Association between the oxytocin receptor (OXTR) gene and children's social cognition at 18 months.

At 18 months, children engage in a variety of social behaviors that reflect their nascent ability to understand the intentions of other people (e.g. joint attention, empathy, cooperation and self-recognition). Although numerous contextual factors have been shown to predict social cognition in young children, the genetic underpinnings of social-cognitive traits has been understudied in this age group. Owing to the known effects of oxytocin on adult social cognition and psychopathology, this study hypothesized that variability in the oxytocin receptor gene (OXTR) would be associated with social cognition in children at 18 months. Participants consisted of 350 children (182 males; 168 females) who were part of an ongoing longitudinal study that aimed to assess environmental and genetic contributions to children's cognitive and socio-emotional functioning. At 18 months, social cognition was measured using previously validated and developmentally sensitive tasks assessing children's joint attention, empathy, cooperation and self-recognition. Five potentially functional OXTR variants were genotyped: rs1042778, rs2254298, rs11131149, rs237897 and rs237899. A family-based association design was used to control for population admixture and stratification, and additional non-genomic covariates were controlled. Results showed that variability in rs11131149 was significantly associated with social cognition (P=0.009), with more copies of the major allele related to higher social cognition, and more copies of the minor (risk) allele associated with lower social cognition. A haplotype consisting of rs11131149-rs2254298 was also associated with social cognition (P=0.020). Implications for normative and pathological development are discussed, and key areas for future research are proposed.

Association of the KCNJ5 gene with Tourette Syndrome and Attention-Deficit/Hyperactivity Disorder.

Linkage and association of Tourette Syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) have previously been reported in the 11q24 chromosomal region. To identify the risk gene within the region we studied the potassium inwardly-rectifying channel J5 (KCNJ5) gene in a sample of 170 nuclear families with TS. We genotyped eight markers across the gene and observed biased transmission of haplotypes from parents to probands in this sample. We then tested these markers in an independent sample of 242 nuclear families with ADHD and found the same haplotype was significantly over transmitted to ADHD probands. Screening of the coding region of KCNJ5 in 48 probands with TS did not identify any variation that could explain the association of the haplotype. We also genotyped two microsatellite markers, one in the promoter and the other in the 3' region and found no evidence for association for either marker for TS, however, we found significant evidence for association with the 3' repeat and ADHD. A small gene (c11orf45) of unknown function lies within the first intron of KCNJ5 that is transcribed in the opposite orientation and this gene may regulate the expression of KCNJ5. We studied the correlation of the expression of KCNJ5 and the antisense transcript in brain tissues from control individuals and found that the antisense transcript and the short KCNJ5 isoform are co-expressed in three brain regions. The results of this study indicate that KCNJ5 is associated with TS and ADHD in our samples, however, the functional variant(s) remain to be identified.

Association of the ROBO1 gene with reading disabilities in a family-based analysis.

Linkage studies have identified a locus on chromosome 3 as reading disabilities (RD) and speech and sound disorder (SSD) susceptibility region, with both RD and SSD sharing similar phonological processing and phonological memory difficulties. One gene in this region, roundabout homolog 1 (ROBO1), has been indicated as a RD candidate and has shown significant association with measures of phonological memory in a population-based sample. In this study, we conducted a family-based association analysis using two independent samples collected in Toronto and Calgary, Canada. Using the two samples, we tested for association between ROBO1 single nucleotide polymorphisms (SNPs) and RD, along with quantitative measures for reading, spelling and phonological memory. One SNP, rs331142, which was selected based on its correlation with ROBO1 expression in brain tissue, was found to be significantly associated with RD in the Toronto sample with over transmission of the minor C allele (P = 0.001), correlated with low expression. This SNP is located ~200 bp from a putative enhancer and results for a marker within the enhancer, rs12495133, showed evidence for association with the same allele in both the Toronto and Calgary samples (P = 0.005 and P = 0.007). These results support previous associations between ROBO1 and RD, as well as correlation with low gene expression, suggesting a possible mechanism of risk conferred by this gene.

