2A Receptor Gene Research Articles

The relationship between melatonin receptor 1A gene (MTNR1A) polymorphism and reproductive performance in Sarda breed sheep

In several species the circadian changes in melatonin secretion acts as the organic informer of the photoperiodic trend. Some physiological functions, such as reproduction, are influenced by seasonal melatonin secretion. In small ruminants polymorphisms at the MTNR1A gene are associated with non-seasonal breeding. The aim of this research was to evaluate if the MTNR1A gene polymorphism influences first conception, second and third lambing in Sarda breed sheep. Two-hundred ewe lambs, born between 10th November and 10th December 2008, were randomly chosen from four selected farms and genotyped for the A612G polymorphism at the MTNR1A gene. To rule out a possible confounding effect of the low frequency of the A/A genotype in Sarda sheep, 800 ewe lambs were genotyped and 85 individuals were selected for each genotype (A/A, A/G and G/G). Fertile rams were given access to the selected ewe lambs from 30th July to 30th October 2009 during the first year, and from 1st May to 30th October 2010 and 2011 on the second and third year, respectively. Mating and lambing dates were recorded for each ewe during the three years. In the first year ewe lambs showed no differences among genotypes in their fertility rates, litter size and mean number of days from ram introduction to parturition. However, in the second and third year G/G and A/G genotypes showed, a shorter interval (expressed in days) from ram introduction to lambing, compared to A/A genotype (P<0.05). During the second year fertility rate for the G/G, A/G and A/A genotypes, were 91.7%, 90.2% and 89.9%, respectively; whereas in the third year fertility rates were 91.5% for G/G, 91.8% for A/G and 93.0% for A/A genotypes. We speculate that the similarity in fertility rates among different genotypes may be due to a carry-over effect because ew\\es carrying different genotypes were not separated. Results indicate that the MTNR1A gene polymorphism does not influence the onset of reproductive activity in Sarda ewe lambs, but this single nucleotide polymorphism (SNP) reveals its influence in the earlier reproductive resumption in the adult ewes. The interval from rams׳ introduction to lambing may be longer if animals with different genotypes were kept separated.

Association of 5-HT2A receptor gene polymorphisms with gastrointestinal disorders in Egyptian children with autistic disorder.

Gastrointestinal disturbances (GID) are frequently reported in children with autism spectrum disorders (ASD). Recently, mounting evidence suggests that there may be a genetic link for autism with gastrointestinal disturbances. We aimed to investigate whether there were any association between the -1438A/G, 102T/C and His452Tyr polymorphisms of the serotonin 2A receptor gene (5-HT2A) in Egyptian children with ASD and GID. Eighty children with autistic disorder and 100 healthy control children were examined. -1438A/G, 102T/C and His452Tyr polymorphisms of 5-HT2A were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant increase of the G allele and the GG genotype of the -1438A/G polymorphism was observed in children with autism than control, but there were no significant differences in the frequencies either of the 102T/C genotype or His452Tyr genotype between the two groups. There was a significant increase of homozygote A allele of the -1438A/G and CC genotype of the 102T/C polymorphism in ASD children with GID. This study supports the possible involvement of the 5-HT2A receptor in the development of ASD and associated GID.

Influences of melatonin treatment, melatonin receptor 1A (MTNR1A) and kisspeptin (KiSS-1) gene polymorphisms on first conception in Sarda ewe lambs.

In order to investigate if the melatonin receptor 1A (MTNR1A) and kisspeptin (KiSS-1) genes influence the reproductive response to melatonin treatment, 510 Sarda ewe lambs were divided into groups C (control) and M; Group M received one melatonin implant (18mg). After 35 days rams were introduced for 40 days and subsequent lambing dates and number of newborns were recorded. The MTNR1A gene Exon II and KiSS-1 gene Exon I were amplified and genotyped by restriction fragment length polymorphism (RFLP) and single-strand conformation polymorphism analysis. Two single nucleotide polymorphisms (SNPs; C606T and G612A) in MTNR1A and one (G1035A) in KiSS-1 were found. The most frequent genotypes were G/G (63%) and C/C (53%) for MTNR1A and G/G (92%) for KiSS-1. Treated animals showed a higher lambing rate (P<0.05) and an advanced lambing date (P<0.05) compared with controls. The three SNPs did not influence the onset of reproductive activity. The majority of the G/G animals of Group M lambed before 190 days after ram introduction (P<0.05), while in Group C a higher number of G/G animals lambed after this date. Data revealed the positive effect of melatonin treatment on the time of first conception in ewe lambs and highlighted that the G/G genotype of the MTNR1A gene is able to influence the reproductive response to melatonin treatment.

