Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA, Sklar P
Molecular genetics of attention-deficit/hyperactivity disorder.
Biol Psychiatry. 2005 Jun 1;57(11):1313-23.
Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25. [Abstract]

Kustanovich V, Merriman B, McGough J, McCracken JT, Smalley SL, Nelson SF.
Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder.
Mol Psychiatry 2003 Mar;8(3):309-15
"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." [Abstract]

Mill J, Richards S, Knight J, Curran S, Taylor E, Asherson P
Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD.
Mol Psychiatry. 2004 Aug;9(8):801-10.
Several lines of evidence suggest a role for SNAP-25 (synaptosomal-associated protein of 25 kDa) in the genetic aetiology of ADHD. Most notable is the coloboma mouse mutant, which displays spontaneous hyperactivity and is hemizygous for a deletion spanning this gene. We have screened the SNAP-25 gene using denaturing high-performance liquid chromatography and sequencing, and genotyped six polymorphic single-nucleotide polymorphisms and two microsatellites in a clinically ascertained sample of 188 probands. Several markers were found to show association with ADHD, both individually and in combination with other markers to form multimarker haplotypes. Analyses of transmission by parental sex suggested that the association of SNAP-25 with ADHD is largely due to transmission of alleles from paternal chromosomes to affected probands, suggesting that this locus may be subject to genomic imprinting. Overall our data provide some evidence for a role of this gene in ADHD, although the precise causal functional variant is yet to be ascertained. [Abstract]

Brophy K, Hawi Z, Kirley A, Fitzgerald M, Gill M.
Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population.
Mol Psychiatry 2002;7(8):913-7
"Several lines of evidence have suggested that ADHD is a polygenic disorder produced by the interaction of several genes each of a minor effect. Synaptosomal-associated protein 25 (SNAP-25) is a presynaptic plasma membrane protein which is expressed highly and specifically in the nerve cells. The gene encodes a protein essential for synaptic vesicle fusion and neurotransmitter release. Animal model studies showed that the coloboma mouse mutant has a hyperactive phenotype similar to that of ADHD. The hyperactive phenotype of this model has been shown to be the result of a deletion of the SNAP-25 gene. DNA variations within or closely mapped to the SNAP-25 gene may alter the level of expression and hence may have an effect on the function of synaptic vesicle fusion and neurotransmitter release. Using HHRR and TDT we analysed 93 ADHD nuclear families from Ireland and found increased preferential transmission of SNAP-25/DdeI allelel to ADHD cases; HHRR (chi(2) = 6.55, P = 0.01) and linkage (TDT) (chi(2) = 6.5, P = 0.015). In contrast to our findings, Barr et al(1) reported an increased transmission of allele 2 of the DdeI polymorphism though this was not statistically significant. However, they also reported a significantly increased transmission of a haplotype (made of allele 1 of MnlI and allele 2 of the DdeI) in their Canadian ADHD sample. It is not clear what the role of SNAP-25 in ADHD is until these findings are either confirmed or refuted in other ADHD samples." [Abstract]

Mill J, Richards S, Knight J, Curran S, Taylor E, Asherson P.
Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD.
Mol Psychiatry. 2004 Mar 9 [Epub ahead of print]
"Several lines of evidence suggest a role for SNAP-25 (synaptosomal-associated protein of 25 kDa) in the genetic aetiology of ADHD. Most notable is the coloboma mouse mutant, which displays spontaneous hyperactivity and is hemizygous for a deletion spanning this gene. We have screened the SNAP-25 gene using denaturing high-performance liquid chromatography and sequencing, and genotyped six polymorphic single-nucleotide polymorphisms and two microsatellites in a clinically ascertained sample of 188 probands. Several markers were found to show association with ADHD, both individually and in combination with other markers to form multimarker haplotypes. Analyses of transmission by parental sex suggested that the association of SNAP-25 with ADHD is largely due to transmission of alleles from paternal chromosomes to affected probands, suggesting that this locus may be subject to genomic imprinting. Overall our data provide some evidence for a role of this gene in ADHD, although the precise causal functional variant is yet to be ascertained." [Abstract]

Feng Y, Crosbie J, Wigg K, Pathare T, Ickowicz A, Schachar R, Tannock R, Roberts W, Malone M, Swanson J, Kennedy JL, Barr CL
The SNAP25 gene as a susceptibility gene contributing to attention-deficit hyperactivity disorder.
Mol Psychiatry. 2005 Aug 9;
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. [Abstract]

Brookes KJ, Knight J, Xu X, Asherson P
DNA pooling analysis of ADHD and genes regulating vesicle release of neurotransmitters.
Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4;
ADHD is one of the most prevalent, and heritable behavioural disorders in childhood. Genetic associations have been reported with polymorphic variants within or near to dopamine pathway genes. Recently snap-25 has also shown association with ADHD in several datasets. We therefore investigated other genes that produce proteins that interact with SNAP-25 in the mechanism of vesicular release of neurotransmitters at the synapse. A total of 106 SNPs were screened for minor allele frequency greater than 5% and 61 SNPs selected for analysis in DNA pools made up from an ADHD clinical sample of DSM-IV combined type probands (n = 180) and a control sample of 90 males and 90 females. Initial screening identified several SNPs that showed allele frequency differences of 5% or more. One SNP in the synaptophysin gene showed suggestive evidence of association following case-control and TDT analysis and warrants further investigation. [Abstract]

Turic D, Langley K, Mills S, Stephens M, Lawson D, Govan C, Williams N, Van Den Bree M, Craddock N, Kent L, Owen M, O'Donovan M, Thapar A.
Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD.
Mol Psychiatry. 2004 Feb;9(2):169-73.
"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." [Abstract]

Adams J, Crosbie J, Wigg K, Ickowicz A, Pathare T, Roberts W, Malone M, Schachar R, Tannock R, Kennedy JL, Barr CL.
Glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region.
Mol Psychiatry. 2004 May;9(5):494-9.
"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." [Abstract]

