Study Report

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Basic Info

Reference	Martucci, L., 2006 PMID: 16549338
Citation	Martucci, L., A. H. Wong, et al. (2006). "N-methyl-D-aspartate receptor NR2B subunit gene GRIN2B in schizophrenia and bipolar disorder: Polymorphisms and mRNA levels." Schizophr Res 84(2-3): 214-221.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control and family-based
Study Type	Candidate-gene association study
Sample Size	180 matched schizophrenia case-control pairs, 86 schizophrenia nuclear family trios and 318 bipolar disorder trios
SNP/Region/Marker Size	3 SNPs
Predominant Ethnicity	Caucasian
Population	Canadian
Gender	male/female ratio is 1: 1.11 of the schizophrenia sample, the male/female ratio is 1: 0.85 of the bipolar trio sample
Age Group	adults : The average age was 37 years of the schizophrenia sample, the average age of the probands was 41 years of the bipolar trio sample

Detail Info

Sample Diagnosis	DSM-IIIR/DSM-IV
Sample Status	A total of 86 nuclear families consisting of probands with schizophrenia and at least one first-degree relative were collected from hospitals in Toronto, Ontario, in addition to 192 schizophrenia case-control pairs. All probands had an independent clinical DSM-IIIR/DSM-IV diagnosis of schizophrenia from their referring psychiatrist, confirmed with a SCID (Structured Clinical Interview for DSM diagnosis). The bipolar trio sample consisted of 318 nuclear families from the Toronto area. The same diagnostic procedures were used as for the schizophrenia sample. The sample was divided in two groups: triads with psychotic probands (N =158) and triads with non-psychotic probands (N =160).
Technique	genotyping
Statistical Method	Informative polymorphisms and haplotype distribution were analyzed for genetic association in the nuclear family samples using the family-based association test (FBAT). Differences in allele frequencies between patients and controls were tested using the Chi-square association test. Haplotype distributions in the case-control sample were obtained with Cocaphase.
Result Summary	They detected genetic association between the G-200T marker and schizophrenia (p = 0.002), between T5988C and bipolar disorder (p = 0.02), and between A5806C and bipolar disorder with psychotic symptoms (p = 0.0038). The T-C-C haplotype was transmitted more frequently with bipolar disorder, but less often with schizophrenia, while the G-C-T haplotype was transmitted more often in schizophrenia. Significant differences were found in overall haplotype frequencies between schizophrenia cases and controls (p = 0.005). GRIN2B expression levels in schizophrenia, bipolar disorder and controls were not significantly different. The genetic findings suggest a role for GRIN2B in schizophrenia and bipolar disorder.

Genetic factors reported by this study for BD

Haplotypes reported by this study for BD (count: 6)

Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Author Comments	Result Category
GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	G-A-C	GRIN2B	P-value = 0.184876, Z=1.326		Negative
GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	G-C-C	GRIN2B	P-value = 0.269829, Z=-1.103		Negative
GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	G-C-T	GRIN2B	P-value = 0.448665, Z=-0.758		Negative
GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	T-C-T	GRIN2B	P-value = 0.081573, Z=-1.742		Negative
GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	T-C-C	GRIN2B	P-value = 0.015899, Z=2.411	A preferential transmission of haplotype T-C-C in the bipola...... A preferential transmission of haplotype T-C-C in the bipolar sample was detected. More...	Positive
GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	T-A-C	GRIN2B	P-value = 0.319957, Z=-0.995		Negative

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

Variant Name	Related Gene	Type	Allele Change	Statistical Values	Author Comments	Result Category
GRIN2B -200G/T	GRIN2B	point mutation	T/G	FBAT P-value = 0.37, z=0.898 in BP triads, P-value = 0.9, z=0.101 for BP psychotic	The bipolar nuclear families were also tested using FBAT, bu...... The bipolar nuclear families were also tested using FBAT, but no significant association was found with the entire bipolar sample, or with the subgroup of bipolar+psychotic symptoms. More...	Negative
GRIN2B A5806C	GRIN2B	point mutation	A/C	FBAT P-value = 0.69, z=0.395 in BP triads, P-value = 0.0038, z=2.892, after correction for multiple testing P-value = 0.008 for BP psychotic	No association was found between the A5806C polymorphism and...... No association was found between the A5806C polymorphism and either schizophrenia or bipolar disorder (both families and case-control). The 5806C allele was transmitted more frequently in bipolar patients with psychotic symptoms, even after multiple testing correction. More...	Positive
GRIN2B T5988C	GRIN2B	point mutation	T/C	FBAT P-value = 0.02, z=2.332, after correction for multiple testing P-value = 0.04 in BP triads, P-value = 0.051, z=1.945 for BP psychotic	In the bipolar sample, the 5988C allele was transmitted more...... In the bipolar sample, the 5988C allele was transmitted more frequently in the complete bipolar sample. More...	Positive