The impact of cue learning, trait anxiety and genetic variation in the serotonin 1A receptor on contextual fear

In everyday life, aversive events are usually associated with certain predictive cues. Normally, the acquisition of these contingencies enables organisms to appropriately respond to threat. Presence of a threat cue clearly signals ‘danger’, whereas absence of such cues signals a period of ‘safety’. Failure to identify threat cues may lead to chronic states of anxious apprehension in the context in which the threat has been imminent, which may be instrumental in the pathogenesis of anxiety disorders.In this study, existing data from 150 healthy volunteers in a cue and context virtual reality fear conditioning paradigm were reanalyzed. The aim was to further characterize the impact of cue acquisition and trait anxiety, and of a single nucleotide polymorphism in the serotonin 1A receptor gene (5-HTR1A, rs6295), on cued fear and contextual anxiety before and after fear contingencies were explicitly introduced. Fear conditioned responding was quantified with fear potentiation of the eyeblink startle reflex and subjective fear ratings.First, we replicated previous findings that the inability to identify danger cues during acquisition leads to heightened anxious apprehension in the threat context. Second, in subjects who did not identify the danger cue initially, contextual fear was associated with trait anxiety after the contingencies were explicitly instructed. Third, genetic variability within 5-HTR1A (rs6295) was associated with contextual fear independent of awareness or trait anxiety.These findings confirm that failure to acquire cue contingencies impacts contextual fear responding, in association with trait anxiety. The observed 5-HTR1A effect is in line with models of anxiety, but needs further replication.

Genetic analysis of human extrapair mating: heritability, between-sex correlation, and receptor genes for vasopressin and oxytocin

As in other socially monogamous species, pair-bonded humans commonly engage in sex with a partner other than their primary mate. For men, extrapair mating is straightforwardly explained from an adaptive perspective in terms of the reproductive benefits of multiple mates. For women, whose reproductive output is limited by their reproductive biology rather than by their number of mates, the adaptive benefits of extrapair mating are less obvious. Dominant adaptive explanations focus on women obtaining genetic benefits for their offspring by mating with high-quality extrapair partners. Non-adaptive explanations have rarely been considered in humans, but recent findings in birds suggest that females' predisposition to extrapair mating may result from indirect selection, via direct selection on males and a between-sex genetic correlation. To examine the plausibility of this non-adaptive explanation of extrapair mating in women, we used data on recent extrapair mating in 7,378 Finnish twins and their siblings. Genetic modelling showed within-sex broad-sense heritability—i.e. the percentage of variation in extrapair mating due to genetic variation—of 62% in men and 40% in women. There was no between-sex correlation in extrapair mating, making indirect selection unlikely. Based on previous animal and human findings, we also tested for association of the arginine vasopressin receptor 1A gene (AVPR1A) and oxytocin receptor gene (OXTR) with extrapair mating. We found gene-based association for AVPR1A in women but not in men, and OXTR showed no significant association in either sex. Overall, these findings confirm genetic underpinnings of extrapair mating in humans, but do not suggest that women's predisposition to extrapair mating is due to selection on men.

Association between AVPR1A, DRD2, and ASPM and endophenotypes of communication disorders.

Speech sound disorder (SSD) is one of the most common communication disorders, with a prevalence rate of 16% at 3 years of age, and an estimated 3.8% of children still presenting speech difficulties at 6 years of age. Several studies have identified promising associations between communication disorders and genes in brain and neuronal pathways; however, there have been few studies focusing on SSD and its associated endophenotypes. On the basis of the hypothesis that neuronal genes may influence endophenotypes common to communication disorders, we focused on three genes related to brain and central nervous system functioning: the dopamine D2 receptor (DRD2) gene, the arginine-vasopressin receptor 1a (AVPR1A) gene, and the microcephaly-associated protein gene (ASPM). We examined the association of these genes with key endophenotypes of SSD - phonological memory measured through multisyllabic and nonword repetition, vocabulary measured using the Expressive One Word Picture Vocabulary Test and Peabody Picture Vocabulary Test, and reading decoding measured using the Woodcock Reading Mastery Tests Revised - as well as with the clinical phenotype of SSD. We genotyped tag single nucleotide polymorphisms in these genes and examined 498 individuals from 180 families. These data show that several single nucleotide polymorphisms in all three genes were associated with phonological memory, vocabulary, and reading decoding, with P less than 0.05. Notably, associations in AVPR1A (rs11832266) were significant after multiple testing correction. Gene-level tests showed that DRD2 was associated with vocabulary, ASPM with vocabulary and reading decoding, and AVPR1A with all three endophenotypes. Endophenotypes common to SSD, language impairment, and reading disability are all associated with these neuronal pathway genes.