Turic D, Langley K, Williams H, Norton N, Williams NM, Moskvina V, Van den Bree MB, Owen MJ, Thapar A, O'Donovan MC
A family based study implicates solute carrier family 1-member 3 (SLC1A3) gene in attention-deficit/hyperactivity disorder.
Biol Psychiatry. 2005 Jun 1;57(11):1461-6.
BACKGROUND: The glutamatergic system, the major excitatory neurotransmitter system in the central nervous system (CNS) has been proposed as contributing a possible role in the etiology of attention deficit hyperactivity disorder (ADHD). This is based upon observations from animal, neuroimaging, neuroanatomical and neuropsychological studies. Genes related to glutamate function are therefore good functional candidates for this disorder. The SLC1A3 (Solute Carrier Family 1, member 3) gene encodes a glial glutamate transporter which maps to chromosome 5p12, a region of linkage that coincides in two published ADHD genome scans so far. SLC1A3 is thus both a functional and positional candidate gene for ADHD. METHODS: We have undertaken detailed association analysis of SLC1A3 using a multi-stage approach for candidate gene analysis. RESULTS: In a family-based sample (n = 299) we found a significant association between marker rs2269272 (p = .007) and ADHD. Two, two-marker haplotypes, rs2269272/rs3776581 (p = .016) and rs2269272/rs2032893 (p = .013) also yielded evidence of association. CONCLUSIONS: The results of our study suggest that genetic variation in SLC1A3 may contribute to susceptibility to ADHD. [Abstract]

Kent L, Green E, Hawi Z, Kirley A, Dudbridge F, Lowe N, Raybould R, Langley K, Bray N, Fitzgerald M, Owen MJ, O'donovan MC, Gill M, Thapar A, Craddock N
Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD.
Mol Psychiatry. 2005 May 31;
Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable, neurodevelopmental disorder with onset in early childhood. Genes involved in neuronal development and growth are, thus, important etiological candidates and brain-derived neurotrophic factor (BDNF), has been hypothesized to play a role in the pathogenesis of ADHD. BDNF is a member of the neurotrophin family and is involved in the survival and differentiation of dopaminergic neurons in the developing brain (of relevance because drugs that block the dopamine transporter can be effective therapeutically). The common Val66Met functional polymorphism in the human BDNF gene (rs 6265) was genotyped in a collaborative family-based sample of 341 white UK or Irish ADHD probands and their parents. We found evidence for preferential transmission of the valine (G) allele of BDNF (odds ratio, OR=1.6, P=0.02) with a strong paternal effect (paternal transmissions: OR=3.2, P=0.0005; maternal transmissions: OR=1.00; P=1.00). Our findings support the hypothesis that BDNF is involved in the pathogenesis of ADHD. The transmission difference between parents raises the possibility that an epigenetic process may be involved. [Abstract]

Friedel S, Horro FF, Wermter AK, Geller F, Dempfle A, Reichwald K, Smidt J, Brönner G, Konrad K, Herpertz-Dahlmann B, Warnke A, Hemminger U, Linder M, Kiefl H, Goldschmidt HP, Siegfried W, Remschmidt H, Hinney A, Hebebrand J
Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132(1):96-9.
Several lines of evidence indicate an involvement of brain derived neurotrophic factor (BDNF) in body weight regulation and activity: heterozygous Bdnf knockout mice (Bdnf(+/-)) are hyperphagic, obese, and hyperactive; furthermore, central infusion of BDNF leads to severe, dose-dependent appetite suppression and weight loss in rats. We searched for the role of BDNF variants in obesity, eating disorders, and attention-deficit/hyperactivity disorder (ADHD). A mutation screen (SSCP and DHPLC) of the translated region of BDNF in 183 extremely obese children and adolescents and 187 underweight students was performed. Additionally, we genotyped two common polymorphisms (rs6265: p.V66M; c.-46C > T) in 118 patients with anorexia nervosa, 80 patients with bulimia nervosa, 88 patients with ADHD, and 96 normal weight controls. Three rare variants (c.5C > T: p.T2I; c.273G > A; c.*137A > G) and the known polymorphism (p.V66M) were identified. A role of the I2 allele in the etiology of obesity cannot be excluded. We found no association between p.V66M or the additionally genotyped variant c.-46C > T and obesity, ADHD or eating disorders. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html. [Abstract]

Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z
Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD.
Mol Psychiatry. 2005 Jun 7;
Genetic and pharmacological studies have emphasised the role of serotonin 5-hydroxytryptamine (5-HT) as a possible etiologic factor in the development of attention-deficit hyperactivity disorder (ADHD). Tryptophan hydroxylase (TPH) is a rate-limiting enzyme in the biosynthesis of serotonin from tryptophan. Originally, the TPH gene was thought to be widely expressed, but a second form of TPH, TPH2, was recently identified and the TPH2 gene was found to be solely expressed in the brain. We examined eight single nucleotide polymorphisms (SNP) in the TPH2 gene for association with ADHD in 179 Irish nuclear families. Transmission disequilibrium test analysis revealed significant association between the T allele of marker rs1843809 with the disorder (chi(2)=12.2, P=0.0006, OR=2.36). Stratifying data by the sex of the transmitting parent showed that this association was enhanced when paternal transmission was considered (OR=3.7). In addition, several haplotypes (all including the associated marker) were associated with ADHD. These preliminary findings suggest that TPH2 is a susceptibility locus for ADHD. Further confirmation, preferably from different ethnic groups, is required to firmly implicate TPH2 in the pathophysiology of ADHD.Molecular Psychiatry advance online publication, 7 June 2005; doi:10.1038/sj.mp.4001698. [Abstract]

Li J, Wang YF, Zhou RL, Yang L, Zhang HB, Wang B.
[Association between tryptophan hydroxylase gene polymorphisms and attention deficit hyperactivity disorder with or without learning disorder]
Zhonghua Yi Xue Za Zhi. 2003 Dec 25;83(24):2114-8.
"OBJECTIVE: To investigate the relationship between two tryptophan hydroxylasec (TPH) gene polymorphisms, A218C and A-6526G polymorphisms, and attention deficit hyperactivity disorder (ADHD) with or without learning disorder (LD). METHODS: Blood samples were taken from 132 trios with probands of ADHD with LD and 221 trios with probands of ADHD without LD. DNA was extracted and PCR was performed to amplify the fragments of A218C amd A-6526G polymorphisms. NheI and MboI were used to detect different alleles of the two polymorphisms separately. transmission disequilibriumtest (TDT) and haplotype analysis were used to test the association of the two polymorphisms of TPH gene and ADHD with or without LD. RESULTS: Haplotype block composed by A218C and A-6526G polymorphisms was related to ADHD with LD (chi(2) = 9.362, df = 3, P = 0.025). The haplotype of 218A/-6526G was significantly untransmitted to the probands with ADHD with LD (chi(2) = 9.252, df = 1, P = 0.002). CONCLUSION: TPH gene and the haplotype of 218A/-6526G may be related to ADHD with LD."
[Abstract]

Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R, Basile VS, Beitchman J, Kennedy JL.
The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder.
Mol Psychiatry 2003;8(1):98-102
"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." [Abstract]

Hawi Z, Dring M, Kirley A, Foley D, Kent L, Craddock N, Asherson P, Curran S, Gould A, Richards S, Lawson D, Pay H, Turic D, Langley K, Owen M, O'Donovan M, Thapar A, Fitzgerald M, Gill M.
Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample.
Mol Psychiatry 2002;7(7):718-25
"Attention deficit hyperactivity disorder (ADHD) is a highly heritable and heterogeneous disorder, which usually becomes apparent during the first few years of childhood. Imbalance in dopamine neurotransmission has been suggested as a factor predisposing to ADHD. However, evidence has suggested an interaction between dopamine and serotonin systems in the pathophysiology of the disorder. Studies using selective agonists of the different 5-HT receptors microinjected into selected brain structures have shown a positive modulating effect on the functional activities of the mesotelencephalic dopaminergic system. This suggests that some of the genetic predisposition to ADHD might be due to DNA variation at serotonin system genes. In this study, we investigated polymorphisms in HTR(1B) and HTR(2A) (which encode the serotonin receptors 5-HT(1B) and 5-HT(2A) respectively) in a European ADHD sample. Using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) analyses, we observed significant preferential transmission of the allele 861G of the HTR(1B) in the total sample (for HHRR; chi(2) = 7.4, P = 0.0065 and TDT; (chi(2) = 6.4, P = 0.014). Analysis of HTR(2A) failed to reveal evidence of association or linkage between the His452Tyr polymorphism and ADHD in the total sample. However, a significantly increased transmission of the allele 452His was observed in the Irish sample alone (chi(2) = 4.9, P = 0.026). These preliminary data suggest an important role for the serotonin system in the development of ADHD. Further studies, preferentially including different ethnic groups are required to substantiate these findings." [Abstract]

Li J, Wang Y, Zhou R, Zhang H, Yang L, Wang B, Khan S, Faraone SV
Serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder in Chinese Han subjects.
Am J Med Genet B Neuropsychiatr Genet. 2005 Jan 5;132(1):59-63.
Serotonin is an endogenous neurotransmitter that regulates aggressive and impulsive behavior and may be involved in the development of attention deficit hyperactivity disorder (ADHD). 5-HT1B knockout mice display hyperactivity, increased exploratory activity and aggression, reduced anxiety, increased vulnerability to cocaine self-administration, and elevated alcohol consumption. Many of these same behaviors are seen in patients with ADHD. Prior studies reported excess transmission of the 861G allele of 5-HT1B to ADHD offspring. We used the transmission disequilibrium test (TDT) and haplotype analysis to investigate the A-161T and G861C polymorphisms in the 5-HT1B receptor gene in ADHD trios from the Chinese Han population. We found no association with ADHD but did find a tendency for excess transmission of the 861G allele (chi(2) = 3.766, P = 0.052) and the G/A haplotype (chi(2) = 2.925, df = 1, P = 0.087), and under-transmission of C/A haplotype (chi(2) = 3.707, df = 1, P = 0.054) to offspring with inattentive ADHD. [Abstract]

Quist JF, Barr CL, Schachar R, Roberts W, Malone M, Tannock R, Basile VS, Beitchman J, Kennedy JL.
Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD).
Mol Psychiatry 2000 Sep;5(5):537-41
"A recent study demonstrated that treatment of hyperactive mice with psychostimulants and serotonergic agents produced a calming effect that was dependent on serotonergic neurotransmission and was not associated with any changes in extracellular dopamine levels. The complex interaction between the serotonergic and dopaminergic neurotransmitter systems suggests that a balance between the two systems may be necessary for mediating hyperactive behaviour. Defects in serotonin system genes, therefore, may disrupt normal brain serotonin function causing an imbalance between these neurotransmitter systems leading to the development of attention deficit hyperactivity disorder (ADHD). Using the transmission disequilibrium test (TDT), the current study assesses for linkage disequilibrium between polymorphisms in the serotonin HTR2A receptor gene and ADHD. One hundred and fifteen families with a total of 143 children diagnosed with ADHD (DSM-IV) were genotyped for the His452 Tyr and the T102C polymorphisms in the serotonin HTR2A receptor gene. TDT analysis revealed a preferential transmission of the 452Tyr allele to the affected offspring (P = 0.03), suggesting linkage disequilibrium of this polymorphism with ADHD. This may open a new door in ADHD molecular genetics research, expanding the existing view of a catecholaminergic hypothesis to include a serotonergic hypothesis and should help elucidate the complex interplay among the neurotransmitter systems in the etiology of ADHD." [Abstract]

Li J, Wang Y, Qian Q, Wang B, Zhou R.
[Association of 5-HT(2A) receptor polymorphism and attention deficit hyperactivity disorder in children]
Zhonghua Yi Xue Za Zhi 2002 Sep 10;82(17):1173-6
"OBJECTIVE: To stude the association of 5-HT(2A) receptor polymorphism and attention deficit hyperactivity disorder (ADHD) in children. METHODS: Blood samples were taken from 323 6 approximately 17.5-year-old children with ADHD disgnosed based on the DSM-IV criteria, 182 healthy 18 approximately 49-year-old controls, and 195 pairs of parents of affected children, all of Han nationality. DNA was extracted. PCR was performed to examine the 5-hydroxytryptamine (5-HT)(2A) receptor T102C polymorphism. Transmission disequilibrium test (TDT) was used to test the association of alleles of 5-HT(2A) T102C polymorphic sites and AFDHD. RESULTS: The frequency of T102T in patients with ADHD combined subtype was lower than that in the controls (22.35 vs 33.5%, OR = 0.569, P = 0.028, 95% CI 0.344 - 0.943), and the frequency of T102C in patients with ADHD combined subtype was higher than that in the controls (64.0% vs 47.3%, OR = 1.987, P = 0.003, 95% CI 1.264 approximately 3.124). TDT showed biased transmission of the alleles of T102C polymorphism among families of girl patients with ADHD combined subtype (P = 0.031). CONCLUSION: For the ADHD combined subtype, the T102T genotype is a protective factor and the T102C genotype is a risk factor. For the girl with ADHD combined subtype, the allele C102 is a disease-predisposing gene." [Abstract]

Levitan RD, Masellis M, Basile VS, Lam RW, Jain U, Kaplan AS, Kennedy SH, Siegel G, Walker ML, Vaccarino FJ, Kennedy JL.
Polymorphism of the serotonin-2A receptor gene (HTR2A) associated with childhood attention deficit hyperactivity disorder (ADHD) in adult women with seasonal affective disorder.
J Affect Disord 2002 Sep;71(1-3):229-33
"INTRODUCTION: Several lines of research point to a possible overlap between seasonal affective disorder (SAD) and attention deficit hyperactivity disorder (ADHD), particularly in females. There is also emerging evidence that variation of the 5-HT2A receptor gene (HTR2A) contributes to both SAD and ADHD. The current study investigated whether variation in HTR2A was associated with symptoms of childhood ADHD in adult women with SAD. METHOD: Sixty-six women with SAD were administered the Wender-Utah Rating Scale (WURS), which retrospectively assesses childhood ADHD, as part of an ongoing genetic study of SAD. WURS scores were compared across the three genotypic groups defined by the T102C polymorphism of HT2RA. RESULTS: Analysis of variance indicated a significant difference in mean 25-item WURS scores across the three genotypic groups (p = 0.035). Post-hoc tests revealed that the C/C genotypic group had a significantly higher mean score than both the T/T group and T/C group. Based on previously established WURS criteria, 38% of subjects with the C/C genotype, and none with the T/T genotype, had scores consistent with childhood ADHD. LIMITATIONS: The current sample size is small, and childhood ADHD diagnoses were based on retrospective recall. CONCLUSION: These preliminary results suggest a possible association between variation in HTR2A, childhood ADHD, and the later development of SAD in women." [Abstract]

Zoroglu SS, Erdal ME, Erdal N, Ozen S, Alasehirli B, Sivasli E.
No evidence for an association between the T102C and 1438 G/A polymorphisms of the serotonin 2A receptor gene in attention deficit/hyperactivity disorder in a Turkish population.
Neuropsychobiology 2003;47(1):17-20
"Disturbances in the serotonergic neurotransmission system have been implicated in the etiology of attention deficit/hyperactivity disorder (ADHD). As the importance of genetic factors is well established, genes encoding for proteins of the serotonergic pathway are important candidates to unravel the underlying genetic contribution. We previously demonstrated that the polymorphisms of the serotonin transporter gene promoter and regions of variable number of tandem repeats were involved in the pathogenesis of ADHD. The purpose of this study was to examine the relationship between ADHD and two polymorphisms (T102C and 1438 G/A) in the 5-HT2A gene in a sample of Turkish children. Using the PCR technique, these polymorphisms were assessed in 70 patients with ADHD and in 100 healthy controls. There was no significant difference between the frequencies of the T, C, G and A alleles of both groups. No association was found between the studied polymorphisms of the 5-HT2A gene and ADHD in this sample consisting of Turkish children. Overall, our results suggest that the investigated 5-HT2A polymorphisms are not major susceptibility factors in the etiology of ADHD." [Abstract]

Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL, Newbury DF, Crawford LR, Palmer CG, Woodward JA, Del'Homme M, Cantwell DP, Nelson SF, Monaco AP, Smalley SL.
A genomewide scan for loci involved in attention-deficit/hyperactivity disorder.
Am J Hum Genet 2002 May;70(5):1183-96
"Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of > or =3 from 96% of the genome and those with a lambda(s) of > or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of >/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs." [Abstract] [Full Text]

Ogdie MN, Macphie IL, Minassian SL, Yang M, Fisher SE, Francks C, Cantor RM, McCracken JT, McGough JJ, Nelson SF, Monaco AP, Smalley SL.
A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11.
Am J Hum Genet 2003 May;72(5):1268-79
"Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is a common, highly heritable neurobehavioral disorder of childhood onset, characterized by hyperactivity, impulsivity, and/or inattention. As part of an ongoing study of the genetic etiology of ADHD, we have performed a genomewide linkage scan in 204 nuclear families comprising 853 individuals and 270 affected sibling pairs (ASPs). Previously, we reported genomewide linkage analysis of a "first wave" of these families composed of 126 ASPs. A follow-up investigation of one region on 16p yielded significant linkage in an extended sample. The current study extends the original sample of 126 ASPs to 270 ASPs and provides linkage analyses of the entire sample, using polymorphic microsatellite markers that define an approximately 10-cM map across the genome. Maximum LOD score (MLS) analysis identified suggestive linkage for 17p11 (MLS=2.98) and four nominal regions with MLS values >1.0, including 5p13, 6q14, 11q25, and 20q13. These data, taken together with the fine mapping on 16p13, suggest two regions as highly likely to harbor risk genes for ADHD: 16p13 and 17p11. Interestingly, both regions, as well as 5p13, have been highlighted in genomewide scans for autism." [Abstract] [Full Text]

Ogdie MN, Fisher SE, Yang M, Ishii J, Francks C, Loo SK, Cantor RM, McCracken JT, McGough JJ, Smalley SL, Nelson SF
Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11.
Am J Hum Genet. 2004 Oct;75(4):661-8.
We completed fine mapping of nine positional candidate regions for attention-deficit/hyperactivity disorder (ADHD) in an extended population sample of 308 affected sibling pairs (ASPs), constituting the largest linkage sample of families with ADHD published to date. The candidate chromosomal regions were selected from all three published genomewide scans for ADHD, and fine mapping was done to comprehensively validate these positional candidate regions in our sample. Multipoint maximum LOD score (MLS) analysis yielded significant evidence of linkage on 6q12 (MLS 3.30; empiric P=.024) and 17p11 (MLS 3.63; empiric P=.015), as well as suggestive evidence on 5p13 (MLS 2.55; empiric P=.091). In conjunction with the previously reported significant linkage on the basis of fine mapping 16p13 in the same sample as this report, the analyses presented here indicate that four chromosomal regions--5p13, 6q12, 16p13, and 17p11--are likely to harbor susceptibility genes for ADHD. The refinement of linkage within each of these regions lays the foundation for subsequent investigations using association methods to detect risk genes of moderate effect size. [Abstract]

Smalley SL, Kustanovich V, Minassian SL, Stone JL, Ogdie MN, McGough JJ, McCracken JT, MacPhie IL, Francks C, Fisher SE, Cantor RM, Monaco AP, Nelson SF.
Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism.
Am J Hum Genet 2002 Oct;71(4):959-63
"Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a genetic etiology of the disorder, although putative alleles, principally in dopamine-related pathways suggested by candidate-gene studies, have very small effect sizes. We use affected-sib-pair analysis in 203 families to localize the first major susceptibility locus for ADHD to a 12-cM region on chromosome 16p13 (maximum LOD score 4.2; P=.000005), building upon an earlier genomewide scan of this disorder. The region overlaps that highlighted in three genome scans for autism, a disorder in which inattention and hyperactivity are common, and physically maps to a 7-Mb region on 16p13. These findings suggest that variations in a gene on 16p13 may contribute to common deficits found in both ADHD and autism." [Abstract] [Full Text]

Jiang S, Xin R, Qian Y, Lin S, Li F, Wu X, Wang D, Tang G, Jiang K.
[Study of susceptibility loci located within Xp11 in attention deficit hyperactivity disorder]
Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2001 Jun;18(3):169-72
"OBJECTIVE: To detect the genetic relationship between monoamine oxidase(MAO) A type gene and attention deficit hyperactivity disorder(ADHD) in Chinese. METHODS: The haplotype-based haplotype relative risk(HHRR) and the transmission disequilibrium test(TDT) methods were used to analyze the genetic association and linkage in 60 ADHD children and their parents. RESULTS: In this sample were found significant association (chi(2)=4.90, P<0.05) and linkage (chi(2)=4.84, P<0.05) between the MAOCA 114bp allele and DSM-III-R-diagnosed ADHD in trios composed of father, mother and affected offspring. CONCLUSION: The above results suggested that ADHD was associated and in linkage with MAO A gene, and the susceptibility loci might reside in chromosome Xp11 for ADHD." [Abstract]

Willcutt EG, Pennington BF, Smith SD, Cardon LR, Gayan J, Knopik VS, Olson RK, DeFries JC.
Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attention-deficit/hyperactivity disorder.
Am J Med Genet 2002 Apr 8;114(3):260-8
"Comorbidity is pervasive among both adult and child psychiatric disorders; however, the etiological mechanisms underlying the majority of comorbidities are unknown. This study used genetic linkage analysis to assess the etiology of comorbidity between reading disability (RD) and attention-deficit hyperactivity disorder (ADHD), two common childhood disorders that frequently co-occur. Sibling pairs (N = 85) were ascertained initially because at least one individual in each pair exhibited a history of reading difficulties. Univariate linkage analyses in sibling pairs selected for ADHD from within this RD-ascertained sample suggested that a quantitative trait locus (QTL) on chromosome 6p is a susceptibility locus for ADHD. Because this QTL is in the same region as a well-replicated QTL for reading disability, subsequent bivariate analyses were conducted to test if this QTL contributed to comorbidity between the two disorders. Analyses of data from sib pairs selected for reading deficits revealed suggestive bivariate linkage for ADHD and three measures of reading difficulty, indicating that comorbidity between RD and ADHD may be due at least in part to pleiotropic effects of a QTL on chromosome 6p." [Abstract]

Jiang S, Xin R, Wu X, Lin S, Qian Y, Ren D, Tang G, Wang D.
Association between attention deficit hyperactivity disorder and the DXS7 locus.
Am J Med Genet 2000 Jun 12;96(3):289-92
"Attention deficit hyperactivity disorder (ADHD) is a prevalent disorder in children. The etiology of this disease is not clear. Genetics studies have suggested the involvement of the dopamine DRD-4 receptor gene and dopamine transporter gene (DAT1). Clinical studies have shown that monoamine oxidase-B (MAO-B) inhibitors are effective in the treatment of ADHD. These findings suggest that monoamine oxidase (MAO) genes might be involved in the origin of ADHD. In the present work, the DXS7 locus of chromosome X, which is closely linked to MAO genes, was selected as a marker to study the possible association between ADHD and MAO genes in the Chinese population. Haplotype-based haplotype relative risk (HHRR) and the transmission disequilibrium test (TDT) methods were employed to analyze the association and the linkage disequilibrium, respectively. Significant association (X(2) = 15.86; 1 df; P < 0.001) and linkage (X(2) = 14.88; 1 df; P < 0.001) were detected between the 157-bp allele of the DXS7 locus and the DSM-III-R-diagnosed ADHD (N = 72) in trios composed of father, mother, and affected offspring. The data suggested that ADHD was associated and in linkage with DXS7 locus." [Abstract]

Park L, Nigg JT, Waldman ID, Nummy KA, Huang-Pollock C, Rappley M, Friderici KH
Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD.
Mol Psychiatry. 2005 Jun;10(6):572-80.
Attention-deficit hyperactivity disorder (ADHD) is a heritable disorder, prevalent from childhood through adulthood. Although the noradrenergic (NA) system is thought to mediate a portion of the pathophysiology of ADHD, genes in this pathway have not been investigated as frequently as those in the dopaminergic system. Previous association studies of one candidate gene in the NA system, ADRA2A, showed inconsistent results with regard to an MspI polymorphism. In the current study, two nearby single-nucleotide polymorphisms, which define HhaI and DraI restriction fragment length polymorphisms, were also genotyped and were in significant linkage disequilibrium with the MspI RFLP. Transmission disequilibrium tests (TDTs) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype (P=0.03), and the quantitative TDT showed association of this polymorphism with the inattentive (P=0.003) and hyperactive-impulsive (P=0.015) symptom dimensions. The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive (P=0.001) and hyperactive-impulsive (P=0.004) symptom dimensions. This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism. [Abstract]

Comings DE, Gade-Andavolu R, Gonzalez N, Blake H, Wu S, MacMurray JP.
Additive effect of three noradrenergic genes (ADRA2a, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects.
Clin Genet 1999 Mar;55(3):160-72
"Halperin et al. (Halperin JM. Newcorn JH, Koda VH, Pick L, McKay KE, Knott P. Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension. J Am Acad Child Adolesc Psychiatry 1997: 36: 1688 1696) reported a significant increase in plasma norepinephrine (NE) in attention-deficit hyperactivity disorder (ADHD) children with reading and other cognitive disabilities compared to ADHD children without learning disabilities (LD). We examined the hypothesis that ADHD + LD was associated with NE dysfunction at a molecular genetic level by testing for associations and additive effects between polymorphisms at three noradrenergic genes the adrenergic alpha2A receptor (ADRA2A), adrenergic alpha2C receptor (ADRA2C), and dopamine beta-hydroxylase (DBH) genes. A total of 336 subjects consisting of 274 individuals with Tourette syndrome (TS) and 62 normal controls were genotyped. Regression analysis showed a significant correlation between scores for ADHD, a history of LD, and poor grade-school academic performance that was greatest for the additive effect of all three genes. Combined, these three genes accounted for 3.5% of the variance of the ADHD score (p = 0.0005). There was a significant increase in the number of variant NE genes progressing from subjects without ADHD (A-) or learning disorders (LD-) to A + LD - to A - LD + to A + LD + (p = 0.0017), but no comparable effect for dopamine genes. These data support an association between NE genes and ADHD, especially in ADHD + LD subjects." [Abstract]

Comings DE, Gonzalez NS, Li S-C C, MacMurray J.
A "line item" approach to the identification of genes involved in polygenic behavioral disorders: The Adrenergic alpha2A (ADRA2A) gene.
Am J Med Genet 2003 Apr 1;118B(1):110-4
"The usual approach for using single base pair polymorphisms (SNPs) for the investigation of the genetics of behavioral disorders is to examine a single diagnostic syndrome or personality trait based on variables relating to a cluster of behavioral symptoms. However, since some of these variables may address behaviors that are associated with one allele while others are associated with the other allele, the overall association may be non-significant and significant sub-syndromal associations may be missed. Thus, we have reversed the process in a technique we term a "line item" approach. As a test of the technique we have examined the association between genotypes of a C- > G-1291 Msp I promotor SNP of the ADRA2A gene and 390 individual symptoms from a structured review of DSM-IV criteria for twelve different groups of symptoms. We examined 334 individuals consisting of controls and subjects with Tourette syndrome (TS). Based on the mean scores for each genotype, those symptoms that were individually significant at alpha </= 0.05 fell into three major groups by mode of inheritance: allele 1 codominant (11 > 12 > 22), allele 2 codominant (22 > 12 > 11), and negative heterosis (12 < 11, 22). Within each mode of inheritance group, the number of symptoms that were significant for the twelve symptom clusters was compared by chi-square analysis. This showed that symptoms were drawn from the diagnostic groups in a significantly non-random fashion. Thus, the allele 1 codominant symptoms came from the anxiety, affective, schizoid, and somatization diagnostic groups (internalizing symptoms) (chi(2) = 80.0, d.f. = 11, P </= 0.0000001), while the allele 2 codominant symptoms came from the ADHD and oppositional defiant/conduct disorder diagnostic groups (externalizing symptoms) (chi(2) = 81.0, d.f. = 11, P </= 0.0000001). The questions that fell in the negative heterosis type of inheritance were not significantly associated with specific diagnostic groups (P = 0.87). These results showed that the ADRA2A gene was associated with symptoms of autonomic, sympathetic dysfunction from different diagnostic groups. The advantages of the "line item" approach include (a) the identification of the symptoms associated with each allele, (b) the identification of symptom clusters independent of DSM diagnoses, (c) the elucidation of heterosis and other mode of inheritance effects, (d) the distinction between an association with a primary disorder versus a comorbid disorder, (e) the identification of associations with sub-syndromal symptom clusters that do meet full DSM-IV criteria, and (f) the identification of symptom clusters across databases." [Abstract]

Roman T, Schmitz M, Polanczyk GV, Eizirik M, Rohde LA, Hutz MH.
Is the alpha-2A adrenergic receptor gene (ADRA2A) associated with attention-deficit/hyperactivity disorder?
Am J Med Genet. 2003 Jul 1;120B(1):116-20.
"Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex childhood-onset psychiatric disorder characterized by marked symptoms of inattention, hyperactivity, and impulsivity. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Although most of the molecular studies have investigated the dopamine D4 receptor gene (DRD4) and the dopamine transporter gene (DAT1) genes in its etiology, pharmacological and brain imaging evidences seem to indicate that genes of the adrenergic system could also be attractive for association studies. We investigated a sample of 96 Brazilian ADHD children and adolescents and their parents for the ADRA2A MspI polymorphism. Although no association with either MspI allele was observed through the haplotype relative risk (HRR) analysis, effects of the ADRA2A gene on inattention and combined (inattention + hyperactivity/impulsivity) symptom scores were detected (U = 222.5, z = 2.19, P = 0.03; and U = 208.5, z = 2.32, P = 0.02, respectively). Our results suggest that the ADRA2A gene might have a small effect on ADHD susceptibility or that this gene might modulate the severity of the disorder. They are also consistent with the noradrenergic theories of ADHD, suggesting a role for the alpha2A adrenergic receptors in the disorder." [Abstract]

Comings DE, Gade-Andavolu R, Gonzalez N, Wu S, Muhleman D, Blake H, Dietz G, Saucier G, MacMurray JP.
Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: multivariate regression analysis of 20 genes.
Clin Genet 2000 Mar;57(3):178-96
"The present study is based on the proposal that complex disorders resulting from the effects of multiple genes are best investigated by simultaneously examining multiple candidate genes in the same group of subjects. We have examined the effect of 20 genes for dopamine, serotonin, and noradrenergic metabolism on a quantitative score for attention deficit hyperactivity disorder (ADHD) in 336 unrelated Caucasian subjects. The genotypes of each gene were assigned a score from 0 to 2, based on results from the literature or studies in an independent set of subjects (literature-based scoring), or results based on analysis of variance for the sample (optimized gene scoring). Multivariate linear regression analysis with backward elimination was used to determine which genes contributed most to the phenotype for both coding methods. For optimized gene scoring, three dopamine genes contributed to 2.3% of the variance, p = 0.052; three serotonin genes contributed to 3%, p = 0.015; and six adrenergic genes contributed to 6.9%, p = 0.0006. For all genes combined, 12 genes contributed to 11.6% of the variance, p = 0.0001. These results indicate that the adrenergic genes play a greater role in ADHD than either the dopaminergic or serotonergic genes combined. The results using literature-based gene scoring were similar. An examination of two additional comorbid phenotypes, conduct disorder and oppositional defiant disorder (ODD), indicated they shared genes with ADHD. For ODD different genotypes of the same genes were often used. These results support the value of the simultaneous examination of multiple candidate genes." [Abstract]

Kent L, Doerry U, Hardy E, Parmar R, Gingell K, Hawi Z, Kirley A, Lowe N, Fitzgerald M, Gill M, Craddock N.
Evidence that variation at the serotonin transporter gene influences susceptibility to attention deficit hyperactivity disorder (ADHD): analysis and pooled analysis.
Mol Psychiatry 2002;7(8):908-12
"Reduced central serotonergic activity has been implicated in poor impulse regulation and aggressive behaviour in animals, adults and also young children.(1,2) Two recently published studies have implicated variation at a polymorphism in the promoter of the serotonin transporter (5HTT; hSERT) in influencing susceptibility to ADHD.(3,4) Consistent with these results we have also found a trend for the long allele of the promoter polymorphism to influence susceptibility to ADHD in a sample of 113 ADHD parent proband trios (65 transmissions vs 49 non-transmissions, chi(2) = 2.25, P = 0.13). A pooled analysis of our, and these published results demonstrated a significant over representation of the long allele of the promoter in ADHD probands compared to controls (chi(2) = 7.14, P = 0.008). We have also examined two other 5HTT polymorphisms (the VNTR in intron 2 and the 3' UTR SNP). TDT analysis demonstrated preferential transmission of the T allele of the 3' UTR SNP (chi(2) = 4.06, P = 0.04). In addition, ETDT analysis of haplotypes demonstrated significant preferential transmission of haplotypes containing the T allele of the 3' UTR SNP with the long allele of the promoter polymorphism (chi(2) = 13.18, 3 df, P = 0.004) and the 10 repeat of the VNTR (chi(2) = 8.77, 3 df, P = 0.03). This study provides further evidence for the possible involvement of the serotonin transporter in susceptibility to ADHD." [Abstract]

Langley K, Payton A, Hamshere ML, Pay HM, Lawson DC, Turic D, Ollier W, Worthington J, Owen MJ, O'Donovan MC, Thapar A.
No evidence of association of two 5HT transporter gene polymorphisms and attention deficit hyperactivity disorder.
Psychiatr Genet. 2003 Jun;13(2):107-10.
"OBJECTIVES: Three studies to date have found evidence (or a trend for evidence) of linkage and association between the long allele of the 44 base pair repeat insertion/deletion 5-HTT functional polymorphism (5-HTTLPR) and attention deficit hyperactivity disorder (ADHD). In an attempt to replicate these findings, we examined this polymorphism and a variable number tandem repeat in the second intron of 5-HTT for association with ADHD. METHODS: One hundred and fifty children who met diagnostic criteria for ADHD and their parents (where available) were genotyped for these polymorphisms. Analysis was undertaken using the transmission disequilibrium test and haplotype analysis, as well as case-control comparisons using a control group of 121 individuals. RESULTS: No association between either the 5-HTTLPR or the variable number tandem repeat (VNTR) in ADHD was found (extended transmission disequilibrium test; P=0.37 and P=0.62, respectively). Haplotype analysis was also non-significant. Further analysis revealed no evidence of association in the subgroups of those without conduct disorder and in medication non-responders. CONCLUSIONS: Failure to replicate findings from previous studies may be due to a lack of statistical power. However, given recent findings by Kent et al. (2002) of association with another polymorphism in the 5HTT gene, we hypothesise that previous positive findings may have arisen by the LPR and VNTR being in linkage disequilibrium with the true susceptibility polymorphism." [Abstract]

Zoroglu SS, Erdal ME, Alasehirli B, Erdal N, Sivasli E, Tutkun H, Savas HA, Herken H.
Significance of serotonin transporter gene 5-HTTLPR and variable number of tandem repeat polymorphism in attention deficit hyperactivity disorder.
Neuropsychobiology 2002;45(4):176-81
"The purpose of this study was to evaluate the relationship between attention deficit hyperactivity disorder (ADHD) and polymorphism of the two regions of the 5-HTT gene [variable number of tandem repeats (VNTR) and 5-HTTLRR] in a sample of Turkish children. Using the PCR technique, these polymorphisms were assessed in 71 patients with ADHD and 128 healthy controls. The 5-HTTLPR S/S genotype was significantly lower in the patients than in the controls (p = 0.018). Homozygous and heterozygous L variant predominated in the ADHD group. But the VNTR STin2.12/12 genotype was significantly less found in the patients than in the controls (p = 0.001). There was no significant difference between the frequency of the short (S), long, 10, and 12 alleles of both groups. The lack of an S/S variant of 5-HTTLPR polymorphism of the STin2.12/12 variant of VNTR polymorphism appears to be associated with an increased risk of ADHD." [Abstract]

Curran S, Purcell S, Craig I, Asherson P, Sham P
The serotonin transporter gene as a QTL for ADHD.
Am J Med Genet B Neuropsychiatr Genet. 2005 Apr 5;134(1):42-7.
Molecular studies of attention deficit hyperactivity disorder (ADHD) have identified susceptibility genes for the categorically diagnosed disorder using operational diagnostic criteria. Here, we take a QTL approach to mapping genes for ADHD using a composite continuous index of ADHD behavior in a large epidemiological sample. Previous studies of clinical ADHD suggest that two functional polymorphisms in the serotonin transporter gene (SLC6A4), one in the 5'-regulatory region of the gene (5-HTTLPR) and the other a VNTR (5-HTTVNTR) in the second intron, as well as a single nucleotide polymorphism in the 3'-untranslated region (3'-UTR SNP), may be associated with the disorder. Here, we investigate these polymorphisms as well as an additional ten SNPs spread across the gene. We found significant association with the long (L) allele of the 5-HTTLPR; P = 0.019, but neither the 5-HTTVNTR nor the 3'-UTR SNP were significantly associated. Significant associations (P < 0.05) were found for a further 5 the 10 other markers tested. We found evidence for two haplotype blocks spanning the region. We found strong evidence for association with the first haplotype block (comprised of four markers), with the significance of a combined primary and secondary test of association reaching an empirical P value = 0.0054 for the global test and an empirical P value = 0.00081 for the largest local test. Thus, we show here that SLC6A4, which has a major influence on brain serotonin availability, may be a QTL for ADHD. [Abstract]

Xu X, Mill J, Chen CK, Brookes K, Taylor E, Asherson P
Family-based association study of serotonin transporter gene polymorphisms in attention deficit hyperactivity disorder: No evidence for association in UK and Taiwanese samples.
Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4;
Five independent studies have reported associations between serotonin transporter gene (5-HTT) polymorphisms and attention deficit hyperactivity disorder (ADHD). Four studies found evidence for association between the long-allele of a 44-base pair insertion/deletion polymorphism (5-HTTLPR), one of the studies found association to a variable number tandem repeat within intron 2, another to the T-allele of a single base pair substitution in the 3'-untranslated regions and another reported preferential transmission of a haplotype of the three markers (long-allele/10-repeat-allele/T-allele). One further study found no evidence for these associations. We investigated the association of these three markers in two samples of ADHD patients from the United Kingdom (n = 197) and Taiwan (n = 212), using within-family tests of association. No association was found between any of the three markers in either of the two populations. Although we found some evidence for the preferential transmission of a rare haplotype (long-allele/9-repeat-allele/T-allele; chi(2) = 4.5, P = 0.034), we concluded that this most likely occurred by chance factors alone. [Abstract]

