Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transmission disequilibrium test (TDT) is widely used as a robust statistical method to test for genetic association due to linkage based upon analysis of parent-proband trios. The TDT and other family-based tests (eg haplotype relative risk method) are commonly used in association studies including those of ADHD because of concerns that the case-control design has a strong tendency for false positives due to poor matching between cases and controls. Unfortunately, it is not always possible to obtain DNA from both parents in studies of this design, even where the onset of disorder is in childhood, and usually the missing parent is the father. Despite the fact that methods exist for analysis where one parent is missing, many family-based studies are based on the collection or analysis of complete trios only. However this selection process might potentially introduce bias, particularly for studies of behavioural phenotypes like ADHD because the phenotype of proband or parents might influence family stability and therefore complete parental ascertainment. We set out to examine whether children with ADHD and for whom DNA samples from fathers were missing ('duos') differed phenotypically from children for whom genotype information was available from both parents ('trios'). Children from duos showed a significantly higher frequency of DMS-IV ADHD-combined type, significantly more co-morbid conduct disorder and conduct disorder symptoms, and a trend for higher total ADHD symptom scores. Excluding duos from sample collection and analysis may result in systematic bias. If comorbid conduct disorder and ADHD-combined type index increased genetic liability, exclusion of duos could further reduce the power of the TDT (and similar tests) to detect susceptibility genes for ADHD, or replicate effects detected by case-control analysis.
Mol Psychiatry 2002
PMID:Evidence to suggest biased phenotypes in children with Attention Deficit Hyperactivity Disorder from completely ascertained trios. 1239 49

Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder in childhood that is known to be associated with dopamine dysregulation. In this study, we investigated dopamine transporter (DAT) density in children with ADHD using iodine-123 labelled N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) tropane ([(123)I]IPT) single-photon emission tomography (SPET) and postulated that an alteration in DAT density in the basal ganglia is responsible for dopaminergic dysfunction in children with ADHD. Nine drug-naive children with ADHD and six normal children were included in the study. We performed brain SPET 2 h after the intravenous administration of [(123)I]IPT and carried out both quantitative and qualitative analyses using the obtained SPET data, which were reconstructed for the assessment of the specific/non-specific DAT binding ratio in the basal ganglia. We then investigated the correlation between the severity scores of ADHD symptoms in children with ADHD assessed with ADHD rating scale-IV and the specific/non-specific DAT binding ratio in the basal ganglia. Drug-naive children with ADHD showed a significantly increased specific/non-specific DAT binding ratio in the basal ganglia compared with normal children. However, no significant correlation was found between the severity scores of ADHD symptoms in children with ADHD and the specific/non-specific DAT binding ratio in the basal ganglia. Our findings support the complex dysregulation of the dopaminergic neurotransmitter system in children with ADHD.
Eur J Nucl Med Mol Imaging 2003 Feb
PMID:Dopamine transporter density in the basal ganglia assessed with [123I]IPT SPET in children with attention deficit hyperactivity disorder. 1255 51

Effects of DRD4 and 5-HTTLPR length polymorphisms have been reported on neonatal and infant temperament as well as adult personality traits. The 7-repeat form of the DRD4 III exon VNTR polymorphism has been associated with childhood ADHD, and recently we have reported its link with attachment disorganization in a nonclinical population of infants. Here, we report associations of these polymorphisms with infant temperament at 12 months of age. Maternal accounts of temperament and observed response to novelty were investigated for 90 infants, who were independently genotyped for the DRD4 III exon, and for 5-HTT-linked promoter region length polymorphisms. Maternal rating of temperament was not affected by these polymorphisms, but we found combined genotype effects for infants' observed responses to a novel, anxiety-provoking stimulus: the appearance of, and approach by, a stranger. Infants with at least one copy of both the 7-repeat DRD4 allele and the long variant of 5-HTTLPR (7(+), l/l&l/s) responded with significantly less anxiety than infants with other genotypes. However, infants with the 7-repeat DRD4 allele and homozygous for the short form of 5-HTTLPR (7(+), s/s) showed more anxiety and resistance to the stranger's initiation of interaction. These genotype effects were not redundant with the previously reported association between the 7-repeat DRD4 allele and disorganized attachment behavior. Although both temperament and attachment behavior were affected by the DRD4 repeat polymorphism, the effect on temperament measures was modified by the infants' 5-HTTLPR genotype.
Mol Psychiatry 2003 Jan
PMID:Association of D4 dopamine receptor gene and serotonin transporter promoter polymorphisms with infants' response to novelty. 1255 12

Recent research has suggested that serotonin, in addition to dopamine, may be involved in the development of attention deficit hyperactivity disorder (ADHD). Serotonin regulates dopaminergic neurotransmission in some areas of the brain via several 5-HT receptors including 5-HT1B. Animal studies have suggested the involvement of the 5-HT1B receptors in locomotor behaviour. For these reasons, we hypothesized that the 5-HT1B receptor gene may be a good candidate for genetic studies of ADHD. We tested for linkage disequilibrium between the 5-HT1B G861C polymorphism and ADHD in 115 families using the transmission disequilibrium test (TDT). We found evidence for a trend towards excess transmission of the 861G allele (chi(2) = 2.91, P = 0.09) that when further analysed for parental allele transmissions exhibited significantly greater paternal transmission of the G allele (chi(2) = 4.80, P = 0.03) to the affected child. Although preliminary, results from this study provide additional evidence that serotonin genes may be important risk factors for the development of ADHD.
Mol Psychiatry 2003 Jan
PMID:The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder. 1255 13

Linkage disequilibrium (LD) mapping was used to follow up reports of linkage between reading disability (RD) and an 18 cM region of chromosome 6p21.3-22. Using a two-stage approach, we tested for association between RD and 22 microsatellite markers in two independent samples of 101 (Stage 1) and 77 (Stage 2) parent/proband trios in which RD was rigorously defined. The most significant replicated associations were observed between combinations of markers D6S109/422/1665 (Stage 1, P=0.002 (adjusted for multiple testing); Stage 2, P=0.0001) and D6S506/1029/1660 (Stage 1, P=0.02 (adjusted), Stage 2, P=0.0001). The only two-marker association observed in both samples was with D6S422/1665 (P=0.01, 0.04). No single marker showed replicated association but D6S506 produced values of P=0.01 and 0.08 which were significant when combined (P=0.02). We observed weaker and less consistent evidence of association in a region of confirmed linkage to RD in previous studies. The most consistently significant haplotypic association D6S109/422/1665, showed association with single-word reading, spelling, phonological awareness, phonological decoding, orthographic accuracy and random automised naming, but not with vocabulary or Attention Deficit Hyperactivity Disorder. Our findings strongly support the presence of a gene contributing to RD in a region of chromosome 6 between markers D6S109 and D6S1260, but do not rule out the presence of a gene between D6S1556 and MOG.
Mol Psychiatry 2003 Feb
PMID:Linkage disequilibrium mapping provides further evidence of a gene for reading disability on chromosome 6p21.3-22. 1261 Jun 50

Abnormalities in dopaminergic neurotransmission are now accepted as factors in predisposing to ADHD. Evidence of associations between dopamine transporter gene polymorphism and ADHD was first reported by Cook et al. We confirmed the DAT1 association and also identified two additional susceptibility loci at the DRD5 and DBH. Notably, none of the associated variants at these three genes are known to be expressed. Other variants within or closely mapped to the associated alleles are likely to be relevant. In this investigation, we analyse additional markers creating a high-density map across and flanking these genes, and measure intermarker linkage disequilibrium (LD). None of the newly examined markers were more strongly associated with ADHD. At DAT1, the pattern of intermarker LD and haplotype association with the phenotype between exon 9 and the 3' of the gene suggests that the functional variant at DAT1 may be located to this region. For DRD5, three markers, covering a region of approximately 68 kb including the single DRD5 exon are all associated with disease, and thus do not provide localizing information. However, the data for DBH point to a region close to the centre of the gene. Correlation between D' and physical distance was observed between markers at DAT1 and DRD5 for distances less than 50 kb. This was not the case for DBH, where LD breakdown was observed between the intron 5 and intron 9 polymorphisms although they are only 9 kb apart. Further genetic analysis is unlikely to refine the location of susceptibility variants and functional assessment of variants within associated regions is required.
Mol Psychiatry 2003 Mar
PMID:Linkage disequilibrium mapping at DAT1, DRD5 and DBH narrows the search for ADHD susceptibility alleles at these loci. 1266 Aug 2