Association of HTR2A T102C and A-1438G polymorphisms with susceptibility to major depressive disorder: a meta-analysis.

Serotonin 2A receptor (HTR2A) gene was implicated to be associated with major depressive disorder (MDD) susceptibility due to its role of key neurotransmitter in many physiologic processes. A great number of related studies reported in different populations have emerged. The results of these studies, however, have been inconsistent and thereby definite conclusions are difficult to establish. With the cumulative data in recent years, it was necessary to carry out a comprehensive analysis of previous findings. Electronic databases were systematically searched for studies published before May 2013. Pooled odds ratios (OR) and 95 % confidence interval (CI) were estimated under three different genetic models. Subgroup and sensitivity analyses were also performed. A total of 21 studies, 3,299 patients and 4,092 controls, met the selection criteria. 15 studies included HTR2A T102C polymorphism (with a total of 2,409 patients and 3,130 controls), and 9 studies included HTR2A A-1438G polymorphism (with a total of 1,510 patients and 2,281 controls). Our results showed that no significant association of MDD susceptibility with T102C polymorphism was found in allelic analysis and genotypic analysis (For T vs. C: OR = 1.06, 95 % CI = 0.95-1.18, P = 0.307; For TT + TC vs. CC: OR = 1.07, 95 % CI = 0.90-1.28, P = 0.451; For TT vs. TC + CC: OR = 1.08, 95 % CI = 0.95-1.22, P = 0.235). With respect to A-1438G polymorphism, however, carriers with A allele tend to suffer from MDD (AA + AG vs. GG: OR = 1.20, 95 % CI = 1.02-1.43, P = 0.030). When stratified by race for T102C polymorphism and A-1438G polymorphism of the HTR2A, we found no significant association. In conclusions, our study suggests that the A allele of A-1438G polymorphism might play a role in susceptibility to MDD. On the contrary, T102C polymorphism does not seem to be capable of modifying MDD risk.

P.1.a.027 Second-to-fourth digit ratio is associated with cognitive empathy in men depending on common polymorphism in the oxytocin receptor gene

Empathy is the ability to recognize and share in the emotions of others. It can be considered a multifaceted concept with cognitive and emotional aspects. Little is known regarding the underlying neurochemistry of empathy and in the current study we used a neurogenetic approach to explore possible brain neurotransmitter pathways contributing to cognitive and emotional empathy. Both the oxytocin receptor (OXTR) and the arginine vasopressin receptor 1a (AVPR1a) genes contribute to social cognition in both animals and humans and hence are prominent candidates for contributing to empathy. The following research examined the associations between polymorphisms in these two genes and individual differences in emotional and cognitive empathy in a sample of 367 young adults. Intriguingly, we found that emotional empathy was associated solely with OXTR, whereas cognitive empathy was associated solely with AVPR1a. Moreover, no interaction was observed between the two genes and measures of empathy. The current findings contribute to our understanding of the distinct neurogenetic pathways involved in cognitive and emotional empathy and underscore the pervasive role of both oxytocin and vasopressin in modulating human emotions.

Serotonin risk factors for the development of hypertension in pregnancy.

