Study Report

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Basic Info

Reference	Gratacos, M.,2009 PMID: 19086053
Citation	Gratacos, M., J. Costas, et al. (2009). Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment. Am J Med Genet B Neuropsychiatr Genet 150B(6): 808-816.
Disease Type	Bipolar Disorder & Major Depressive Disorder
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	Total 3214 samples consisited of 2277 cases(203 with Bipolar Disorder,422 with Major Depression,168 with Obsessive-Compulsive Disorder,173 with Panic Disorder,229 with Eating Disorders,917 with Schizophrenia and other Psychotic disorders and 165 with Substance Abuse) and 937 controls(330 from Madrid and 607 from Reus)
SNP/Region/Marker Size	748 SNPs
Predominant Ethnicity	Caucasian
Population	Spainish
Gender	Males:44.3% in Bipolar Disorder cases,32.7% in Major Depression cases,34.0% in Obsessive-Compulsive Disorder cases,24.1% in Panic Disorder cases,7.4% in Eating Disorders cases,65.4% in Schizophrenia and other Psychotic disorders cases,72.6% in Substance Abuse cases,56.1% in Control Subset 1 (Madrid) and 51.7% in Control Subset 2 (Reus)
Age Group	Adults : Mean Age(SD)(years):44.96(14.60)in Bipolar Disorder cases,49.55(17.37) in Major Depression cases,35.92(11.22) in Obsessive-Compulsive Disorder cases,36.02(10.11) in Panic Disorder cases,24.42(6.42) in Eating Disorders cases,45.59(16.74) in Schizophrenia and other Psychotic disorders cases,39.0(14.3) in Substance Abuse cases,38.3(14.3) in Control Subset 1 (Madrid) and 46.8(16.49) in Control Subset 2 (Reus)

Detail Info

Sample Diagnosis	DSM
Sample Status	Both the clinical sample and the controls used in this study were obtained through the collaborative initiative of the Psychiatric Genetics Network (http//www.rgpg.net), supported by the Carlos III Research Institute in Spain. All participants in this Network have collected DNA samples and clinical data corresponding to different psychiatric diagnoses. All patients had a consensus diagnosis from two senior psychiatrists according to semi-structured interviews for DSM-IV criteria, namely: Structured Clinical Interview for DSMIV (SCID) [First et al., 1997], MINI InternationalNeuropsychiatric Interview (MINI) [Sheehan et al., 1998] and Psychiatric Research Interview for Substance and Mental Disorders (PRISM) [Hasin et al., 1995; Torrens et al., 2004]. Concordant kappa values between psychiatrists varied between 0.6 and 0.95. Details of the selection and recruitment of controls are given in Supplementary Materials and Methods Section. In summary, the first control sample (Reus) consisted of 615 population-based controls.The second control sample (Madrid) consisted of 335 healthy volunteers recruited from hospital blood donors in Hospital Ram on y Cajal.
Technique	genotyping
Statistical Method	the likelihood ratio test (LRT) for autosomal SNPs;chi-squared statistic for SNPs on the X chromosome;Permutation approach was used to address multiple comparisons
Result Summary	We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive-compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.

SNPs reported by this study for BD (count: 21)

