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DRD4 Gene and Human Behavior M. Monakhov. DRD4 gene and human behavior. March 15, 2015. DRD4 gene and human behavior Abstract DRD4 gene, encoding dopamine receptor type 4, is one of most popular candidates in genetic association studies of human behavior. Variable Number of Tandem Repeats (VNTR) region in exon III is associated with attention deficit hyperactivity disorder (ADHD), opioid dependence, and probably with many other phenotypes. In order to evaluate validity of these findings it is essential to understand the mechanism whereby DRD4 exon III VNTR may affect behavior. The mechanism necessarily includes several levels, starting from characteristics of receptor and leading, via intracellular and physiological processes, toward complex behavioral phenotypes. In vitro studies suggest that 7R allele of exon III VNTR is hypofunctional, relative to 2R and 4R alleles. D4 receptor regulates synthesis of melatonin in pineal gland. The pattern of changing concentration of melatonin in blood is associated with diurnal preference, and diurnal preference is associated with multiple forms of behavior. Elevated blood melatonin decreases cognitive performance. We hypothesize that DRD4 affects shape of blood melatonin profile which, in turn, modulates behavior. Hence, exon III VNTR may contribute to behavioral variability via it’s effect on blood melatonin levels. We propose series of experiments for testing this hypothesis. Introduction DRD4 gene The DRD4 gene encodes dopamine receptor type 4 (D4), one of five dopamine receptors in humans. The D4 belong to family of G protein coupled receptors. It is localized in plasma membrane. Upon activation with dopamine the receptor triggers various intracellular signaling processes, including inhibition of adenylate cyclase activity (Oak, Oldenhof et al. 2000). D4 receptor is found in various regions of the brain, including cerebral cortex, hippocampus, hypothalamus and striatum, and in other organs such as adrenal gland and testes (reviewed in (Tarazi and Baldessarini 1999)). Highest levels of DRD4 expression are detected in retina and pineal gland (Missale, Nash et al. 1998, Su, Wiltshire et al. 2004, Kim, Bailey et al. 2010). M. Monakhov. DRD4 gene and human behavior. March 15, 2015. The gene contains several polymorphic loci, including 48bp Variable Number of Tandem Repeats (VNTR) in exon III. The VNTR leads to variation in length of 3rd cytoplasmic loop of the protein. Eleven alleles of the VNTR were found worldwide – from 1 repeat (Li, Liu et al. 1999) to 11 repeats. Most common alleles are 2R, 4R and 7R (Chang, Kidd et al. 1996). Interestingly, the region is polymorphic in some other mammalian species such as dogs (Wan, Hejjas et al. 2013), cetaceans, but not mice and rats (Larsen, Mogensen et al. 2005). In vitro studies have demonstrated functional differences between the alleles. In reporter gene assay lowest transcriptional activity was shown for 7R, highest – for 2R, and intermediate – for 4R (Schoots and Van Tol 2003). There was no significant association between the VNTR and DRD4 expression in human post-mortem samples of frontal cortex (p = 0.1), however, carriers of 7R allele had lower expression values (Simpson, Vetuz et al. 2010). Number of repeats in this locus affects pharmacological profile of receptor: affinity to spiperone is increasing with length of repeat region, but only in presence of NaCl (Van Tol, Wu et al. 1992, Asghari, Schoots et al. 1994). Although, authors of the study noted that the differences are small and unlikely to have physiological or clinical relevance. The VNTR sequence can be deleted from the receptor without consequence to its binding profile (Asghari, Schoots et al. 1994), coupling to G proteins, and effect on calcium flux (Kazmi, Snyder et al. 2000). In cultured cells, transfected with DRD4 gene, potency of dopamine to inhibit cAMP formation was reduced for 7R variant, compared with 2R and 4R (Asghari, Sanyal et al. 1995). 10R variant was shown to be 2- to 3-fold more potent in dopamine-mediated coupling to adenylyl cyclase than 2R (Jovanovic, Guan et al. 1999). In transfected frog oocytes 2R and 7R variants were more active than 4R in respect to opening potassium channels (Wedemeyer, Goutman et al. 2007). The 7R variant is more sensitive to chaperone-like effect of quinpirole, than 2R and 4R (Van Craenenbroeck, Clark et al. 2005). Studies of receptor dimerization demonstrated that 2R and 4R, but not 7R, variants can form heterodimers with dopamine receptor D2S (short splicing form of D2). Accordingly, intracellular signalling mediated by D4 receptor was potentiated by activation of D2 receptor only when 2R or 4R variants, but not 7R, of D4 were used (González, Rangel-Barajas et al. 2011). Similar effect was observed in heterodimerization of D4 with D2L (long form of D2): binding of M. Monakhov. DRD4 gene and human behavior. March 15, 2015. D4 7R with D2L was less efficient, and functional consequences of the dimerization were less pronounced, than for 2R and 4R variants (Borroto-Escuela, Van Craenenbroeck et al. 2011). In case of homodimerization of D4 