Study Report

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Basic Info

Reference	Hamshere, M. L.,2012 PMID: 22614287
Citation	Hamshere, M. L., J. T. Walters, et al. (2012). "Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC." Mol Psychiatry.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	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
SNP/Region/Marker Size	78 SNPs
Predominant Ethnicity	Caucasian
Population	British

Detail Info

Sample Diagnosis	DSM
Sample Status	CLOZUK: Patients taking clozapine provide blood samples to allow detection of adverse drug-effects. Through collaboration with Novartis, the manufacturer of a proprietary form of clozapine (Clozaril), we acquired blood from people with treatment-resistant schizophrenia according to the clozapine registration forms completed by treating psychiatrists. In the United Kingdom, treatment-resistant schizophrenia implies a lack of satisfactory response to adequate trials of at least two other antipsychotics. The CLOZUK sample has not been used in published genetic studies, although it has been used by the WTCCC2 as a replication sample in an article in press.Bipolar samples: The bipolar sample is an extension of the sample in the study conducted by the Wellcome Trust Case Control Consortium,collected in the UK. Controls: Comprised 4539 individuals who were not screened for psychiatric illness.
Technique	Genotyping
Statistical Method	Chi square test
Result Summary	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.

Genetic factors reported by this study for BD

SNPs reported by this study for BD (count: 2)

SNP	Related Gene(s)	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
rs11191580	NT5C2	T/C		Association analysis: P-value = 0.018	Significant association was observed in BD. Significant association was observed in BD.	Positive
rs2021722	TRIM26	C/T		Association analysis: P-value = 0.034	Significant association was observed in BD. Significant association was observed in BD.	Positive

Other variants reported by this study for BD (count: 2)

Variant Name	Related Gene	Type	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
DRD2 TaqIA	DRD2	point mutation			Logistic Regression Analysis:for A1/A1, OR=2.17, 95%CI=0.70-6.77, P-value = 0.18 in BP-I;;OR=2.26, 95%CI=0.79-6.46, P-value = 0.13 in BP-II.For A1/A2, OR=0.83, 95%CI=0.34-2.03, P-value = 0.68 in BP-I;;OR=1.24, 95%CI=0.57-2.70, P-value = 0.58 in BP-II	No significant association was observed in BD. No significant association was observed in BD.	Negative
BDNF Val66Met	BDNF	point mutation	Val66Met		Logistic Regression Analysis:for Val/Val, OR=1.1, 95%CI=0.47-2.60, P-value = 0.82 in BP-I;;OR=0.4, 95%CI=0.16-0.97, P-value = 0.04* in BP-II.For Val/Met, OR=1.18, 95%CI=0.54-2.58, P-value = 0.67 in BP-I;;OR=1.39, 95%CI=0.69-2.80, P-value = 0.36 in BP-II	Significant association was observed in BP-II. Significant association was observed in BP-II.	Positive

Genes reported by this study for BD (count: 4)

Gene	Statistical Values/Author Comments	Result Category
TRIM26	We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disord...... We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder. More...	Positive
BDNF	The significant interaction effect for the Val/Val genotype of the BDNF Val66Met polymorphism and A1...... The significant interaction effect for the Val/Val genotype of the BDNF Val66Met polymorphism and A1/A2 genotype of DRD2/ANKK1 Taq1A polymorphism was found only in BP-II patients. We provide initial evidence that the BDNF Val66Me and DRD2/ANKK1 Taq1A polymorphisms interact only in BP-II disorder and that BP-I and BP-II are genetically distinct. More...	Positive
NT5C2	We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disord...... We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder. More...	Positive
DRD2	The significant interaction effect for the Val/Val genotype of the BDNF Val66Met polymorphism and A1...... The significant interaction effect for the Val/Val genotype of the BDNF Val66Met polymorphism and A1/A2 genotype of DRD2/ANKK1 Taq1A polymorphism was found only in BP-II patients. We provide initial evidence that the BDNF Val66Me and DRD2/ANKK1 Taq1A polymorphisms interact only in BP-II disorder and that BP-I and BP-II are genetically distinct. More...	Positive

Gene-gene interactions reported by this study for BD (count: 1)

Gene Group	Markers	Statistical Values	Author Comments	Result Category
BDNF DRD2	BDNF_Val66Met - DRD2_Taq-IA	Logistic Regression Analysis: For haplotype "BDNF Val/Val-(DRD2 Taq-IA A1/A1)", OR=0.56, 95%CI=0.12-2.70, P-value = 0.47 in BP-I;;OR=1.21, 95%CI=0.26-5.59, P-value = 0.81 in BP-II. For haplotype "BDNF Val/Val-(DRD2 Taq-IA A1/A2)", OR=2.16, 95%CI=0.66-7.07, P-value = 0.2 in BP-I;OR=4.17, 95%CI=1.33-13.08, P-value = 0.015 in BP-II. For haplotype "BDNF Val/Met-(DRD2 Taq-IA A1/A1)", OR=0.4, 95%CI=0.10-1.62, P-value = 0.2 in BP-I;;OR=0.33, 95%CI=0.09-1.21, P-value = 0.09 in BP-II. For haplotype "BDNF Val/Met-(DRD2 Taq-IA A1/A2)", OR=1.33, 95%CI=0.46-3.88, P-value = 0.6 in BP-I;;OR=0.92, 95%CI=0.36-2.341, P-value = 0.87 in BP-II.	Significant association was observed in BP-II for haplotype ...... Significant association was observed in BP-II for haplotype "BDNF Val/Val-(DRD2 Taq-IA A1/A2)", but no significant association was observed for other three haplotypes. More...	Positive

Genetic factors reported by this study for SZ and/or MDD

SNPs reported by this study for SZ/MDD

Disease	SNP	Related Gene(s)	Statistical Values	Description	Result Category
SZ	rs2021722	TRIM26	Association analysis:OR=1.17, P-value = 5.8E-04	Significant association was observed in SZ.	Positive association was observed in SZ.
SZ	rs11191580	NT5C2	Association analysis:OR=1.19, P-value = 0.01	Significant association was observed in SZ.	Positive association was observed in SZ.

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
SZ	NT5C2	We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.	Positive
SZ	TRIM26	We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.	Positive