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Ziarih Hawi

Publications and source records attributed to Ziarih Hawi.

16 recordsLinked to original sources
PubMed2006

No association between TPH2 gene polymorphisms and ADHD in a UK sample.

Tryptophan Hydroxylase 2 (TPH2) is the rate-limiting enzyme in the biosynthesis of serotonin which is exclusively expressed in the brain. Recent molecular studies reported significant association between markers mapped to TPH2 and psychiatric conditions including ADHD. We have examined four single nucleotide polymorphisms (SNPs) two of which (rs1843809, rs1386493) were reported to associate with ADHD in an Irish ADHD sample. Transmission disequilibrium analysis revealed no significant association between any of these markers and ADHD. Dividing by the sex of the transmitting parent has also failed to replicate the previously reported paternal over-transmission of the associated alleles to ADHD probands. A larger sample size will be required to clarify if TPH2 alleles are or are not associated with ADHD.

Adolescent↗
PubMed2006

Impaired temporal resolution of visual attention and dopamine beta hydroxylase genotype in attention-deficit/hyperactivity disorder.

BACKGROUND: Dopamine beta hydroxylase (DbetaH) catalyzes the conversion of dopamine to noradrenaline. Attention-deficit/hyperactivity disorder (ADHD) has been associated with the A2 allele of a Taq I polymorphism of the DBH gene. Since catecholamines regulate visual attention, we examined whether participants with ADHD were impaired on a task requiring temporal attention and how DBH genotype influenced temporal attention in ADHD. METHODS: Thirty-seven children and adolescents with ADHD and 52 matched, normal control subjects participated. Participants were presented with two visual stimuli, separated in time by either 50, 100, or 200 milliseconds, and were asked to judge the temporal order of their onset. Genotypes for the Taq 1 polymorphism were available for 33 of the ADHD participants. RESULTS: Attention-deficit/hyperactivity disorder participants were more error prone than control subjects, particularly when stimuli were presented close together in time (i.e., at the 50 milliseconds asynchrony). Moreover, ADHD individuals homozygous for the A2 allele performed more poorly than those without this allele, and this difference was accentuated at the 50 milliseconds asynchrony. CONCLUSIONS: Attention-deficit/hyperactivity disorder participants have an impaired rate of perceptual processing for rapidly presented visual events. Deficits in the temporal resolution of visual attention in ADHD are associated with the A2 allele of the Taq I DBH polymorphism or another variant with which it is in linkage disequilibrium.

Adolescent↗
PubMed2006

The cognitive genetics of attention deficit hyperactivity disorder (ADHD): sustained attention as a candidate phenotype.

Here we describe the application of cognitive genetics to the study of attention deficit hyperactivity disorder (ADHD). Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven fashion. We examined the relationship between sustained attention deficits in ADHD and genetic variation in a catecholamine-related gene, dopamine beta hydroxylase (DbetaH). DBH encodes the enzyme that converts dopamine to noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq I DBH gene polymorphism was related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART). Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right frontoparietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.

Adolescent↗
PubMed2005

Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder.

Family, twin, and adoption studies have demonstrated a significant genetic contribution to the etiology of attention-deficit/hyperactivity disorder (ADHD). Pharmacological, neuroimaging, and animal-model findings suggest imbalances in monoaminergic (dopaminergic, serotonergic, and noradrenergic) neurotransmission in ADHD. We have examined monoaminergic candidate genes for possible genetic association with ADHD in the Irish population, focusing particularly on genes of the dopaminergic and serotonergic systems. We have observed that several of these genes are associated with ADHD, including DAT1, DBH, DRD4, DRD5, and 5HT1B. Here, we present what appears to be a systematic overtransmission of paternal alleles at candidate genes associated with ADHD. For the nine genes included in the analysis, the overall odds ratio for paternal transmission was 2, compared with 1.3 for maternal transmission (paternal vs. maternal chi 2=9.6; P=.0019). Transmission to females, from either parent, was significantly stronger than to males. Possible reasons for this preferential transmission include imprinting and ascertainment bias, although results of further analyses show that the latter is unlikely.