receptors the 2R and 4R formed more dimers than 7R, although 7R receptors had higher affinity to each other (but not toward 2R and 4R) (Van Craenenbroeck, Borroto-Escuela et al. 2011). One study reported that 7R variant, compared to 2R and 4R, has higher affinity to proteins Nck and Grb2, and the binding was mediated by SH3-binding motifs in 3rd cytoplasmic loop of D4 (Oldenhof, Vickery et al. 1998). Despite mixed evidence it appears that 7R variant corresponds to diminished receptor function, compared to 2R and 4R. Several other polymorphic markers were found in DRD4 gene, including 120bp VNTR in promoter region, 12bp and 13bp VNTRs in 1st exon, poly(G) STR in intron 1 and multiple SNP (Wong, Buckle et al. 2000). Functional analysis of these markers was conducted as well, although much less thoroughly than in case of exon III VNTR, which is considered so far the most important polymorphism of the gene, due to it’s large size and location in coding sequence. Association studies of DRD4 gene Since it’s discovery in 1992 (Van Tol, Wu et al. 1992) the DRD4 exon III VNTR became a popular object of genetic association studies. Initial interest was caused by observations of high affinity of atypical antipsychotic drug clozapine to D4 receptor, compared to D2 receptor (Van Tol, Bunzow et al. 1991), and findings of elevated DRD4 expression in schizophrenia (Seeman, Guan et al. 1993). Naturally, it was hypothesized that genetic variation in DRD4 may explain variations in individual susceptibility to schizophrenia and in response to clozapine. The results of early association studies of schizophrenia (Barr, Kennedy et al. 1993, Nanko, Hattori et al. 1993, Sommer, Lind et al. 1993) and clozapine response (Shaikh, Collier et al. 1993) were not significant. Subsequent research demonstrated that clozapine binds to multiple targets in the brain besides D4 receptors (Roth, Sheffler et al. 2004), and specific D4 antagonist is not effective in treatment of schizophrenia (Bristow, Kramer et al. 1997, Kramer, Last et al. 1997). Moreover, initial finding of elevated DRD4 expression in schizophrenic brains was not replicated (Oak, Oldenhof et al. 2000). M. Monakhov. DRD4 gene and human behavior. March 15, 2015. Meanwhile, in the middle 90-s researchers started to test associations between DRD4 and other mental disorders (e.g., alcoholism (George, Cheng et al. 1993), Parkinson disease (Nanko, Hattori et al. 1993)), as well as other behavioral phenotypes such as personality traits (Ebstein, Novick et al. 1996). The justification for selection of DRD4 gene for those tests was usually based on role of dopamine in reward and reinforcement. Since then significant number of association studies was published, implicating multiple phenotypes as diverse as creativity (Mayseless, Uzefovsky et al. 2013), pre-school aggression (Farbiash, Berger et al. 2013), incarceration rate (Schwartz and Beaver 2013), anorexia nervosa (Gervasini, Gordillo et al. 2013), longevity (Grady, Thanos et al. 2013), political attitude (Settle, Dawes et al. 2010), skiing and snowboarding (Thomson, Hanna et al. 2013). Many of these results were not replicated (e.g., see (Kluger, Siegfried et al. 2002) for meta-analysis of personality trait Novelty Seeking) and for many more no replication studies were published. However, associations of two phenotypes – ADHD (Wu, Xiao et al. 2012) and opioid dependence (Chen, Liu et al. 2011) - were supported by meta-analyses. What can we do to reveal which phenotypes are truly associated with DRD4 exon III VNTR? First, the mechanism (if any) of DRD4 role in behavior should be understood. Second, genetic association studies should be based on the understanding of this mechanism. A hypothesis to be tested in genetic association study should be clearly defined. Without such hypothesis one may justify virtually any number of statistical tests, and it will decrease statistical power. For instance, using broad hypothesis like “dopamine is implicated in reward” suggests testing all polymorphic markers in all dopamine-related genes, with all behaviors contingent on reward processing. The list of statistical tests in such case can be any long. Complex behavioral phenotypes, such as AHDH and substance abuse, are dependent on many factors, probably including genetic variants. All those factors would interact with each other and create picture that might be too complex to unravel in any study with reasonable sample size. But more proximal traits (“endophenotypes”), including characteristics of tissues and organs, could be relatively easier to tackle. Prediction of complex behaviors based on few genetic variants might be unlikely. But prediction of cellular and physiological phenotypes, based on genes implicated in cellular and tissue function, could be plausible. M. Monakhov. DRD4 gene and human behavior. March 15, 2015. Following sections describe how DRD4 gene polymorphism might be linked to such physiological phenotypes and ultimately to behavioral phenotypes. D4 and melatonin There are at least two lines of evidence that may elucidate function of D4 receptors in the brain.
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