A family-based association analysis and meta-analysis of the reading disabilities candidate gene DYX1C1.

Reading disabilities (RD) have a significant genetic basis and have shown linkage to multiple regions including chromosome 15q. Dyslexia susceptibility 1 candidate gene 1 (DYX1C1) on chromosome 15q21 was originally proposed as a candidate gene with two potentially functional polymorphisms at the -3G/A and 1249G/T positions showing association with RD. However, subsequent studies have yielded mixed results. We performed a literature review and meta-analysis of the -3G/A and 1249G/T polymorphisms, including new unpublished data from two family-based samples. Ten markers in DYX1C1 were genotyped in the two independently ascertained samples. Single marker and -3G/A:1249G/T haplotype analyses were performed for RD in both samples, and quantitative trait analyses using standardized reading-related measures was performed in one of the samples. For the meta-analysis, we used a random-effects model to summarize studies that tested for association between -3G/A or 1249G/T and RD. No significant association was found between the DYX1C1 SNPs and RD or any of the reading-related measures tested after correction for the number of tests performed. The previously reported risk haplotype (-3A:1249T) was not biased in transmission. A total of 9 and 10 study samples were included in the meta-analysis of the -3G/A and 1249G/T polymorphisms, respectively. Neither polymorphism reached statistical significance, but the heterogeneity for the 1249G/T polymorphism was high. The results of this study do not provide evidence for association between the putatively functional SNPs -3G/A and 1249G/T and RD.

Arginine vasopressin 1a receptor gene and maternal behavior: evidence of association and moderation.

This study examined associations among maternal sensitivity, mothers' early adversity and the Arginine Vasopressin 1a Receptor (AVPR1A) gene. Early adversity in mothers' background has been found to be associated with lower maternal sensitivity. Animal literature suggests that variation in the AVPR1A gene is associated with parenting quality. The goal of the study was to examine the role of the AVPR1A gene in maternal sensitivity, especially under conditions of high early adversity. Participants included 151 Caucasian women from a community sample. The women were videotaped in their home while interacting separately with two of their children (target child = 18 months, older sibling <6 years). Evidence was found for an association between the AVPR1A gene and maternal sensitivity. Mothers with two copies of the long RS3 alleles were less sensitive than mothers with one or zero copies of the long alleles. This association was strongest under conditions of high maternal early adversity.

Mutation screen and association analysis of the glucocorticoid receptor gene (NR3C1) in childhood-onset mood disorders (COMD).

Depressive disorders are highly heterogeneous psychiatric disorders involving deficits to cognitive, psychomotor, and emotional processing. Considerable evidence links disruption to the hypothalamic-pituitary-adrenal (HPA) axis to the etiology of depression, with specific deficits reported in glucocorticoid receptor (GR)-mediated negative feedback. Given the role of GR-mediated negative feedback in mediating response to stress, and the clear link between stress and depression, it is plausible that polymorphisms in the GR gene (NR3C1) act to increase susceptibility. Maternal behavior in rats epigenetically alters a NGF1-A transcription factor binding-site in the promoter region of the GR gene, providing a mechanism by which environmental cues can regulate GR expression and thus response to stress. The analogous region of the human GR gene (NR3C1) has not been studied, but it is possible that polymorphisms in this region may alter the binding of transcription factors known to regulate GR expression. In this study, we have performed bioinformatic analyses on the promoter region of NR3C1 to identify conserved promoter sequences and predicted transcription factor binding sites. These regions were screened with denaturing high-performance liquid chromatography (DHPLC) and direct re-sequencing, and several novel polymorphic variants were identified. We genotyped nine polymorphisms across NR3C1 in a large sample of Hungarian nuclear families ascertained through affected probands with a diagnosis of childhood-onset mood disorders (COMD). Single-marker analysis provided little evidence for an association of this gene with COMD, but multi-marker analysis across a region of high linkage disequilibrium revealed modest evidence for the biased transmission of several haplotypes.

Association of ADHD and the Protogenin gene in the chromosome 15q21.3 reading disabilities linkage region.

