The 5HT1Dβ Receptor Gene in Bipolar Disorder A Family-based Association Study

The 5-HT 1B receptor has been implicated in several psychopathologies, including pathological aggression, alcoholism and suicide. To test these and related potential genetic relationships in a single population, the human 5-HT 1B receptor (h5-HTR 1B ) genotype for the G861C polymorphism was determined in 394 psychiatric patients and 96 healthy volunteers. Structured clinical interviews generated DSM III-R diagnoses. No significant association of the genotype or allele frequencies of the h5-HTR 1B G861C locus was observed with diagnoses of alcoholism, bipolar disorder, schizophrenia or a history of a suicide attempt. Exploratory analyses indicated an association of the genotype and allele frequencies of the h5-HTR 1B G861C locus with a history of substance abuse disorder (w 2 ¼ 9.51, df ¼ 2, p ¼ 0.009; w 2 ¼ 7.31, df ¼ 1, p ¼ 0.007, respectively) and with a diagnosis of a major depressive episode (w 2 ¼ 6.83, df ¼ 2, p ¼ 0.033; w 2 ¼ 5.81, df ¼ 1, p ¼ 0.016, respectively). Significant gene dose effects on the risk for substance abuse disorder and a major depressive episode were observed with the 861C allele (Armitage linearity tendency test:009, respectively). Substance abuse disorder and major depression appear to be associated with the h5-HTR 1B G861C locus in the patient population, but other psychopathologies such as bipolar disorder, schizophrenia, alcoholism, and suicide attempts were not found to be associated with this polymorphism. This preliminary result will need replication, given the limitations of association studies.

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“…In contrast, no association was found with bipolar disorder. This agrees with a report of a negative linkage finding (Mundo et al, 2001). …”

Section: Discussionsupporting

confidence: 94%

Substance Abuse Disorder and Major Depression are Associated with the Human 5-HT1B Receptor Gene (HTR1B) G861C Polymorphism

Huang

Oquendo

Friedman

et al. 2003

Neuropsychopharmacol

135

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“…Set 2: University of Toronto triads A total of 275 triads ascertained through probands with BP I or BP II disorders from Toronto and across Central Canada 23 were analyzed. Subjects were interviewed using SCID-I 24 and diagnoses were made using DSM-IV criteria by a 'best estimate' procedure.…”

Section: Subjectsmentioning

confidence: 99%

Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder

et al. 2003

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In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarraybased expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 5 0 -UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5 0 -UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (v 2 ¼ 9.6, one-sided P value ¼ 0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.

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“…16 Association tests of T371G and schizophrenia, bipolar disorders, and eating disorders have yielded negative results. 8,[16][17][18] G861C, a synonymous ('silent') SNP, has been commonly used for the study of association since it is quite informative. 5 A variety of reports of association of G861C have been published to phenotypes such as: antisocial alcoholism in the Finnish; 19 alcoholism in the presence of inactive aldehyde dehydrogenase 2 (ALDH2) in the Japanese; 20 a history of suicide attempts in EuropeanAmerican personality disorder patients; 21 minimum lifetime body mass index in Canadian bulimia nervosa patients; 22 and obsessive compulsive disorder.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the 5′-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression

et al. 2003

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We present evidence of complex balancing regulation of HTR1B transcription by common polymorphisms in its promoter. Computational analysis of the HTR1B gene predicted that a 5 0 segment, spanning common DNA sequence variations, TÀ261G, AÀ161T, and À182INS/ DELÀ181, contained a putative functional promoter. Using a secreted alkaline phosphatase (SEAP) reporter gene system, we found that the haplotype À261G_À182INSÀ181_AÀ161 enhanced transcriptional activity 2.3-fold compared with the haplotype TÀ261_À182INSÀ181_AÀ161. Conversely, À161T reversed this, and the net effect when À261G and À161T were in the same haplotype (À261G_À182INSÀ181_À161T) was equivalent to the major haplotype (TÀ261_À182INSÀ181_AÀ161). Electrophoretic mobility shift experiments showed that À261G and À161T modify the binding of transcription factors (TFs): À261G generates a new AP2 binding site, while alleles AÀ161 and À161T exhibit different binding characteristics to AP1. TÀ261G and AÀ161T were found to be in linkage disequilibrium (LD) with G861C in a European ancestry population. Interestingly, G861C has been reported to be associated with several psychiatric disorders. Our results indicate that HTR1B is the target of substantial transcriptional genetic regulation by common haplotypes, which are in LD with the HTR1B single-nucleotide polymorphism (SNP) most commonly used in association studies. Molecular Psychiatry (2003) 8, 901-910.

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The 5HT1Dβ Receptor Gene in Bipolar Disorder A Family-based Association Study

Abstract: The serotonin (5HT)

Cited by 22 publications

References 32 publications

Substance Abuse Disorder and Major Depression are Associated with the Human 5-HT1B Receptor Gene (HTR1B) G861C Polymorphism

Substance Abuse Disorder and Major Depression are Associated with the Human 5-HT1B Receptor Gene (HTR1B) G861C Polymorphism

Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder

Polymorphisms in the 5′-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression

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