To determine platelet serotonin (5-HT) concentrations and genotype and allele frequencies of serotonergic type 2A receptor gene (HTR2A) and 5-HT transporter gene (SLC6A4) in women with pre-eclampsia, gestational hypertension without proteinuria (PIH) and in control normotensive pregnant women. The study included 96 control women, 131 women with PIH and 84 women with pre-eclampsia (ICD-10 criteria) in the last trimester of pregnancy. Variants of the HTR2A T102C (rs6313) and SLC6A4 (5-HTTLPR and rs25531) were determined by the PCR and real-time PCR procedures. Platelet 5-HT concentrations were analyzed by the spectrofluorimetric method. The frequency of the 5HTTLPR and of HTR2A T102C genotypes or alleles was similar between three groups of pregnant women and was not associated with low platelet 5-HT concentrations observed in pregnant women with PIH or pre-eclampsia. The results confirm alterations in the peripheral 5-HT system in pregnancy-induced hypertension. Low platelet 5-HT concentration is a common feature of both PIH and pre-eclampsia. The results did not support the hypothesis that hypertension in pregnancy is a trait associated with polymorphic variants of the HTR2A and SLC6A4 or that they have a role in the predisposition to hypertensive disorders in pregnancy. The further studies are necessary to elucidate the role of 5-HT and genetic factors in the development of hypertensive disorders in pregnancy.

Pharmacogenomics in psychiatry: implications for practice.

Psychotropic medications are used for numerous psychiatric and neurologic disorders, and are associated with in some cases life-threatening adverse effects, high acquisition costs, stringent monitoring requirements, and potential interactions with other medications. Because of the risks of adverse effects and need for adherence, risk mitigation strategies are being implemented to protect consumers. An understanding of receptor activities, cytochrome P450 2D6 and 2C19 metabolism, overlapping pharmacology, and polymorphic biomarkers for the dopamine 2 D2 receptor gene (DRD2) and dopamine 3 D3 receptor gene (DRD3), serotonin 2A and 2C receptor genes (5HTR2A and 5HTR2C), and human leukocyte antigen (HLA) variants creates opportunities for the integration of pharmacogenomics, and can assist in the application of personalized medicine in this arena. In this review, we discuss the current impression of pharmacogenomic principles pertaining to select psychotropics, with attention given to the atypical antipsychotics, due to their wide use across a broad spectrum of psychiatric disorders (e.g. bipolar disorder, depression, schizophrenia). Patents involving aripiprazole, clozapine, olanzapine, and risperidone will be discussed.

Gene expression profiling in understanding the molecular pathogenesis of and response to canakinumab therapy in traps

TNF receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease causing unprovoked fevers, myalgia, abdominal pain, rash, headaches, and, in severe cases, AA amyloidosis. It is an autosomal dominant condition resulting from variants in the TNF super family receptor 1A (TNFRSF1A) gene [1]. A hallmark of TRAPS is a huge activation of the inflammatory response in the absence of autoantibodies or antigen-specific T-cells [1]. Canakinumab (CAN) is a high-affinity, fully human, selective, anti-IL-1β monoclonal antibody, developed for the treatment of autoinflammatory diseases [2].

Influence of melatonin receptor 1A gene polymorphisms on seasonal reproduction in Sarda ewes with different body condition scores and ages

In several species, circadian changes in melatonin concentrations play a key role in the photoperiodic control of seasonality. In sheep, two silent mutations in the melatonin receptor 1A gene (MTNR1A) at positions 606 and 612 of the exon II are associated with seasonal reproduction. However, in some sheep breeds, no relationships have been found between MTNR1A polymorphisms and reproductive seasonality. This lack of relationship could be due to effects of breed, body condition, age, and/or environmental conditions. Thus, the present study was conducted with the Sarda sheep breed with the aim of documenting the effect of MTNR1A gene polymorphisms on reproductive resumption and to evaluate whether such this effect was modified by differences in body condition score (BCS) and age. Six hundred three- to six-year-old multiparous ewes with BCSs between 2.5 and 3.5 were selected. Genomic DNA was extracted and subjected to PCR to amplify the ovine exon II of the MTNR1A gene. The amplicons were subjected to digestion with the restriction enzymes RsaI and MnlI to detect the T606C and A612G polymorphisms, respectively. Ewes carrying the G/G, G/A, C/C, and C/T genotypes exhibited higher fertility rates (P<0.05) and fewer numbers of days between the introduction of rams and parturition (P<0.05) than did the A/A and T/T genotypes. The data revealed that the MTNR1A gene polymorphisms influenced spring reproductive resumption in the Sarda sheep breed. Moreover, the data also indicated that, over the limited ranges evaluated in this study, BCS and age had no significant influence on reproductive activity.