SNP	Related Gene(s)	Statistical Values	Author Comments	Result Category
rs6668659	NPPB	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0028(corrected by genomic control, Reus), P-value = 0.0375(passed multiple testing correction, Madrid); OR(95% CI): Reus: 2.20 (1.41-3.44), Madrid: 1.71 (1.05-2.77)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs4669765	NTSR2	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0175(corrected by genomic control, Reus), P-value = 0.0002(passed multiple testing correction, Madrid); OR(95% CI): Reus: 1.72 (1.16-2.53), Madrid: 2.46 (1.55-3.91)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs4256166	PLD1	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0038(corrected by genomic control, Reus), P-value = 0.0506(passed multiple testing correction, Madrid); OR(95% CI): Reus: 0.16 (0.04-0.67), Madrid: 0.26 (0.06-1.18)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs275645	AGTR1	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0136(corrected by genomic control, Reus), P-value = 0.0029(passed multiple testing correction, Madrid); OR(95% CI): Reus: 0.64 (0.46-0.89), Madrid: 20.44(2.64-158.24)Dominant	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs2281180	ASTN1	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0012(corrected by genomic control, Reus), P-value = 0.0293(passed multiple testing correction, Madrid); OR(95% CI): Reus: 4.87 (2.07-11.45), Madrid: 2.63 (1.12-6.20)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs2250334	SSTR1	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0389(corrected by genomic control, Reus), P-value = 0.0018(passed multiple testing correction, Madrid); OR(95% CI): Reus: 0.60 (0.39-0.94), Madrid: 0.48 (0.30-0.76)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs2071220	GLRA1	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0460(corrected by genomic control, Reus), P-value = 0.0462(passed multiple testing correction, Madrid); OR(95% CI): Reus: 1.54 (1.06-2.24), Madrid: 1.55 (1.02-2.35)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs2071084	BDKRB1	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0030(corrected by genomic control, Reus), P-value = 0.0012(passed multiple testing correction, Madrid); OR(95% CI): Reus: 4.71 (1.90-11.70), Madrid: 6.75 (1.88-24.22)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs1503433	HTR1F	Single SNP association: In control and bipolar disorder samples: Log-additive Model, P-value = 0.0191(corrected by genomic control, Reus), P-value = 0.0205(passed multiple testing correction, Madrid); OR(95% CI): Reus: 1.35 (1.08-1.69), Madrid: 1.34 (1.05-1.72)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs1396860	CCKBR	Single SNP association: In control and bipolar disorder samples: Log-additive Model, P-value = 0.0079(corrected by genomic control, Reus), P-value = 0.0179(passed multiple testing correction, Madrid); OR(95% CI): Reus: 0.63 (0.46-0.86), Madrid: 0.68 (0.49-0.94)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs11684394	TACR1	Single SNP association: In control and bipolar disorder samples: Dominant Model, P-value = 0.0063(corrected by genomic control, Reus), P-value = 0.0005(passed multiple testing correction, Madrid); OR(95% CI): Reus: 0.61 (0.44-0.85), Madrid: 20.440.53 (0.36-0.76)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs10914453	HCRTR1	Single SNP association: In control and bipolar disorder samples: Log-additive Model, P-value = 0.040(corrected by genomic control, Reus), P-value = 0.0461(passed multiple testing correction, Madrid); OR(95% CI): Reus: 1.46 (1.16-1.85), Madrid: 1.29 (1.00-1.67)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs10860845	PMCH	Single SNP association: In control and bipolar disorder samples: Dominant Model, P-value = 0.0108(corrected by genomic control, Reus), P-value = 0.0094(passed multiple testing correction, Madrid); OR(95% CI): Reus: 1.73 (1.16-2.57), Madrid: 1.75 (1.14-2.68)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs10414815	POU2F2 ZNF574 GRIK5	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.040(corrected by genomic control, Reus), P-value = 5.3E-05(passed multiple testing correction, Madrid); OR(95% CI): Reus: 2.61(1.19-5.74), Madrid: 20.44(2.64-158.24)	It Showed Statistical Significance in the Different Categori...... It Showed Statistical Significance in the Different Categories of Psychiatric Disorders After Correction for Multiple Tests. More...	Positive
rs945032	BDKRB2	Single SNP association: In control and bipolar disorder samples: Dominant Model, P-value = 0.0098(corrected by genomic control, Reus), P-value = 0.0381(passed multiple testing correction, Madrid); OR(95% CI): Reus: 1.65 (1.17-2.34), Madrid: 1.51 (1.02-2.22)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs7720677	PRLR	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0002(corrected by genomic control, Reus), P-value = 0.0050(passed multiple testing correction, Madrid); OR(95% CI): Reus: 2.61(1.19-5.74), Madrid: 2.47 (1.34-4.56)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs9436299	LEPR LEPROT	Single SNP association: In control and bipolar disorder samples: Dominant Model, P-value = 0.0125(corrected by genomic control, Reus), P-value = 0.0464(passed multiple testing correction, Madrid); OR(95% CI): Reus: 1.56 (1.13-2.15), Madrid: 1.43 (1.00-2.05)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs758857	ADORA2B	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0412(corrected by genomic control, Reus), P-value = 0.004(passed multiple testing correction, Madrid); OR(95% CI): Reus: NA, Madrid: NA	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs7645772	TRH	Single SNP association: In control and bipolar disorder samples: Dominant Model, P-value = 0.0157(corrected by genomic control, Reus), P-value = 0.04997(passed multiple testing correction, Madrid); OR(95% CI): Reus: 1.62 (1.12-2.36), Madrid: 1.49 (1.00-2.24)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs6999100	TRIM55 CRH	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0201(corrected by genomic control, Reus), P-value = 0.0057(passed multiple testing correction, Madrid); OR(95% CI): Reus: 3.48 (1.39-8.69), Madrid: 5.53 (1.50-20.33)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
rs7567183	NTSR2	Single SNP association: In control and bipolar disorder samples: Recessive Model, P-value = 0.0332(corrected by genomic control, Reus), P-value = 0.0013(passed multiple testing correction, Madrid); OR(95% CI): Reus: 1.77 (1.12-2.78), Madrid: 2.53 (1.46-4.38)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive

Other variants reported by this study for BD (count: 3)

Variant Name	Related Gene	Type	Statistical Values	Author Comments	Result Category
LEPR hcv518168	LEPR	point mutation	Single SNP association:In control and bipolar disorder samples:Log-additive Model, P-value = 0.0469683(corrected by genomic control, Reus), P-value = 0.043(passed multiple testing correction, Madrid);OR(95% CI):Reus:1.33 (1.03-1.73), Madrid:1.33 (1.01-1.77)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
GRM7 hcv11751218	GRM7	point mutation	Single SNP association:In control and bipolar disorder samples:Recessive Model, P-value = 0.027787(corrected by genomic control, Reus), P-value = 0.0141933(passed multiple testing correction, Madrid);OR(95% CI):Reus:0.58 (0.37-0.91), Madrid:0.55(0.34-0.88)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive
ADRA1B hcv1738292	ADRA1B	point mutation	Single SNP association:In control and bipolar disorder samples:Recessive Model, P-value = 0.0463162(corrected by genomic control, Reus), P-value = 0.0288679(passed multiple testing correction, Madrid);OR(95% CI):Reus:0.41 (0.17-0.97), Madrid:0.38 (0.15-0.95)	Nominal statistical significance was observed as P-value < 0...... Nominal statistical significance was observed as P-value < 0.05 using both control sets under the same genotypic mode. More...	Positive

Genes reported by this study for BD (count: 22)

Gene	Statistical Values/Author Comments	Result Category
TACR1	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
PLD1	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
NTSR2	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
ADRA1B	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
GLRA1	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
PMCH	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
NPPB	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
HTR1F	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
GRIK5	Strong associations of GRIK5 to bipolar disorder have been identifiedã€‚ Strong associations of GRIK5 to bipolar disorder have been identifiedã€‚	Positive
GRM7	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
SSTR1	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
AGTR1	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
LEPR	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
TRH	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
CCKBR	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
PRLR	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
CRH	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
BDKRB2	In summary, we have identified a functional variant in the BDKRB2 gene strongly associated (odd rati...... In summary, we have identified a functional variant in the BDKRB2 gene strongly associated (odd ratios between 1.65 and 3.06) to several psychiatric disorders, mainly panic disorder, substance abuse and bipolar disorder. More...	Positive
BDKRB1	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
HCRTR1	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
ADORA2B	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive
ASTN1	Nominal associations with bipolar disorder was observed. Nominal associations with bipolar disorder was observed.	Positive