ابعاد کنترل روانشناختی والدین: ارتباطات با پرخاشگری فیزیکی و رابطه پیش دبستانی در روسیه

The dopamine system plays an important role in the regulation of attention and motor behavior, subsequently, several dopamine-related genes have been associated with Attention Deficit/Hyperactivity Disorder (ADHD). Among them are the dopamine receptors D1 and D5 that mediate adenylyl cyclase activation through coupling with Gs-like proteins. We thus hypothesized that the Gs-like subunit Gαolf, expressed in D1-rich areas of the brain, contributes to the genetic susceptibility of ADHD. To evaluate the involvement of the Gαolf gene, GNAL, in ADHD, we examined the inheritance pattern of 12 GNAL polymorphisms in 258 nuclear families ascertained through a proband with ADHD (311 affected children) using the transmission/disequilibrium test (TDT). Categorical analysis of individual marker alleles demonstrated biased transmission of one polymorphism in GNAL intron 3 (rs2161961; P = 0.011). We also observed significant relationships between rs2161961 and dimensional symptoms of inattention and hyperactivity/impulsivity (P = 0.003 and P = 0.008). In addition, because of recent evidence of imprinting at the GNAL locus, secondary analyses were split into maternal and paternal transmissions to assess a contribution of parental effects. We found evidence of strong maternal effect, with preferential transmission of maternal alleles for rs2161961A (P = 0.005) and rs8098539A (P = 0.035). These preliminary findings suggest a possible contribution of GNAL in the susceptibility to ADHD, with possible involvement of parent-of-origin effects.

Attention Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition characterized by a pattern of inattention, hyperactivity and impulsivity. Current hypotheses on the biological basis of ADHD have centered on the dysregulation of fronto-striatal circuits and the neurotransmitters involved in these pathways. In particular, accumulating evidence implicate altered dopamine signalling in the disorder (Davids et al., 2003, Durston, 2003, Seeman and Madras, 1998 and Viggiano et al., 2003) and genetic association of several genes engaged in dopamine signalling is supported by meta-analysis of pooled data (e.g. DRD4, DRD5, DAT1, and SNAP25) ( Thapar et al., 2005). We previously reported the association between the dopamine receptor D1 gene (DRD1) and ADHD ( Misener et al., 2004), particularly between one haplotype and inattention symptoms (P = 0.008). Recently, we replicated the association between this haplotype and inattentive behaviors in children selected for reading difficulties (P = 0.004) (Luca et al., submitted for publication). Positive findings were also found for one DRD1 marker in an ADHD case-control sample ( Bobb et al., 2005), although negative results were also obtained with smaller family-based samples for single markers ( Bobb et al., 2005 and Kirley et al., 2002). Our findings for DRD1 in ADHD symptoms are suggestive of a potential role of the D1/D5 signalling pathways in genetic susceptibility of this disorder. This is further supported by a large combined analysis of 14 independent samples of 1980 probands (P = 0.00005), odds ratio 1.24 ( Lowe et al., 2004) for DRD5 (a D1-like receptor). In the same vein, we have recently reported evidence of association between ADHD and the calcyon gene, a D1-interacting protein ( Laurin et al., 2005). D1/D5 signalling mediates executive abilities including working memory (Goldman-Rakic et al., 2000), attention (Bayer et al., 2000 and Granon et al., 2000), motor control (Dreher and Jackson, 1989 and Meyer, 1993), and reward and reinforcement mechanisms (Beninger and Miller, 1998). Impairment of those functions is often observed in individuals with ADHD (Arnsten and Li, 2005b, Lijffijt et al., 2005, Luman et al., 2005, Martinussen et al., 2005 and Willcutt et al., 2005). Moreover, a recent study in rodents suggested that D1 stimulation contributes to cognitive-enhancing effects of methylphenidate, a leading treatment for ADHD (Arnsten and Dudley, 2005a). D1 signalling is mediated in the brain by the heterotrimeric G proteins Gs and Golf (Corvol et al., 2001 and Zhuang et al., 2000), which cause activation of adenylyl cyclase, cAMP-dependant protein kinase, and DARPP32. D1 receptors also signal via phospholipase C-dependent mobilization of intracellular calcium (Undie and Friedman, 1990 and Wang et al., 1995), likely involving calcyon (Lezcano et al., 2000). Lesion experiments and knockout studies have indicated that the coupling of D1 receptors to adenylyl cyclase is mostly provided by Gαolf in the striatal neurons, and that Gαolf is required for D1-mediated behaviour and biochemical effects in the striatum (Corvol et al., 2001, Herve et al., 1993 and Zhuang et al., 2000). Gαolf appears to be highly regulated by receptor usage and availability of interacting/effector proteins (Corvol et al., 2004, Corvol et al., 2001, Herve et al., 2001, Herve et al., 1993, Iwamoto et al., 2004, Schwindinger et al., 2003 and Zhuang et al., 2000), suggesting that it represents a limiting factor in the coupling efficiency of D1 receptors. Based on our previous finding for DRD1 in ADHD symptoms and the regulatory role played by Gαolf in D1 signalling, we believe that the Gαolf gene, GNAL, is a reasonable candidate for involvement in ADHD susceptibility. This is further supported by the locomotor behaviour of the mice deficient for Gαolf. When tested in open field exercises, the GNAL+/− mice exhibit a slight decrease in basal locomotor activity, while the −/− mice display locomotor hyperactivity ( Belluscio et al., 1998 and Schwindinger et al., 2003) similar to a D1 knockout ( Xu et al., 1994a and Xu et al., 1994b). The GNAL gene is located on the short arm of chromosome 18 in a region that has been linked to bipolar disorder and schizophrenia ( Berrettini, 2000, Schwab et al., 2000 and Segurado et al., 2003), with some evidence of parent-of-origin effects ( Gershon et al., 1996, Nothen et al., 1999 and Stine et al., 1995). However, replication studies have led to conflicting results ( Van Broeckhoven and Verheyen, 1998 and Zill et al., 2003). In the present study, we sought evidence for association between GNAL and ADHD in a sample of clinically ascertained nuclear families. We tested for the non-random transmission of alleles of 12 single nucleotide polymorphisms (SNPs) using the transmission/disequilibrium test (TDT) statistic ( Spielman and Ewens, 1996). Given previous findings suggesting parent-of-origin effects at 18p and evidence of epigenetic modification of GNAL ( Corradi et al., 2005), we also assessed transmissions from mothers and fathers separately. Finally, we performed quantitative analysis using ADHD inattentive and hyperactive/impulsive symptom counts.