetic diversity; Genetic Predisposition to Disease; Genetics; Genetics & genetic processes; Genetics, Population; Genomes; Genomics; Grb2 protein; Génétique & processus génétiques; Health risk assessment; Humans; Life sciences; Medical research; Medicine; Memory; Mental disorders; Middle Aged; Mutation; Mutation, Missense - genetics; Nerve Tissue Proteins - genetics; Nervous system diseases; Pathogenesis; Pathology; Patients; Patologi; Population; Proteins; Psychiatry; Psychology; Psykologi; Reproducibility of Results; SAMHÄLLSVETENSKAP; Schizophrenia; Schizophrenia - epidemiology; Schizophrenia - genetics; Sciences du vivant; Sequence Analysis, DNA - methods; Signal Transduction - genetics; SOCIAL SCIENCES; Socialvetenskap; Studies; Subgroups; Sweden - epidemiology; Young Adult; Sweden; Belgium
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023450

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.