The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder.

BACKGROUND: Bipolar disorder (BPD) is characterized by altered intracellular calcium (Ca(2+)) homeostasis. Underlying mechanisms involve dysfunctions in endoplasmic reticulum (ER) and mitochondrial Ca(2+) handling, potentially mediated by B-cell lymphoma 2 (Bcl-2), a key protein that regulates Ca(2+) signaling by interacting directly with these organelles, and which has been implicated in the pathophysiology of BPD. Here, we examined the effects of the Bcl-2 gene single nucleotide polymorphism (SNP) rs956572 on intracellular Ca(2+) dynamics in patients with BPD. METHODS: Live cell fluorescence imaging and electron probe microanalysis were used to measure intracellular and intra-organelle free and total calcium in lymphoblasts from 18 subjects with BPD carrying the AA, AG, or GG variants of the rs956572 SNP. Analyses were carried out under basal conditions and in the presence of agents that affect Ca(2+) dynamics. RESULTS: Compared with GG homozygotes, variant AA-which expresses significantly reduced Bcl-2 messenger RNA and protein-exhibited elevated basal cytosolic Ca(2+) and larger increases in inositol 1,4,5-trisphosphate receptor-mediated cytosolic Ca(2+) elevations, the latter in parallel with enhanced depletion of the ER Ca(2+) pool. The aberrant behavior of AA cells was reversed by chronic lithium treatment and mimicked in variant GG by a Bcl-2 inhibitor. In contrast, no differences between SNP variants were found in ER or mitochondrial total Ca(2+) content or in basal store-operated Ca(2+) entry. CONCLUSIONS: These results demonstrate that, in patients with BPD, abnormal Bcl-2 gene expression in the AA variant contributes to dysfunctional Ca(2+) homeostasis through a specific ER inositol 1,4,5-trisphosphate receptor-dependent mechanism.

Stable isotope-resolved metabolomic analysis of lithium effects on glial-neuronal metabolism and interactions.

Despite the long-established therapeutic efficacy of lithium in the treatment of bipolar disorder (BPD), its molecular mechanism of action remains elusive. Newly developed stable isotope-resolved metabolomics (SIRM) is a powerful approach that can be used to elucidate systematically how lithium impacts glial and neuronal metabolic pathways and activities, leading ultimately to deciphering its molecular mechanism of action. The effect of lithium on the metabolism of three different (13)C-labeled precursors ([U-(13)C]-glucose, (13)C-3-lactate or (13)C-2,3-alanine) was analyzed in cultured rat astrocytes and neurons by nuclear magnetic resonance (NMR) spectroscopy and gas chromatography mass spectrometry (GC-MS). Using [U-(13)C]-glucose, lithium was shown to enhance glycolytic activity and part of the Krebs cycle activity in both astrocytes and neurons, particularly the anaplerotic pyruvate carboxylation (PC). The PC pathway was previously thought to be active in astrocytes but absent in neurons. Lithium also stimulated the extracellular release of (13)C labeled-lactate, -alanine (Ala), -citrate, and -glutamine (Gln) by astrocytes. Interrogation of neuronal pathways using (13)C-3-lactate or (13)C-2,3-Ala as tracers indicated a high capacity of neurons to utilize lactate and Ala in the Krebs cycle, particularly in the production of labeled Asp and Glu via PC and normal cycle activity. Prolonged lithium treatment enhanced lactate metabolism via PC but inhibited lactate oxidation via the normal Krebs cycle in neurons. Such lithium modulation of glycolytic, PC and Krebs cycle activity in astrocytes and neurons as well as release of fuel substrates by astrocytes should help replenish Krebs cycle substrates for Glu synthesis while meeting neuronal demands for energy. Further investigations into the molecular regulation of these metabolic traits should provide new insights into the pathophysiology of mood disorders and early diagnostic markers, as well as new target(s) for effective therapies.

Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines.

