Hamshere, M L3; Walters, J T R3; Smith, R3; Richards, Alan4; Green, E3; Grozeva, D3; Jones, Ian5; Forty, L3; Jones, Leigh Robert6; Gordon-Smith, K3; Riley, B3; O'Neill, T3; Kendler, K S3; Sklar, P3; Purcell, S3; Kranz, J3; Morris, David Jackson7; Gill, M3; Holmans, P3; Craddock, N3; Corvin, A3; Owen, M J3; O'Donovan, M C3; Hansen, Thomas3; Olsen, Line3; Ingason, Andrés3; Schmock, Henriette3; Skjødt, Celina3; Rosengren, Anders3; Høffding, Louise.K.Enggaard3; Thygesen, Johan Hilge3; Werge, Thomas Mears8
1 Graduate School of Health and Medical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet2 Section of Neurology, Psychiatry and Sensory Sciences, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Institut for Odontologi - Tandsygdomslære5 Risø National Laboratory6 Odontologisk Institut, Tandlægeskolen7 Institut for Nordiske Studier og Sprogvidenskab, KU8 Section of Neurology, Psychiatry and Sensory Sciences, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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.Molecular Psychiatry advance online publication, 22 May 2012; doi:10.1038/mp.2012.67.
Molecular Psychiatry, 2013, Vol 18, Issue 6, p. 708-712