Alleles↗
PubMed2005

DRD4 gene variants and sustained attention in attention deficit hyperactivity disorder (ADHD): effects of associated alleles at the VNTR and -521 SNP.

Associations between attention deficit hyperactivity disorder (ADHD) and genetic variants within the dopamine D4 receptor gene have been much reported. Variants investigated include the 7-repeat allele of a VNTR within the third exon, and two SNPs (-521 and -616) located with the promoter region. We investigated the relationship between the VNTR, -521, and -616 SNPs and sustained attention performance in 54 ADHD probands, relative to a non-genotyped control group. Participants performed the Sustained Attention to Response Task (SART) in which the response to an unpredictably occurring target digit must be inhibited. This task, therefore, challenged sustained attention and included a response inhibition component. Consistent with previous reports, ADHD participants possessing the 7-repeat allele of the VNTR outperformed those children not possessing this allele, both in terms of errors and response variability. In family based analyses, better performance on the SART tended to predict biased transmission of the 7-repeat allele from heterozygous parents. For the -521 SNP, A allele homozygotes showed greater impairment than heterozygotes or those not possessing this allele, both in terms of total errors and response variability. Family based analysis showed that higher total errors on the SART predicted transmission of the A allele from heterozygous parents. There were no effects of the -616 SNP. Our results suggest dissociable effects of the "associated alleles" of DRD4 gene variants on sustained attention: while the 7-repeat allele of the VNTR is associated with relatively better performance, the A allele of the -521 SNP is associated with poorer performance.

Adolescent↗
PubMed2005

Association analysis of the monoamine oxidase A and B genes with attention deficit hyperactivity disorder (ADHD) in an Irish sample: preferential transmission of the MAO-A 941G allele to affected children.

Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Monoamine oxidases A and B (MAO-A and MAO-B) degrade biogenic amines such as dopamine and serotonin and thereby control the levels of these neurotransmitters in the central nervous system. We examined four polymorphisms in the MAO-A gene (30 bp promoter VNTR, CA microsatellite in intron 2, 941G/T SNP in exon 8, and A/G SNP in intron 12) as well as two markers in the MAO-B gene (CA microsatellite in intron 2 and T/C SNP in intron 13) for association with ADHD in an Irish sample of 179 nuclear families. TDT analysis of the examined MAO-A markers revealed a significant association of the more active MAO-A 941G allele with the disorder (chi2 = 5.1, P = 0.03, OR = 1.7). In addition, haplotype analysis revealed a significantly increased transmission of a haplotype consisting of the shorter allele of the promoter VNTR (allele 1), the 6-repeat allele of the CA microsatellite and the G-allele of the 941G/T SNP (famhap global statistic 34.54, P = 0.01) to ADHD cases. No significant distortion in the number of transmitted alleles was observed between the two examined MAO-B polymorphisms and ADHD. These findings suggest the importance of the 941G/T MAO-A polymorphism in the development of ADHD at least in the Irish population.

Adult↗
PubMed2005

The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD.

ADHD is a highly heritable psychiatric disorder of childhood. A functional polymorphism (Val158Met) of the catechol-O-methyltransferase (COMT) gene has attracted interest as a candidate gene for ADHD. The high-activity valine variant of this polymorphism degrades prefrontal dopamine three to four times more quickly than the low-activity methionine variant and could therefore contribute to the proposed hypodopaminergic state in ADHD. Here we tested for association of this polymorphism with ADHD and examined its influence on prefrontal cognition in ADHD. We have previously reported no association of the Val158Met COMT gene polymorphism in 94 Irish ADHD families (Hawi et al. (2000) Am J Med Genet 96:282-284). Here we re-examined this finding with an extended sample of 179 ADHD cases using a family control design. We also examined the performance of children and adolescents with ADHD (n = 61) on a standardised test of sustained attention. Analysis confirmed the absence of an association between the Val158Met COMT gene polymorphism and the clinical phenotype of ADHD. COMT genotype, however, affected prefrontal cognition in ADHD: ADHD children who were homozygous for the valine variant had significantly better sustained attention than those ADHD children possessing at least one copy of the methionine variant. Children possessing the methionine variant performed significantly below age-related norms on tests of sustained attention. Contrary to expectations, the methionine variant of the Val158Met COMT gene polymorphism impaired prefrontally-mediated cognition in ADHD. This effect may be understood by positing a hyper-functioning of prefrontal dopaminergic systems. Against this background, the slower clearance of dopamine associated with the methionine variant of the COMT gene polymorphism may be disadvantageous to cognition in ADHD.

