Serotonin (5-HT) receptor 5A sequence variants affect human plasma triglyceride levels

Abstract

Neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) work closely with leptin and insulin to fine-tune the metabolic and neuroendocrine responses to dietary intake. Losing the sensitivity to excess food intake can lead to obesity, diabetes, and a multitude of behavioral disorders. It is largely unclear how different serotonin receptor subtypes respond to and integrate metabolic signals and which genetic variations in these receptor genes lead to individual differences in susceptibility to metabolic disorders. In an obese cohort of families of Northern European descent (n = 2,209), the serotonin type 5A receptor gene, HTR5A, was identified as a prominent factor affecting plasma levels of triglycerides (TG), supported by our data from both genome-wide linkage and targeted association analyses using 28 publicly available and 12 newly discovered single nucleotide polymorphisms (SNPs), of which 3 were strongly associated with plasma TG levels (P < 0.00125). Bayesian quantitative trait nucleotide (BQTN) analysis identified a putative causal promoter SNP (rs3734967) with substantial posterior probability (P = 0.59). Functional analysis of rs3734967 by electrophoretic mobility shift assay (EMSA) showed distinct binding patterns of the two alleles of this SNP with nuclear proteins from glioma cell lines. In conclusion, sequence variants in HTR5A are strongly associated with high plasma levels of TG in a Northern European population, suggesting a novel role of the serotonin receptor system in humans. This suggests a potential brain-specific regulation of plasma TG levels, possibly by alteration of the expression of HTR5A.

Trajectory classes of violent behavior and their relationship to lipid levels in schizophrenia inpatients

“…First, although the common postulation indicates that lower TC levels, particularly LDL-C levels, lead to reduced central serotonin activity by changing the expression of the 5-HT-2 receptors (Golomb, 1998;Golomb et al, 2000;Kaplan et al, 1997), a recent study found that 5-HT-5A receptors may also regulate plasma TG levels (Zhang et al, 2010). Thus, lower levels in many lipid indexes, including TC, LDL-C, and TG, might be associated with more violence via reduced central serotonin activity modulated through different types of serotonin receptors.…”

A novel method, the Variant Impact On Linkage Effect Test (VIOLET), leads to improved identification of causal variants in linkage regions

“…Indeed, our research team had not considered rs39179 (minor allele frequency 2.6% in our cohort; present in 25 of the 258 families and explained 0.7% of the variation in triglycerides) a promising candidate and rather focused on other SNPs. 17,18 Our results suggest that either rs39179 or SNPs in strong linkage disequilibrium (LD) with rs39179 may be causal. Using SNAP, 36 a single ungenotyped SNP (rs10276884) in strong LD with rs39179 was identified.…”

“…16 Although this region has been densely genotyped, MGA yielded associations that explained little of the observed linkage. 17,18 Using VIOLET, a single SNP (rs39179) accounting for 24% of the LOD score was identified (but it did not reach the traditional CLA threshold). This SNP was only nominally associated in MGA (P ¼ 0.04) and was ranked eighty-ninth in the P-value ranking.…”

“…16 After dense single-nucleotide polymorphism (SNP) genotyping, associations were found, but only a modest portion of the linkage was explained. 17,18 Simulated data set -GAW17-simulated data set. GAW17 used the 1000 Genomes 19 exome sequence data 14,15 to generate a data set with 697 individuals in 8 pedigrees.…”

“…16 From the initial cohort, 1235 individuals from 258 families contributing to the linkage were selected for dense genotyping (Table 1) of 1048 tag SNPs using an Affymetrix MegAllele custom-designed array (Affymetrix, Santa Clara, CA, USA). 17,18,21 Additionally, 354 SNPs from chromosome 14 were available for analysis. Chromosome 14 SNPs were used to determine VIOLET's specificity.…”