Twin studies indicate genetic overlap between symptoms of attention deficit hyperactivity disorder (ADHD) and reading disabilities (RD), and linkage studies identify several chromosomal regions possibly containing common susceptibility genes, including the 15q region. Based on a translocation finding and association to two specific alleles, the candidate gene, DYX1C1, has been proposed as the susceptibility gene for RD in 15q. Previously, we tested markers in DYX1C1 for association with ADHD. Although we identified association for haplotypes across the gene, we were unable to replicate the association to the specific alleles reported. Thus, the risk alleles for ADHD are yet to be identified. The susceptibility alleles may be in a remote regulatory element, or DYX1C1 may not be the risk gene. To continue study of 15q, we tested a coding region change in DYX1C1, followed by markers across the gene Protogenin (PRTG) in 253 ADHD nuclear families. PRTG was chosen based on its location and because it is closely related to DCC and Neogenin, two genes known to guide migratory cells and axons during development. The markers in DYX1C1 were not associated to ADHD when analyzed individually; however, six markers in PRTG showed significant association with ADHD as a categorical trait (P = 0.025-0.005). Haplotypes in both genes showed evidence for association. We identified association with ADHD symptoms measured as quantitative traits in PRTG, but no evidence for association with two key components of reading, word identification and decoding was observed. These findings, while preliminary, identify association of ADHD to a gene that potentially plays a role in cell migration and axon growth.

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and childhood-onset mood disorders.

BACKGROUND/AIMS: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. METHODS: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. RESULTS: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. CONCLUSION: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

Association study between Gilles de la Tourette Syndrome and two genes in the Robo-Slit pathway located in the chromosome 11q24 linked/associated region.

Gilles de la Tourette Syndrome (GTS) is an inherited neuropsychiatric disorder characterized by the presence of motor and phonic tics. Previous genetic studies have identified linkage and association between GTS and the 11q24 chromosomal region. We selected for study, within this region, two possible susceptibility genes for GTS, the ROBO3 and ROBO4 genes. These two genes were selected because of the recent identification of SLITRK1 as a potential susceptibility gene for GTS based on a translocation breakpoint and the further finding of two mutations in the SLITRK1 gene in three patients with GTS. While thus far, the SLITRK1 gene appears to account for only a few cases of GTS, these findings, if confirmed, point to other genes in these pathways that may contribute to GTS. Based on this, we examined two genes in the Slit-Robo pathway involved in cell migration, axonal pathfinding, and/or neuronal differentiation because of their location in 11q24, a region previously identified as linked and associated with GTS. We selected six haplotype tagging single nucleotide polymorphisms (SNPs) for ROBO3 and four for ROBO4 and genotyped them in our sample of trios and sibpair families diagnosed with GTS. Based on 155 nuclear families with 255 affected children, we did not find evidence for association between GTS and either the ROBO3 or ROBO4 genes. Thus, these two genes are unlikely to be the susceptibility genes contributing to GTS on 11q24.

Association of the dopamine receptor D1 gene, DRD1, with inattention symptoms in families selected for reading problems.

Twin studies have provided evidence for shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) and specific reading disabilities (RD), with this overlap being highest for the inattentive symptom dimension of ADHD. Previously, we found evidence for association of the dopamine receptor D1 gene (DRD1) with ADHD, and with the inattentive symptom dimension in particular. This, combined with evidence for working memory (WM) deficits in individuals with RD or ADHD, and the importance of D1 receptors in attentional processes and WM function, suggests that DRD1 may be a common genetic influence underlying both disorders. Here, in a study of 232 families ascertained through probands with reading problems, we tested for association of the DRD1 gene with RD, as a categorical trait, and with quantitative measures of key reading component skills, WM ability, and inattentive symptoms. Although no associations were found with RD, or with reading component skills or verbal WM, we found evidence for association with inattentive behaviour. Specifically, DRD1 Haplotype 3, the haplotype previously found to be associated with inattentive symptoms in ADHD, is also associated with parent- and teacher-reported symptoms of inattention in this sample selected for reading problems (P=0.023 and 0.004, respectively). Together, the replicated finding of Haplotype 3 association with inattentive symptoms in two independent study samples strongly supports a role for DRD1 in attentional ability. Furthermore, the association of DRD1 with inattention, but not with RD, or the other reading and reading-related phenotypes analysed, suggests that DRD1 contributes uniquely to inattention, without overlap for reading ability.

Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder.

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.

Association study of the adrenergic receptors and childhood-onset mood disorders in Hungarian families.

The adrenergic system has been implicated in the etiology of depression based on a number of lines of evidence, particularly, the mechanism of some classes of antidepressants which increase the synaptic levels of norepinephrine. Further, several genome scans for mood disorders, both unipolar and bipolar, have indicated linkage to the chromosomal regions of 5q23-q33.3, 8p12-p11.2, 4p16, and 10q24-q26, the location of the adrenergic receptors alpha1B (ADRA1B), beta3 (ADRB3), alpha2C (ADRA2C), alpha2A (ADRA2A), and beta1 (ADRB1). In this manuscript, we report on the relationship of the adrenergic receptors and depression using a family based association approach and 189 families (223 affected children) with childhood-onset mood disorder (COMD) collected in Hungary. We found no significant evidence for an association with any of the 24 markers, in total, tested across these genes using single marker analysis or haplotypes of markers across these genes. The results in the present sample indicate that these nine genes are unlikely to be major susceptibility genes contributing to COMD.

The SNAP25 gene as a susceptibility gene contributing to attention-deficit hyperactivity disorder.

The synaptosomal-associated protein of 25 kDa gene (SNAP25) has been suggested as a genetic susceptibility factor in attention-deficit hyperactivity disorder (ADHD) based on the mouse strain coloboma. This strain is hemizygous for the SNAP25 gene and displays hyperactivity that responds to dextroamphetamine, but not to methylphenidate. Previously, we reported association of SNAP25 and ADHD using two polymorphisms. To further investigate this gene, we screened the exons for DNA variation and genotyped ten additional polymorphisms in an expanded sample of families from Toronto and a second sample of families collected in Irvine, CA. Significant results were observed in the Toronto sample for four markers, although not in the Irvine sample. The paper discusses the possible influence of the selection criteria on these differential results. The Irvine sample selected subjects that met the DSM-IV combined subtype diagnosis, whereas the Toronto sample included all subtypes. Analysis of the DSM-IV subtypes in the Toronto sample indicated that the differential results were not attributable to ADHD subtype. Differences in ethnicity, differential medication response, and other clinical characteristics of the samples cannot be ruled out at this time. Quantitative analysis of the dimensions of hyperactivity/impulsivity and inattention in the Toronto sample found that both behavioral traits were associated with SNAP25. Our findings continue to support SNAP25 in the susceptibility to ADHD.

Association study of CREB1 and childhood-onset mood disorders.

Several lines of evidence suggest that the cellular pathways involved in synaptic plasticity contribute to the risk of depression. These findings include the evidence that chronic antidepressant treatment upregulates the cAMP signal transduction cascade resulting in increased expression and function of the cAMP responsive element binding protein (CREB), a transcription factor that increases the expression of key growth factors involved in synaptogenesis and neurogenesis. Recently, linkage to CREB1 was reported for early-onset depression in families recruited from the Pittsburgh area. This finding was significant only in female sibling pairs from those families. Two specific DNA variants, -656G/A and a C insertion/deletion in intron 8, were identified in CREB1 that co-segregated with depression in two of the families. We sought to investigate the relationship of CREB1 to childhood-onset mood disorders (COMD) using a sample of 195 nuclear families (225 affected children) collected in Hungary. We genotyped the two CREB1 DNA variants previously identified as linked to depression as well as three additional polymorphisms spanning the gene. In addition, we genotyped the -656G/A DNA change and the intron 8 polymorphism in a sample of 112 probands with mood disorders collected in the Pittsburgh area and matched controls, and examined the distribution of alleles. The -656A allele was not observed in our samples and there was no evidence for association of the intron 8 polymorphism in either the sample from Pittsburgh (chi(2) = 0.061, 1 d.f., P = 0.803) or Hungary (chi(2) = 0.040, 1 d.f., P = 0.842). We found no evidence for an association with the other three polymorphisms or with the haplotypes of these markers. Further, we found no sex-specific relationship. Our results, therefore, do not support the previous evidence for this gene as a major factor contributing to depression.

