title: 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits.
abstract: A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10(-5), OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.
authors.affiliation: 1] Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK.
authors.forename: P A
authors.initials: PA
authors.lastname: Thomson
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Parla
authors.affiliation: University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia.
authors.forename: A F
authors.initials: AF
authors.lastname: McRae
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kramer
authors.affiliation: Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: K
authors.initials: K
authors.lastname: Ramakrishnan
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yao
authors.affiliation: Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Soares
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: S W
authors.initials: SW
authors.lastname: Morris
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cardone
authors.affiliation: Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: S
authors.initials: S
authors.lastname: Cass
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Ghiban
authors.affiliation: 1] Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK [2] Institute for Molecular Medicine, Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: W
authors.initials: W
authors.lastname: Hennah
authors.affiliation: 1] Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK.
authors.forename: K L
authors.initials: KL
authors.lastname: Evans
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Rebolini
authors.affiliation: Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Millar
authors.affiliation: 1] Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK.
authors.forename: S E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: MacIntyre
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Watson
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK.
authors.forename: I J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: 1] University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia [2] Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: P M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: D H
authors.initials: DH
authors.lastname: Blackwood
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: McCombie
authors.affiliation: 1] Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Porteous
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics; D003071:Cognition; D004252:DNA Mutational Analysis; D003865:Major Depressive Disorder / Q000235:genetics; D005091:Exons; D005190:Family; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D001523:Mental Disorders / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics; D012606:Scotland; D044465:White People / Q000235:genetics
chemical_list: C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins