Study Report

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Basic Info

Reference	Reif, A., 2006 (a) PMID: 16389274
Citation	Reif, A., S. Herterich, et al. (2006). "A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function." Mol Psychiatry 11(3): 286-300.
Disease Type	Bipolar I Disorder & Schizophrenia
Study Design	case-control
Study Type	Mutation study and candidate-gene association study
Sample Size	195 chronic schizophrenic, 72 bipolar-I patients and 286 controls
SNP/Region/Marker Size	5 variants
Predominant Ethnicity	Caucasian
Population	German
Gender	125 male and 148 female patients, 150 male and 134 female controls
Age Group	adults : mean age=44 (SD=14) years of patients, mean age=35 (SD=13) years of controls

Detail Info

Sample Diagnosis	ICD-10
Sample Status	One hundred and ninety-five patients suffered from schizophrenic disorders according to ICD-10 criteria (56, paranoid type; 39, hebephrenic type; six, catatonic type; nine, undifferentiated type; 25, residual type; 7, SCZ simplex; 3, SCZ not otherwise specified; 13, delusional disorder; 37, schizoaffective disorder). Seventy-two inpatients suffered from BPD according to ICD-10 criteria. Only patients with at least one manic and one depressive episode leading to treatment were classified as BPD (i.e., strict bipolar-I criteria). While 82 SCZ spectrum disorder subjects had a positive family history for psychosis in first-degree relatives, 66 BPD patients had a positive family history, in almost all cases for depression or BPD. None of the subjects showed significant neurological comorbidity, epilepsy, mental retardation or other somatic disorders suggesting organic psychiatric disorder. Patients with substance-induced psychotic or affective episodes were excluded from the study as well.
Technique	genotyping, PCR amplification and sequencing
Statistical Method	Single association tests were performed by means of chi square tests using SPSS for Windows 9.0.. Tests for global haplotype associations and for significance of differences between controls and patients in estimated frequencies of specific haplotypes were performed using the GENECOUNTING/ PERMUTE utility of the GENECOUNTING software.
Result Summary	Single-marker association analysis showed that the exon 1c promoter polymorphism was linked to schizophrenia (SCZ), whereas synonymous coding region polymorphisms were not associated with disease. Long promoter alleles of the repeat polymorphism were associated with less severe psychopathology. Analysis of the mini-haplotype also revealed a significant association with SCZ. Mutational screening did not detect novel exonic polymorphisms in patients, suggesting that regulatory rather than coding variants convey the genetic risk on psychosis. Finally, promoter polymorphisms impacted on prefrontal functioning as assessed by neuropsychological testing and electrophysiological parameters elicited by a Go-Nogo paradigm in 48 patients (continuous performance test). Collectively these findings suggest that regulatory polymorphisms of NOS1 contribute to the genetic risk for SCZ, and modulate prefrontal brain functioning.

Genetic factors reported by this study for BD

Other variants reported by this study for BD (count: 19)

Variant Name	Related Gene	Type	Allele Change	Statistical Values	Author Comments	Result Category
NOS1 promoter VNTR	NOS1	VNTR	L/S	P-value = 0.156, X²=3.71, df=2	neither VNTR1 nor SNP1 were significantly associated with BP...... neither VNTR1 nor SNP1 were significantly associated with BPD More...	Negative
NOS1 SNP1	NOS1	point mutation	A/G	P-value = 0.863, X²=0.03, df=1	neither VNTR1 nor SNP1 were significantly associated with BP...... neither VNTR1 nor SNP1 were significantly associated with BPD More...	Negative
NOS1 exon13 SNP2	NOS1	point mutation	C/T (Ile/Ile)	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon15 IVS15+38C/T	NOS1	point mutation	C/T	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon16 2607C/T	NOS1	point mutation	C/T (Pro/Pro)	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon17 2712C/T	NOS1	point mutation	C/T (His/His)	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon17 IVS17+15A/G	NOS1	point mutation	A/G	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon18 SNP3	NOS1	point mutation	C/T (His/His)	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon19 IVS19+13T/G	NOS1	point mutation	T/G	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon20 137244A/G	NOS1	point mutation	A/G	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon21 3258C/T	NOS1	point mutation	C/T (Asp/Asp)	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon27 4065G/A	NOS1	point mutation	G/A (Val/Val)	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon27 4063G/A	NOS1	point mutation	G/A (Val/Ile)	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon27 IVS27+14T/G	NOS1	point mutation	T/G	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon27 4154G/A	NOS1	point mutation	G/A (Gly/Asp)	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon27 SNP5	NOS1	point mutation	C/A (Val/Val)	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon27 IVS27+9C/A	NOS1	point mutation	C/A	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon7 IVS7-15C/G	NOS1	point mutation	C/G	Mutations and SNPs detected in the mutational analysis		Trend
NOS1 exon29 SNP4	NOS1	point mutation	C/T	Mutations and SNPs detected in the mutational analysis		Trend

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

Gene	Statistical Values/Author Comments	Result Category
NOS1	No significant association was detected. No significant association was detected.	Negative

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

Other variants reported by this study for SZ/MDD

Disease	Variant Name	Related Gene	Type	Statistical Values	Description	Result Category
SZ	NOS1 exon27 SNP5	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon27 IVS27+9C/A	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon7 IVS7-15C/G	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon29 SNP4	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon20 137244A/G	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon21 3258C/T	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon18 SNP3	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon19 IVS19+13T/G	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon27 4154G/A	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon27 IVS27+14T/G	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon27 4063G/A	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon27 4065G/A	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 SNP1	NOS1	point mutation	P-value = 0.154, X²=2.03, df=2 in unsystematic SCZ, P-value = 0.004, X²=8.42, df=2 in systematic SCZ, P-value = 0.020, X²=5.42, df=2 in total sample with SCZ	SNP1 A/A and A/G genotypes were significantly more frequent among schizophrenic patients than among controls; there was no significant effect in the group A SCZ subgroup; the association between SNP1 and SCZ was mainly due to considerably higher frequencies of the A/A and A/ G genotypes in the group B SCZ subgroup	Positive
SZ	NOS1 exon13 SNP2	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 promoter VNTR	NOS1	VNTR	P-value = 0.355, X²=2.07, df=2 in unsystematic SCZ, P-value = 0.429, X²=1.70, df=2 in systematic SCZ, P-value = 0.353, X²=2.08, df=2 in total sample with SCZ	schizophrenic patients did not differ significantly from controls in dichotomized VNTR1 genotype frequencies; there was no significant effect of VNTR1 with regard to the two SCZ subgroups.	Negative
SZ	NOS1 exon17 2712C/T	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon17 IVS17+15A/G	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon15 IVS15+38C/T	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend
SZ	NOS1 exon16 2607C/T	NOS1	point mutation	Mutations and SNPs detected in the mutational analysis		Trend

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
SZ	NOS1	Collectively these findings suggest that regulatory polymorphisms of NOS1 contribute to the genetic risk for SCZ, and modulate prefrontal brain functioning.	Positive