Genetic study of the myelin oligodendrocyte glycoprotein (MOG) gene in schizophrenia.

Schizophrenia (SCZ) is a neuropsychiatric disorder that affects approximately 1% of the general population. The human leukocyte antigen (HLA) system has been implicated in several genetic studies of SCZ. The myelin oligodendrocyte glycoprotein (MOG) gene, which is located close to the HLA region, is considered a candidate for SCZ due to its association with white matter abnormalities and its importance in mediating the complement cascade. Four polymorphisms in the MOG gene (CA)n (TAAA)n, and two intronic polymorphisms, C1334T and C10991T, were investigated for the possibility of association with SCZ using 111 SCZ proband and their families. We examined the transmission of the alleles of each of these polymorphisms with the transmission disequilibrium test. We did not observe significant evidence for biased transmission of alleles at the (CA)n (chi2=2.430, 6 df, P=0.876) (TAAA)n (chi2=3.550, 5 df, P=0.616), C1334T (chi2=0.040, 1 df, P=0.841) and C10991T (chi2=0.154, 1 df, P=0.695) polymorphisms. Overall haplotype analysis using the TRANSMIT program was also not significant (chi2=7.954, 9 df, P=0.539). Furthermore, our results comparing mean age at onset in the genotype groups using the Kruskal-Wallis Test were not significant. Our case-control analyses (182 cases age-, sex- and ethnicity-matched with healthy controls) and combined z-score [(CA)n: z-score=-1.126, P=0.130; (TAAA)n: z-score=-0.233, P=0.408; C1334T: z-score=0.703, P=0.241; C10991T: z-score=0.551, P=0.291] were also not significant. Although our data are negative, the intriguing hypothesis for MOG in SCZ may warrant further investigation of this gene.

Support for EKN1 as the susceptibility locus for dyslexia on 15q21.

Dyslexia has been linked to a number of chromosomal regions including 15q. Recently a gene, EKN1, with unknown function in the linked region, was identified via a translocation breakpoint. This gene was further supported as a susceptibility locus by association studies in a Finnish sample. We investigated the possibility of this locus as a susceptibility gene contributing to dyslexia, analyzed as a categorical trait, and analyzed key reading phenotypes as quantitative traits using six polymorphisms including the two previously reported to be associated with dyslexia. In our sample of 148 families identified through a proband with reading difficulties, we found significant evidence for an association to dyslexia analyzed as a categorical trait and found evidence of association to the reading and related processes of phonological awareness, word identification, decoding, rapid automatized naming, language ability, and verbal short-term memory. However, association was observed with different alleles and haplotypes than those reported to be associated in a Finnish sample. These findings provide support for EKN1 as a risk locus for dyslexia and as contributing to reading component processes and reading-related abilities. Based on these findings, further studies of this gene in independent samples are now required to determine the relationship of this gene to dyslexia.

Glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region.

The glutamate system may be involved in the development of attention-deficit/hyperactivity disorder (ADHD) based on animal models and the role of N-methyl-D-aspartate receptors (NMDAR) in cognition and motor processes. A follow-up study of the first genome scan for ADHD identified significant evidence for linkage to the 16p13 region. The glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the NMDA receptor, resides in this region and a recent study has reported an association between this gene and ADHD. We tested for linkage between the alleles and haplotypes of four polymorphisms at the GRIN2A locus and ADHD in our sample of 183 nuclear families with 229 affected children. In contrast to previous findings, we did not identify any evidence for a relationship of these markers and ADHD. Owing to the role of GRIN2A in aspects of cognition, we investigated the relationship of this gene to the cognitive phenotypes of inhibitory control, verbal short-term memory and verbal working memory. There was no significant evidence of linkage between GRIN2A and these phenotypes. While the results were not significant in our sample, the previous association finding suggests that further study of this gene is warranted.