Kim SJ, Badner J, Cheon KA, Kim BN, Yoo HJ, Kim SJ, Cook E, Leventhal BL, Kim YS
Family-based association study of the serotonin transporter gene polymorphisms in Korean ADHD trios.
Am J Med Genet B Neuropsychiatr Genet. 2005 Aug 4;
The dopamine (DA) system has been implicated in attention deficit hyperactivity disorder (ADHD) based on pharmacologic evidence. Because of an interaction between the serotonin (5-HT) and DA systems, the serotonin transporter gene (SLC6A4) has been considered as a candidate ADHD susceptibility gene. Two common polymorphisms, 5-HTTLPR and the intron 2 VNTR, have been studied for association in ADHD, with both positive (increased frequency of long allele of 5-HTTLPR and decreased frequency of 12 repeats of the intron 2 VNTR) and negative findings. However, there has not been an association study in an East Asian ADHD population. In this study, we examined the genotypes of these two polymorphisms in 126 Korean ADHD families and investigated linkage disequilibrium (LD) between SLC6A4 and ADHD, using the transmission disequilibrium test (TDT) and haplotype analysis. Additionally, association with quantitative measures of inattention, hyperactivity-impulsivity, and overall severity was tested using logistic regression and QTDT analysis. TDT of both polymorphisms and haplotype analysis failed to detect LD. However, after excluding ADHD NOS subtype, TDT revealed nominally significant LD between 5-HTTLPR and ADHD (chi(2) = 4.9, P = 0.036). QTDT revealed positive association between 12 repeats of the intron 2 VNTR and attention (P = 0.031), but case-control and TDT logistic regression analyses were negative. These markers have low heterozygosity in the Korean population, which would be expected to reduce the power of association. This result suggests that future studies should include more polymorphic markers and subjects to thoroughly investigate a potential association between SLC6A4 and ADHD in the Korean population. (c) 2005 Wiley-Liss, Inc. [Abstract]

Comings DE, Chen C, Wu S, Muhleman D.
Association of the androgen receptor gene (AR) with ADHD and conduct disorder.
Neuroreport 1999 May 14;10(7):1589-92
"The male predominance of externalizing behaviors suggests that the X-linked androgen gene might be involved. Since the shorter alleles of the CAG and GGC polymorphisms of the AR gene are associated with increased gene expression we sought to determine whether they were also associated with externalizing behaviors. We examined 302 subjects consisting of Tourette syndrome probands and controls. ANOVA showed a significant association between the AR haplotypes and ADHD (p < 0.0001), conduct disorder (CD; p < 0.017), and oppositional defiant disorder (ODD; p < 0.004) with the lowest scores in those with the longer alleles at both polymorphisms. These results suggest that genetic variation at the human AR gene plays a role in human externalizing disorders." [Abstract]

Biederman J, Faraone SV, Keenan K, Benjamin J, Krifcher B, Moore C, Sprich-Buckminster S, Ugaglia K, Jellinek MS, Steingard R, et al.
Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples.
Arch Gen Psychiatry 1992 Sep;49(9):728-38
"We examined 140 probands with attention deficit hyperactivity disorder, 120 normal controls, and their 822 first-degree relatives using "blind" raters and structured diagnostic interviews. Compared with controls, probands with attention deficit hyperactivity disorder were more likely to have conduct, mood, and anxiety disorders. Compared with relatives of controls, relatives of probands with attention deficit hyperactivity disorder had a higher risk for attention deficit hyperactivity disorder, antisocial disorders, major depressive disorder, substance dependence, and anxiety disorders. Patterns of comorbidity indicate that attention deficit hyperactivity disorder and major depressive disorders may share common familial vulnerabilities, that attention deficit hyperactivity disorder plus conduct disorder may be a distinct subtype, and that attention deficit hyperactivity disorder and anxiety disorders are transmitted independently in families. These results extend previous findings indicating family-genetic influences in attention deficit hyperactivity disorder by using both pediatrically and psychiatrically referred proband samples. The distributions of comorbid illnesses in families provide further validation for subgrouping probands with attention deficit hyperactivity disorder by comorbidity." [Abstract]

Biederman J, Faraone SV, Keenan K, Knee D, Tsuang MT.
Family-genetic and psychosocial risk factors in DSM-III attention deficit disorder.
J Am Acad Child Adolesc Psychiatry 1990 Jul;29(4):526-33
"Using family study methodology and assessments made by blind raters, this study evaluated family-genetic and psychosocial risk factors for DSM-III attention deficit disorder (ADD) among the 457 first-degree relatives of clinically referred children and adolescents with ADD (N = 73), compared with psychiatric (N = 26) and normal controls (N = 26). Relatives of ADD probands had a higher morbidity risk for ADD (25.1% versus 5.3% versus 4.6%, ps less than 0.00001), antisocial disorders (25.3% versus 6.9% versus 4.2%, ps less than 0.00001), and mood disorders (27.1% versus 13.9%, p = 0.038 and 27.1% versus 3.6%, p = 0.00001) than did relatives of psychiatric and normal controls. The increased risk for ADD could not be accounted for by gender or generation of relative, the age of proband, social class, or the intactness of the family. These results confirm and extend previous findings indicating important family-genetic risk factors in ADD." [Abstract]

Barr CL, Wigg KG, Feng Y, Zai G, Malone M, Roberts W, Schachar R, Tannock R, Kennedy JL.
Attention-deficit hyperactivity disorder and the gene for the dopamine D5 receptor.
Mol Psychiatry 2000 Sep;5(5):548-51
"A recent study has suggested a possible association of a polymorphism near the dopamine D5 receptor gene (DRD5) and attention-deficit hyperactivity disorder. The polymorphism studied was a (CA)n repeat located in the cosmid containing the D5 receptor gene2 and the allele that was reported to be associated with attention-deficit hyperactivity disorder (ADHD) was the 148-bp allele. In this study we sought to rep