title: Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC.
abstract: The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Heath Park, Cardiff, UK.
authors.forename: M L
authors.initials: ML
authors.lastname: Hamshere
authors.forename: J T R
authors.initials: JT
authors.lastname: Walters
authors.forename: R
authors.initials: R
authors.lastname: Smith
authors.forename: A L
authors.initials: AL
authors.lastname: Richards
authors.forename: E
authors.initials: E
authors.lastname: Green
authors.forename: D
authors.initials: D
authors.lastname: Grozeva
authors.forename: I
authors.initials: I
authors.lastname: Jones
authors.forename: L
authors.initials: L
authors.lastname: Forty
authors.forename: L
authors.initials: L
authors.lastname: Jones
authors.forename: K
authors.initials: K
authors.lastname: Gordon-Smith
authors.forename: B
authors.initials: B
authors.lastname: Riley
authors.forename: F A
authors.initials: FA
authors.lastname: O'Neill
authors.forename: T
authors.initials: T
authors.lastname: O'Neill
authors.forename: K S
authors.initials: KS
authors.lastname: Kendler
authors.forename: P
authors.initials: P
authors.lastname: Sklar
authors.forename: S
authors.initials: S
authors.lastname: Purcell
authors.forename: J
authors.initials: J
authors.lastname: Kranz
authors.forename: D
authors.initials: D
authors.lastname: Morris
authors.forename: M
authors.initials: M
authors.lastname: Gill
authors.forename: P
authors.initials: P
authors.lastname: Holmans
authors.forename: N
authors.initials: N
authors.lastname: Craddock
authors.forename: A
authors.initials: A
authors.lastname: Corvin
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.forename: M C
authors.initials: MC
authors.lastname: O'Donovan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000510:Alpha-Globulins / Q000235:genetics*; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001324:Autoantigens / Q000235:genetics*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000235:genetics; D020746:Calcium Channels, L-Type / Q000235:genetics*; D003024:Clozapine / Q000627:therapeutic use; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics* / Q000276:immunology*; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D000510:Alpha-Globulins; D014150:Antipsychotic Agents; D001324:Autoantigens; C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D009363:Neoplasm Proteins; C472380:SDCCAG8 protein, human; C011877:inter-alpha-inhibitor; D003024:Clozapine