Genes reported by this study for BD (count: 1)

Gene	Statistical Values/Author Comments	Result Category
GRIN2B	GRIN2B expression levels in schizophrenia, bipolar disorder and controls were not significantly diff...... GRIN2B expression levels in schizophrenia, bipolar disorder and controls were not significantly different. The genetic findings suggest a role for GRIN2B in schizophrenia and bipolar disorder. More...	Positive

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

Haplotypes reported by this study for SZ/MDD

Disease	Markers	Haplotype	Related Gene(s)/Region(s)	Statistical Values	Description	Result Category
SZ	GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	T-C-T	GRIN2B	P-value = 0.102451, Z=-1.633 in schizophrenia family sample; P-value = 0.271 in schizophrenia case-controls sample	The overall difference in haplotype transmission between cases and controls is statistically significant (p =0.005).	Negative
SZ	GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	G-A-C	GRIN2B	P-value = 0.324213, Z=0.986 in schizophrenia family sample; P-value = 0.013 in schizophrenia case-controls sample	The overall difference in haplotype transmission between cases and controls is statistically significant (p =0.005).	Negative
SZ	GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	G-C-T	GRIN2B	P-value = 0.995395, Z=0.006 in schizophrenia family sample; P-value = 0.008 in schizophrenia case-controls sample	Haplotype analyses on the schizophrenia case-control sample also showed significant elevation in the frequency of haplotype G-C-T in schizophrenia, and T-C-C in controls. The overall difference in haplotype transmission between cases and controls is statistically significant (p =0.005).	Positive
SZ	GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	T-C-C	GRIN2B	P-value = 0.97519, Z=-0.031 in schizophrenia family sample; P-value = 0.01 in schizophrenia case-controls sample	Haplotype analyses on the schizophrenia case-control sample also showed significant elevation in the frequency of haplotype G-C-T in schizophrenia, and T-C-C in controls. The overall difference in haplotype transmission between cases and controls is statistically significant (p =0.005).	Positive
SZ	GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	G-C-C	GRIN2B	P-value = 0.650714, Z=-0.453 in schizophrenia family sample; P-value = 0.104 in schizophrenia case-controls sample	The overall difference in haplotype transmission between cases and controls is statistically significant (p =0.005).	Negative
SZ	GRIN2B_T200G - GRIN2B_A5806C - GRIN2B_T5988C	T-A-C	GRIN2B	P-value = 0.242452, Z=1.169 in schizophrenia family sample; P-value = 0.116 in schizophrenia case-controls sample	The overall difference in haplotype transmission between cases and controls is statistically significant (p =0.005).	Negative

Other variants reported by this study for SZ/MDD

Disease	Variant Name	Related Gene	Type	Statistical Values	Description	Result Category
SZ	GRIN2B -200G/T	GRIN2B	point mutation	P-value (corrected)=0.0003, X²=17.974, df=2 of allele frequencies and association analysis in the schizophrenia case-control sample; case-control P-value < 0.0001, corrected for multiple testing P-value = 0.0003, case-control+triad P-value = 0.0009 of G/G genotype for the combined family and case-control schizophrenia samples; case-control P-value < 0.0001, corrected for multiple testing P-value = 0.0003, case-control+triad P-value = 0.0027 of G allele for the combined family and case-control schizophrenia samples; FBAT P-value = 0.44, z=0.775 in SCZ triads	For the T-200G polymorphism, there was a statistically significant association between the G allele with schizophrenia in the case-control sample; for the G/G genotype as well as for the presence of the G allele. The result is still statistically significant after correcting for multiple testing. The nuclear families were tested for association using FBAT, showing no preferential transmission of either allele. Combining the z scores from the nuclear families and the case-control, we obtained an overall statistically significant result.	Positive
SZ	GRIN2B A5806C	GRIN2B	point mutation	P-value (corrected)=0.305, X²=2.373, df=2 of allele frequencies and association analysis in the schizophrenia case-control sample; FBAT P-value = 0.73, z=0.349 in SCZ triads	No association was found between the A5806C polymorphism and either schizophrenia or bipolar disorder (both families and case-control).	Negative
SZ	GRIN2B T5988C	GRIN2B	point mutation	P-value (corrected)=0.654, X²=0.849, df=2 of allele frequencies and association analysis in the schizophrenia case-control sample; FBAT P-value = 0.56, z=0.6 in SCZ triads	The T5988C polymorphism was not associated with schizophrenia in either sample.	Negative

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
SZ	GRIN2B	GRIN2B expression levels in schizophrenia, bipolar disorder and controls were not significantly different. The genetic findings suggest a role for GRIN2B in schizophrenia and bipolar disorder.	Positive