The serotonin receptor HTR1B: Gene polymorphisms in attention deficit hyperactivity disorder

Abstract

Serotonin plays an essential role in cognition, locomotor activity, and the regulation of sleep, pain, mood, and aggression. Polymorphisms of the HTR1B gene have been implicated in a variety of psychiatric disorders including attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The objectives of this study were to: (i) expand our original investigation of the relationship between the HTR1B receptor gene and attention deficit/ hyperactivity and; (ii) to investigate a possible association of obsessive behaviors/perfectionism and the HTR1B gene in a sample of 203 families with an ADHD proband. Six single nucleotide polymorphisms (SNPs) of the HTR1B receptor gene were genotyped using standard methods. Evidence for an association between the HTR1B gene and ADHD as a qualitative diagnosis, or the inattentive and hyperactive-impulsive quantitative traits was not supported by either TDT single marker analysis or haplotype analysis. In addition we did not find evidence to suggest an association between HTR1B and perfectionism in this sample of ADHD families. INTRODUCTIONBoth attention-deficit/hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) are common neuropsychiatric disorders. ADHD has an estimated prevalence of 3%-5% of school-age children [Cantwell, 1996] and OCD is estimated to affect 2%-3% children and adolescents [Geller et al., 1998]. The co-occurrence of ADHD and OCD is not unusual in clinical populations. ADHD-like symptoms are seen in as many as 30% of youths with OCD [Geller et al., 2002] A recent publication reported obsessive-compulsive behaviors and increased perfectionism in 11% of school-age children diagnosed with ADHD [Arnold et al., 2005]. Evidence from family and twin studies suggests that genetic factors play a major role in the etiology of both ADHD and OCD [Thapar et al., 1999;Nestadt et al., 2000]. However, to date, there have not been any published articles examining possible shared genetic influences between ADHD and OCD.Serotonergic mechanisms have been implicated in the pathophysiology of ADHD and there is evidence supporting the notion that serotonin plays a mediator role in the hyperactive and impulsive behaviors associated with ADHD [Gainetdinov et al., 1999;Quist and Kennedy, 2001]. Serotonin became a leading target for investigation of the neurobiology of OCD largely due to the remarkable therapeutic effects of serotonin re-uptake inhibitors on obsessions and compulsions [Greist et al., 1995;Swinson et al., 1998] and the suggestion that there is a relationship between pre-treatment levels of the cerebro-spinal fluid metabolites of serotonin (i.e., 5-hydroxyindolacetic acid, homovanillic acid) and clinical response to medication targeting serotonin re-uptake [Baumgarten and Grozdanovic, 1998].Evidence for HTR1B as a susceptibility gene in ADHD was suggested in several independent studies that found preferential transmission of the ''G ''allele of the rs6296 (C861G, HincII) single nucleotide polymorphism (SNP) of the HTR1B gene in A...

A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with aggressive human behaviors

“…Genetic studies have shown an association between variation in the HTR1B gene and a number of phenotypes, including attention deficit hyperactivity disorder, [28][29][30] obsessive compulsive disorder, 31 antisocial alcoholism, 32 substance dependence and major depression. 33 However, many of the association findings have been inconsistent, [34][35][36] and this may be due to an incomplete awareness of the extent of functional variation within the HTR1B gene. Another difficulty in determining the contribution of the HTR1B gene to behavior is the lack of an appropriate behavioral measure.…”

Candidate gene studies of ADHD: a meta-analytic review

“…For the meta-analysis of rs6296, data were available from four TDT (Brookes et al 2006a;Ickowicz et al 2007;Li et al 2005;Smoller et al 2006) and Wve Case-Control/ HHRR (Bobb et al 2005;Guan et al 2008;Hawi et al 2002;Heiser et al 2007;Ribases et al 2009) studies. Based on the initial study , the 'G' allele was designated as the 'risk' allele.…”

Does serotonin deficit mediate susceptibility to ADHD?

“…In family-based studies Kent et al, reported significant (p=0.04) association of the T689 allele with ADHD cases (Kent et al 2002) which has not been confirmed by subsequent familybased (Banerjee et al, 2009, Heiser et al, 2007, Wigg et al, 2006, Xu et al, 2005 and case-control haploblock comprising rs6296, rs6297, rs130060, rs6298, rs130058 and rs11568817 is linked with the inattentive subtype of ADHD. The findings were not, however, replicated in a subsequent study (Ickowicz et al, 2007).…”