Attention-deficit hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder, affecting 5-10% of school-age children. Although the biological basis of this disorder is unknown, twin and family studies provide strong evidence that ADHD has a genetic basis involving multiple genes. A previous study found an association between ADHD and two polymorphisms in the 3' untranslated region (UTR) of SNAP-25, a gene encoding a synaptic vesicle docking protein known to play a role in the hyperactivity observed in the Coloboma mouse strain. In this paper, we test biased transmission of the 3' UTR SNAP-25 haplotype using a larger ADHD sample of 113 families with 207 affected children. Using the transmission disequilibrium test (TDT), we found a trend consistent with biased transmission of the TC haplotype of SNAP-25 in all transmissions and detected a significant distortion (P=0.027) when paternal transmissions were evaluated.
Mol Psychiatry 2003 Mar
PMID:Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder. 1266 Aug 3

For centuries, scientists are intrigued by the differences in personality between individuals. As early as in the ancient Greek civilization, people tried to formulate theories to systematize this diversity. With the increased interest in behavior genetics, personality was also considered a challenging phenotype. From the early start, studies suggested a heritable component in personality. After the successes of molecular genetic studies in unraveling the genetic basis of (mostly) monogenic diseases, the focus shifted towards complex traits, including psychiatric disorders. It was observed in several studies that personality measures differed between patients with psychiatric disorders and healthy controls. Therefore, normal personality was considered a viable endophenotype in the search for genes involved in psychiatric disorders such as affective disorders, ADHD and substance dependence. Genes that were to be found in studies on personality could be candidate genes for particular psychiatric disorders. In the course of time, however the study of genes for personality turned out to be at least as hard as the search for genes involved in other complex disorders. In this review, past studies, present problems and future directions concerning the study of personality genetics are discussed.
Mol Psychiatry 2003 Oct
PMID:Genetics of personality: are we making progress? 1451 35

Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop ADHD. Reports implicate variants of genes important for the synthesis, uptake, transport and receptor binding of dopamine in the etiology of ADHD, including DRD4, DAT1, DRD2, and DRD5. In the present study, we genotyped a large multiplex sample of ADHD affected children and their parents for polymorphisms in genes previously reported to be associated with ADHD. Associations were tested by the transmission disequilibrium test (TDT). The sample is sufficient to detect genotype relative risks (GRRs) for putative risk alleles. The DRD4 gene 120-bp insertion/deletion promoter polymorphism displayed a significant bias in transmission of the insertion (chi(2)=7.58, P=0.006) as suggested by an analysis of a subset of these families. The seven repeat allele of the DRD4 48-bp repeat polymorphism (DRD4.7) was not significantly associated with ADHD in the large sample in contrast to our earlier findings in a smaller subset. We replicate an association of a dinucleotide repeat polymorphism near the DRD5 gene with ADHD by showing biased nontransmission of the 146-bp allele (P=0.02) and a trend toward excess transmission of the 148-bp allele (P=0.053). No evidence for an association was found for polymorphisms in DRD2 or DAT1 in this sample. The DRD5 146-bp (DRD5.146) allele and the DRD4 240-bp (DRD4.240) allele of the promoter polymorphism emerge as the two DNA variants showing a significant association in this large sample of predominantly multiplex families with ADHD, with estimated GRRs of 1.7 and 1.37, respectively.
Mol Psychiatry 2004 Jul
PMID:Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5. 1469 30

Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder, for which there is good evidence that genetic factors contribute to the aetiology. Recently reported linkage findings suggested evidence of a susceptibility locus on chromosome 16p13 (maximum LOD score of 4.2, P=5 x 10(-6)). The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage. As this is also a good functional candidate gene for ADHD, we undertook family-based association analysis in a sample of 238 families. We found significant evidence of association with a GRIN2A exon 5 polymorphism (chi(2)=5.7, P=0.01). Our data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al. We conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted.
Mol Psychiatry 2004 Feb
PMID:Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD. 1496 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>