Adolescent↗
PubMed2005

Association between dopamine transporter (DAT1) genotype, left-sided inattention, and an enhanced response to methylphenidate in attention-deficit hyperactivity disorder.

A polymorphism of the dopamine transporter gene (DAT1, 10-repeat) is associated with attention-deficit hyperactivity disorder (ADHD) and has been linked to an enhanced response to methylphenidate (MPH). One aspect of the attention deficit in ADHD includes a subtle inattention to left space, resembling that seen after right cerebral hemisphere damage. Since left-sided inattention in ADHD may resolve when treated with MPH, we asked whether left-sided inattention in ADHD was related to DAT1 genotype and the therapeutic efficacy of MPH. A total of 43 ADHD children and their parents were genotyped for the DAT1 3' variable number of tandem repeats polymorphism. The children performed the Landmark Test, a well-validated measure yielding a spatial attentional asymmetry index (leftward to rightward attentional bias). Parents rated their child's response to MPH retrospectively using a three-point scale (no, mediocre or very good response). Additionally, parents used a symptom checklist to rate behavior while on and off medication. A within-family control design determined whether asymmetry indices predicted biased transmission of 10-repeat parental DAT1 alleles and/or response to MPH. It was found that left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. Our results suggest a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention. MPH may be most efficacious in this group because it ameliorates a DAT1-mediated hypodopaminergic state.

Adolescent↗
PubMed2004

Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: evidence of linkage and association with the SNP -616.

Abnormalities of dopamine neurotransmission have been hypothesized to play an important role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Support for this has come from numerous association studies on candidate genes including the dopamine D4 receptor gene (DRD4). One of the most replicated associations between ADHD and the dopaminergic system is the 7-repeat allele of the VNTR polymorphism of this gene. A lack of association between this marker and ADHD has also been reported in several investigations. In the absence of a firm link between the number of the VNTR repeats and the function of the gene, we sought to investigate several additional markers at the 5'-end of the gene with potential influence on the expression of the DRD4. We observed a significant over transmission of single nucleotide polymorphism (SNP) (chi(2) = 7.45, P = 0.008, OR = 1.63). In addition, an excess transmission of the A allele of the -521 SNP was observed, although it did not attain statistical significance (chi(2) = 2.14, P = 0.17, OR = 1.25). Linkage disequilibrium (LD) analysis demonstrated a weak level of D' between any of the tested markers implying that this may be a region of high recombination. It also raises the possibility that the new association with ADHD may be independent of the 7-repeat allele. Further analyses, preferably in samples demonstrating association with the VNTR, or in other ethnic groups, are required to confirm these observations.

Adult↗
PubMed2004

Phenotype studies of the DRD4 gene polymorphisms in ADHD: association with oppositional defiant disorder and positive family history.

The objective of this study was to investigate association of DRD4 polymorphisms with ADHD subtypes for which there is evidence for increased heritability. The genetic variants tested were the 120 bp insertion/deletion, the -616, -521, -376, and the 48 bp DRD4 VNTR. The primary analyses were of association with oppositional defiant disorder (ODD), conduct disorder (CD), and diagnostic subtypes. Secondary analyses of clinical subtype were exploratory in nature and included analysis of association of DRD4 polymorphisms with family history of ADHD. We observed significant association between DRD4 7-repeat allele transmission and ADHD children with comorbid ODD (chi(2) = 6.74, df = 1, P = 0.01, OR = 2.45) The DRD4 7-repeat allele was also significantly associated with family history positive ADHD (chi(2) = 10.12, df = 1, P = 0.0021, OR = 3.57). We observed no significant distortion in the transmission of any of the tested DRD4 variants with inattentive or hyperactive-impulsive subtypes or symptom dimensions. In conclusion, our findings of increased DRD4 7-repeat allele transmission in ODD extend those reported by Holmes et al. To our knowledge, this is the first study to report association of the DRD4 7-repeat allele with ADHD children who have a positive family history of ADHD. Overall, the results from this study support the investigation of clinical subtypes in molecular genetic studies of ADHD.