Meta-analysis of 5-hydroxytryptamine type 2A receptor polymorphisms and migraine susceptibility

Epidemiologic studies have investigated the association of polymorphisms in 5-hydroxytryptamine type 2A receptor (5HT2A) gene and migraine susceptibility, but the results of those studies are inconclusive. To obtain a more systematic estimation of the association, we conducted a comprehensive search to examine all the eligible studies of 5HT2A polymorphisms and migraine risk. The odd ratios (ORs) with 95% confidence intervals (CIs) were used to determine the strength of the association. Publication bias was analyzed by Begg's funnel plots. Seven eligible studies regarding 5HT2A T102C and A-1438G polymorphisms with 721 cases and 713 controls were included in this meta-analysis. Overall, no significant associations were found between 5HT2A T102C (for T vs. C: OR = 1.029, 95% CI = 0.870–1.217, p = 0.739; for TT vs. CC: OR = 1.083, 95% CI = 0.760–1.544, p = 0.657; for TT + TC vs. CC: OR = 1.066, 95% CI = 0.802–1.416, p = 0.662; for TT vs. TC + CC: OR = 1.017, 95% CI = 0.774–1.336, p = 0.904) or A-1438G (for T vs. C: OR = 0.996, 95% CI = 0.726–1.365, p = 0.979; for TT vs. CC: OR = 0.983, 95% CI = 0.511–1.891, p = 0.960; for TT + TC vs. CC: OR = 1.118, 95% CI = 0.654–1.910, p = 0.684; for TT vs. TC + CC: OR = 0.890, 95% CI = 0.528–1.499, p = 0.661) polymorphisms and migraine risk. The further subgroup analysis by ethnicity, assay and disease type also found no significant association using four genetic models. Meanwhile, the publication bias analysis suggests that there is no publication bias in these studies. In conclusion, our current meta-analysis implies that 5HT2A T102C and A-1438G polymorphisms may be not risk factors in the pathogenesis of migraine.

Association between the arginine vasopressin receptor 1A (AVPR1A) gene and preschoolers’ executive functioning

Recent evidence implicates the arginine vasopressin (AVP) system in complex neuropsychological disorders which are characterized by deficits in executive functioning (EF). Despite the genetic contribution to EF, little is currently known about its molecular genetic basis. Drawing on research from social neuroscience and the role of related physiological systems in psychopathology, the current study hypothesized that variability in the AVP receptor 1a gene (AVPR1A) would be associated with EF in an epidemiological sample of 323 normally developing preschool-aged children. Using a family-based association design, the current study found that variability in the rs7298346 marker, located in the 5′-flanking region, was significantly related to a composite measure of EF in 4-year-old children after controlling for a variety of covariates and children’s theory of mind. The converse association between AVPR1A and theory of mind (after controlling for EF) was not significant, suggesting a level of specificity in this relationship. The results are discussed in terms of the difficulties faced by genetic association studies in teasing apart the behavioral phenotypes that characterize complex psychological diseases and the involvement of multiple physiological systems in human behavior.

Sequence analysis and identification of new variations in the coding sequence of melatonin receptor gene (MTNR1A) of Indian Chokla sheep breed

Melatonin receptor 1A gene is the prime receptor mediating the effect of melatonin at the neuroendocrine level for control of seasonal reproduction in sheep. The aims of this study were to examine the polymorphism pattern of coding sequence of MTNR1A gene in Chokla sheep, a breed of Indian arid tract and to identify new variations in relation to its aseasonal status. Genomic DNAs of 101 Chokla sheep were collected and an 824bp coding sequence of Exon II was amplified. RFLP was performed with enzyme RsaI and MnlI to assess the presence of polymorphism at position C606T and G612A, respectively. Genotyping revealed significantly higher frequency of M and R alleles than m and r alleles. RR and MM were found to be dominantly present in the group of studied population. Cloning and sequencing of Exon II followed by mutation/polymorphism analysis revealed ten mutations of which three were non-synonymous mutations (G706A, C893A, G931C). G706A leads to substitution of valine by isoleucine Val125I (U14109) in the fifth transmembrane domain. C893A leads to substitution of alanine by aspartic acid in the third extracellular loop. G931C mutation brings about substitution of amino acid alanine by proline in the seventh transmembrane helix, can affect the conformational stability of the molecule. Polyphen-2 analysis revealed that the polymorphism at position 931 is potentially damaging while the mutations at positions 706 and 893 were benign. It is concluded that G931C mutation of MTNR 1A gene, may explain, in part, the importance of melatonin structure integrity in influencing seasonality in sheep.