5'-untranslated region of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder.

Recently the molecular genetic basis of attention-deficit hyperactivity disorder (ADHD) has been the focus of a number of studies with the majority of these investigating the role of dopamine system genes. A great deal of attention has been focused on the possible involvement of the dopamine D4 receptor gene (DRD4) following a report of an association of ADHD with the allele containing seven copies of the 48-bp repeat in the third exon. In this paper we extended the search for the molecular explanation for the observed association by testing three polymorphisms in the region 5' to the dopamine receptor D4 gene transcription start site for linkage to ADHD. We specifically targeted polymorphisms in the region 5' to the start site of transcription as DNA variants in this region could alter the transcription level of the gene and hence the phenotype. We did not observe significant evidence for biased transmission of any of the alleles at these three polymorphisms to ADHD probands using the transmission disequilibrium test. We conclude that these three polymorphisms are not related to the ADHD phenotype.

Linkage study of polymorphisms in the gene for myelin oligodendrocyte glycoprotein located on chromosome 6p and attention deficit hyperactivity disorder.

Family and twin studies have shown that there is a substantial genetic contribution to both reading disabilities (RD) and attention deficit hyperactivity disorder (ADHD), and recent twin studies have suggested that the overlap between these phenotypes is largely due to common genetic influences. Studies using a linkage approach to search for genes for susceptibility to RD and ADHD have identified regions linked to each of these phenotypes separately, with recent studies suggesting that some chromosomal regions may contribute to both. Linkage to the human leukocyte antigen (HLA) region has been targeted in particular for RD and ADHD, as both of these disorders have been suggested to be autoimmune. Linkage to the HLA region of 6p for RD has now been reported by several groups. Alleles at two genes in the HLA (C4B and DRB1) have also been reported to be associated with ADHD, prompting one investigator to suggest a possible connection between the linkage of RD and ADHD to this region. The location of the gene for myelin oligodendrocyte glycoprotein (MOG), in the region of 6p with the strongest evidence for linkage to RD, and its proposed role as a minor component of myelin in the central nervous system suggest that it may be a factor in neuronal functioning and therefore a candidate for RD and ADHD. In this study, we tested the gene for linkage to ADHD by genotyping two polymorphisms in the MOG gene-a dinucleotide repeat located upstream from the MOG transcription start site and a Val145Ile substitution in exon 3-in a sample of 104 nuclear families identified through a proband with ADHD. We examined the transmission of the alleles of the Val145Ile and the dinucleotide repeat polymorphisms using the transmission disequilibrium test. We did not observe biased transmission of the alleles at either polymorphism to ADHD probands or siblings. Our findings using this sample do not support the role of the MOG gene in ADHD.

Attention-deficit hyperactivity disorder and the adrenergic receptors alpha 1C and alpha 2C.

The adrenergic system has been hypothesized to be involved in the etiology of attention-deficit hyperactivity disorder (ADHD) based on pharmacological interventions and animal models. Noradrenergic neurons are implicated in the modulation of vigilance, improvement of visual attention, initiation of adaptive response, learning and memory. In this study we tested the genes for two adrenergic receptors, alpha 1C (ADRA1C) located on chromosome 8p11.2, and alpha 2C (ADRA2C) located on chromosome 4p16, as genetic susceptibility factors in ADHD. For the adrenergic receptor alpha 1C we used a C to T polymorphism that results in a change of Cys to Arg at codon 492 for the linkage study. For the adrenergic receptor alpha 2C gene we examined a dinucleotide repeat polymorphism located approximately 6 kb from the gene. We examined these polymorphisms in a sample of 103 families ascertained through an ADHD proband. Using the transmission disequilibrium test, we did not observe biased transmission of any of the alleles of these polymorphisms. We conclude that the alleles at the polymorphisms tested in these two genes are not linked to the ADHD phenotype in this sample of families.