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Functional polymorphisms in the serotonin 1B receptor gene (HTR1B) predict self-reported anger and hostility among young men.

ABSTRACT: We examined associations between haplotypes of the serotonin 1B receptor gene and individual differences in anger and hostility. Data were analyzed from a study of 361 university students (47% male). Participants were genotyped at five polymorphisms in the HTR1B gene (rs11568817, rs130058, rs6296, rs6297, rs13212041), including promoter and 3'UTR polymorphisms with opposite functional effects on gene expression. Participants reported their emotional states across 30 consecutive days for up to 4 years. Haplotype pairs were constructed statistically and assigned to a level of HTR1B expression based on the presence of the functional polymorphisms. Six haplotypes accounted for >97% of chromosomes. Three low expression haplotypes contained the 3'UTR variant (rs13212041 A-allele) that enables a microRNA-mediated reduction in expression. One intermediate expression haplotype contained the 3'UTR A-allele paired with the high-activity promoter. Two high expression haplotypes contained the 3'UTR variant (rs13212041 G-allele) that attenuates microRNA-mediated reduction in expression. Men with low expression haplotypes reported greater anger and hostility than men with one or two high expression haplotypes. Diplotype classification accounted for 8.4% of the variance in men's anger and hostility, primarily due to the 3'UTR polymorphism (rs13212041), but with some contribution of the functional promoter combination (rs11568817, rs130058). Associations with anger and hostility were not found in women. These findings extend our understanding of the genetic basis of anger and hostility by showing that newly characterized HTR1B haplotypes, particularly those with rs13212041, which modulates microRNA-mediated regulation of HTR1B expression, may have important implications for aggression-related phenotypes among young men.

SUBMITTER: Conner TS

PROVIDER: S-EPMC3312780 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Functional polymorphisms in the serotonin 1B receptor gene (HTR1B) predict self-reported anger and hostility among young men.

Conner Tamlin S TS Jensen Kevin P KP Tennen Howard H Furneaux Henry M HM Kranzler Henry R HR Covault Jonathan J

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20100101 1

We examined associations between haplotypes of the serotonin 1B receptor gene and individual differences in anger and hostility. Data were analyzed from a study of 361 university students (47% male). Participants were genotyped at five polymorphisms in the HTR1B gene (rs11568817, rs130058, rs6296, rs6297, rs13212041), including promoter and 3'UTR polymorphisms with opposite functional effects on gene expression. Participants reported their emotional states across 30 consecutive days for up to 4 ...[more]

PMID: 19350534

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Project description:BACKGROUND:The 5-hydroxytryptamine 1B receptor (5-HT1B) plays an essential role in the serotonin (5-HT) system and is widely involved in a variety of brain activities. HTR1B is the gene encoding 5-HT1B. Genome-wide association studies have shown that HTR1B polymorphisms are closely related to multiple mental and behavioral disorders; however, the functional mechanisms underlying these associations are unknown. This study investigated the effect of several HTR1B haplotypes on regulation of gene expression in vitro and the functional sequences in the 5' regulatory region of HTR1B to determine their potential association with mental and behavioral disorders. METHODS:Six haplotypes consisting of rs4140535, rs1778258, rs17273700, rs1228814, rs11568817, and rs130058 and several truncated fragments of the 5' regulatory region of HTR1B were transfected into SK-N-SH and HEK-293 cells. The relative fluorescence intensities of the different haplotypes and truncated fragments were detected using a dual-luciferase reporter assay system. RESULTS:Compared to the major haplotype T-G-T-C-T-A, the relative fluorescence intensities of haplotypes C-A-T-C-T-A, C-G-T-C-T-A, C-G-C-A-G-T, and C-G-T-A-T-A were significantly lower, and that of haplotype C-G-C-A-G-A was significantly higher. Furthermore, the effects of the rs4140535T allele, the rs17273700C-rs11568817G linkage combination, and the rs1228814A allele made their relative fluorescence intensities significantly higher than their counterparts at each locus. Conversely, the rs1778258A and rs130058T alleles decreased the relative fluorescence intensities. In addition, we found that regions from -?1587 to -?1371?bp (TSS, +?1), -?1149 to -?894?bp, -?39 to +?130?bp, +?130 to +?341?bp, and?+?341 to +?505?bp upregulated gene expression. In contrast, regions -?603 to -?316?bp and?+?130 to +?341?bp downregulated gene expression. Region +?341 to +?505?bp played a decisive role in gene transcription. CONCLUSIONS:HTR1B 5' regulatory region polymorphisms have regulatory effects on gene expression and potential correlate with several pathology and physiology conditions. This study suggests that a crucial sequence for transcription is located in region +?341?~?+?505?bp. Regions -?1587 to -?1371?bp, -?1149 to -?894?bp, -?603 to -?316?bp, -?39 to +?130?bp, and?+?130 to +?341?bp contain functional sequences that can promote or suppress the HTR1B gene expression.

Dataset Information

Functional polymorphisms in the serotonin 1B receptor gene (HTR1B) predict self-reported anger and hostility among young men.

Publications

Functional polymorphisms in the serotonin 1B receptor gene (HTR1B) predict self-reported anger and hostility among young men.

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