T102C and 1438 G/A Polymorphisms of the Serotonin 2A Receptor Gene in Etiology and Course of ADHD

The aim of this study was to investigate the -1438A>G and T102C polymorphisms of serotonin 2A (5-HT2A) receptor gene frequencies in patients with ADHD compared with a healthy control group, and to ...

THU0482 Gene Expression Profiling of Whole Blood Samples of TRAPS Patients Shows Insight into the Molecular Pathogenesis of TRAPS and Response to Canakinumab Treatment

BackgroundTNF receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease causing unprovoked fevers, myalgia, abdominal pain, rash, headaches, and, in severe cases, AA amyloidosis. It is an autosomal dominant condition resulting...

AB0861 Genetic Role of Serotonergic System on Pathogenesis of Primer Fibromyalgia

BackgroundFibromyalgia is a chronic pain syndrome, characterized by widespread pain and tenderness at spesific anatomical localizations.ObjectivesThe purpose is investigating candidate genes related to the serotonergic system which is thought to...

Serotonin 2A receptor gene (HTR2A) regulatory variants: possible association with severity of depression symptoms in children with autism spectrum disorder.

Our aim was to characterize the association of 2 functional single nucleotide polymorphisms (rs6311 and rs6314) in the serotonin 2A receptor gene (HTR2A) with severity of depression symptoms in children with autism spectrum disorder. These polymorphisms have been shown to be associated with depression symptom severity and response to selective serotonin reuptake inhibitor drugs in adults with diagnosed depressive disorder. Parents of 104 children with autism spectrum disorder rated their children's depressive symptoms using a validated scale based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. We compared severity of depression symptoms across the rs6311 and rs6314 genotypes, measured from the children's genomic DNA. Children homozygous for the G allele of rs6311 had significantly more severe depression symptoms than those with G/A or A/A genotypes (P=0.025). The effect size (partial eta-squared) was small (ηp=0.047) but was somewhat larger when we controlled for severity of generalized anxiety disorder symptoms (P=0.006, ηp=0.072). When we restricted our analyses to white participants, our results were essentially the same as for the entire sample (P=0.004, ηp=0.086). There was no significant association between rs6314 (C/C versus T carriers) and severity of depression. Our findings suggest that the HTR2A functional rs6311 polymorphism, which other studies have associated with differential HTR2A mRNA expression, may modulate the severity of depression symptoms in children with autism spectrum disorder. These tentative, hypothesis-generating findings need replication with larger, independent samples.

Converging translational evidence for the involvement of the serotonin 2A receptor gene in major depressive disorder.

An association between serotonin 2A receptor (5-HT2AR), encoded by HTR2A gene, and major depressive disorder (MDD) has been suggested. Here, we combined preclinical and ecological clinical approaches to explore the impact of impaired 5-HT2AR-mediated transmission on MDD or anxio-depressive-like phenotype in mice. Htr2a knock-out mice (Htr2a(-/-)) and wild-type mice were compared for the ability of chronic corticosterone to elicit some anxio-depressive-like phenotype in three behavioral paradigms (elevated plus maze, tail suspension test and splash test). Accordingly, two single nucleotide polymorphisms of the HTR2A gene (rs6314 ie His452Tyr and rs6313 ie 102C/T), which specific allelic variants may decrease 5-HT2AR-mediated transmission (as in Htr2a(-/-)mice), were studied in a sample of 485 Caucasian patients with MDD. In response to chronic corticosterone exposure, Htr2a(-/-) mice displayed more pronounced anxiodepressive-like phenotype than wild-type mice, as shown by a significant higher "emotionality score" (p<0.01). In patients, the C allele of rs6313 was more frequent in depressed patients (p=0.019) and was also associated with a more severe major depressive episode (p=0.03). This translational and ecological study involving constitutive Htr2a(-/-) knock-out mice and related SNPs in depressed patients suggests that a lower neurotransmission at the 5-HT2AR may favor the susceptibility and severity of MDE. It also suggests that specific allelic variants of the rs6313 and rs6314 may reduce 5-HT2AR-mediated transmission.