Adult↗
PubMed2004

Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)(n) repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12-1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes.

Attention Deficit Disorder with Hyperactivity↗
PubMed2004

No association between allelic variants of HOXA1/HOXB1 and autism.

Two recent studies have reported conflicting findings of association of a variant in the HOXA1 gene and autism. To try to resolve the conflict in findings, we conducted an association study in 78 Irish families of the reported DNA variants. We did not find statistically significant association between the variants and autism. Similarly there was no evidence of preferential transmission of variants from parent of either sex to affected offspring. We also report negative findings for HOXB1 variants. We conclude that the HOXA1/B1 are unlikely to be the susceptibility genes for autism in our sample.

Alleles↗
PubMed2003

Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD.

Several studies have implicated the dopamine transporter gene (DAT1) as conferring susceptibility to attention deficit hyperactivity disorder (ADHD), in particular, a VNTR situated at the 3' end of the gene. In addition, the 10-repeat VNTR allele associated with ADHD has been reported to be associated with an over-active transporter protein (DAT). Thus children possessing this variant might be particularly responsive to methylphenidate, a drug known to act by blocking DAT. We have examined this hypothesis and now report an association between the 10-repeat VNTR DAT1 polymorphism and retrospectively rated methylphenidate response in a sample of 119 Irish children with ADHD (chi(2) = 7.918, df = 1, P = 0.005). Our findings suggest a role for the 10-repeat DAT1 risk allele in medication response and may help to predict positive clinical outcome in ADHD.

Attention Deficit Disorder with Hyperactivity↗
PubMed2002

Association of DRD4 in children with ADHD and comorbid conduct problems.

Recent family and twin study findings suggest that ADHD when comorbid with conduct problems may represent a particularly familial and heritable form of ADHD. Although several independent groups have shown association between the DRD4 7 repeat allele and ADHD, others have failed to replicate this finding. Previous TDT analyses of UK and Eire samples had also been negative. We set out to further examine the role of DRD4 but selecting a subgroup of children with ADHD and comorbid conduct problems. Families were recruited from Manchester, Ireland, Birmingham and London clinics. From these, 67 children who fulfilled diagnostic criteria for ADHD and who displayed conduct disorder symptoms were selected. TDT analysis, which had previously yielded negative results for the total sample, showed evidence of association between DRD4 and "ADHD with conduct problems" (7 repeat allele-24 transmissions, 13 non-transmissions; one-tailed P=0.05). These results provide further support for the role of DRD4 in ADHD. Furthermore, these results when considered together with family and twin study findings, suggest that those children with ADHD and comorbid conduct problems may be particularly informative for molecular genetic studies of ADHD. Further work is needed to examine these phenotype issues.

Adolescent↗
PubMed2002

Dopaminergic system genes in ADHD: toward a biological hypothesis.

Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD). Several genetic association studies have been published, but so far, no DNA variants have been unequivocally demonstrated as contributing to ADHD susceptibility. Four dopamine related gene loci have been implicated, however: DAT 1, DRD 4, DBH, and DRD 5. Each of these may influence the liability of ADHD to a small degree. Notably, all are involved in signal transduction at the neuronal synapse. In this article, we investigate as candidate genes for ADHD, DNA polymorphisms at dopamine receptors, the dopamine transporter, and genes known to be involved in dopamine synthesis and metabolism. In a recent article, we confirmed the previously reported association of DAT 1 (480 bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD 5 (148 bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4 bp deletion in the untranslated exon 1 of the DOPA decarboxylase gene was also observed but was of marginal significance. Nonsignificant trends of association were found for TH (allele 2) and DRD2 (Ser-311). No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD 1, DRD 2 (Taq I), DRD 3, DRD 4, and COMT. Analyzing the data by sex of transmitting parent showed significant preferential paternal transmission of alleles at TH (allele 2) and a nonsignificant trend for paternal transmission for DRD 2 (Ser-311). We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses.

Adolescent↗