BACKGROUND: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by abnormalities in reciprocal social interactions and language development and/or usage, and by restricted interests and repetitive behaviors. Differential gene expression of neurologically relevant genes in lymphoblastoid cell lines from monozygotic twins discordant in diagnosis or severity of autism suggested that epigenetic factors such as DNA methylation or microRNAs (miRNAs) may be involved in ASD. METHODS: Global miRNA expression profiling using lymphoblasts derived from these autistic twins and unaffected sibling controls was therefore performed using high-throughput miRNA microarray analysis. Selected differentially expressed miRNAs were confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis, and the putative target genes of two of the confirmed miRNA were validated by knockdown and overexpression of the respective miRNAs. RESULTS: Differentially expressed miRNAs were found to target genes highly involved in neurological functions and disorders in addition to genes involved in gastrointestinal diseases, circadian rhythm signaling, as well as steroid hormone metabolism and receptor signaling. Novel network analyses of the putative target genes that were inversely expressed relative to the relevant miRNA in these same samples further revealed an association with ASD and other co-morbid disorders, including muscle and gastrointestinal diseases, as well as with biological functions implicated in ASD, such as memory and synaptic plasticity. Putative gene targets (ID3 and PLK2) of two RT-PCR-confirmed brain-specific miRNAs (hsa-miR-29b and hsa-miR-219-5p) were validated by miRNA overexpression or knockdown assays, respectively. Comparisons of these mRNA and miRNA expression levels between discordant twins and between case-control sib pairs show an inverse relationship, further suggesting that ID3 and PLK2 are in vivo targets of the respective miRNA. Interestingly, the up-regulation of miR-23a and down-regulation of miR-106b in this study reflected miRNA changes previously reported in post-mortem autistic cerebellum by Abu-Elneel et al. in 2008. This finding validates these differentially expressed miRNAs in neurological tissue from a different cohort as well as supports the use of the lymphoblasts as a surrogate to study miRNA expression in ASD. CONCLUSIONS: Findings from this study strongly suggest that dysregulation of miRNA expression contributes to the observed alterations in gene expression and, in turn, may lead to the pathophysiological conditions underlying autism.

Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia.

BACKGROUND: The extracellular-regulated protein kinase (ERK) pathway has been implicated in processes such as neuronal plasticity and resilience in psychiatric disorders including major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia. The extent of the possible involvement of this pathway in psychiatric disorders remains unknown, as does its potential utility as a pharmacological target for the future development of novel therapeutics. METHODS: Western blot analyses were used to measure levels of different proteins-Rap1, B-Raf, MEK1, MEK2, ERK1/2, RSK1, CREB, NSE, and beta-actin-in the postmortem frontal cortex of individuals with schizophrenia, MDD, and BPD, as well as healthy non-psychiatric controls. RESULTS: Levels of most studied protein members of the ERK cascade were lower in individuals with psychiatric disorders than controls; differences between psychiatric groups were not statistically significant. In general, protein levels were lower in individuals with schizophrenia than in those with BPD or MDD, but protein levels varied across groups. LIMITATIONS: The small number of individuals in each diagnostic group may limit our interpretation of the results. Factors such as postmortem interval, medication status at time of death, and mood state at time of death may also have influenced the findings. DISCUSSION: The results are consistent with the hypothesis that the ERK pathway is implicated in reduced neuronal plasticity associated with the course of these psychiatric illnesses. The results warrant an expanded investigation into the activity of other members of this pathway as well as other brain areas of interest.

Dynamic regulation of mitochondrial function by glucocorticoids.

Glucocorticoids play an important biphasic role in modulating neural plasticity; low doses enhance neural plasticity and spatial memory behavior, whereas chronic, higher doses produce inhibition. We found that 3 independent measures of mitochondrial function-mitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity-were regulated by long-term corticosterone (CORT) treatment in an inverted "U"-shape. This regulation of mitochondrial function by CORT correlated with neuroprotection; that is, treatment with low doses of CORT had a neuroprotective effect, whereas treatment with high doses of CORT enhanced kainic acid (KA)-induced toxicity of cortical neurons. We then undertook experiments to elucidate the mechanisms underlying these biphasic effects and found that glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to CORT treatment and translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of CORT in primary cortical neurons. However, after 3 days of treatment, high, but not low, doses of CORT resulted in decreased GR and Bcl-2 levels in mitochondria. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose CORT in vivo. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience and to inform the future development of improved therapeutics.

Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage.

Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia.

Genome-wide gene expression profiling in GluR1 knockout mice: key role of the calcium signaling pathway in glutamatergically mediated hippocampal transmission.

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) convey fast synaptic transmission in the CNS and mediate various forms of hippocampal plasticity. Disruption of glutamate receptor type 1 (GluR1), a member of the AMPAR family, causes synaptic alterations and learning/memory deficits in mice. To gain mechanistic insight into the synaptic and behavioral changes associated with GluR1 deletion, hippocampal genome-wide expression profiling was conducted using groups of GluR1 knockout (KO) mice and their wild-type littermates. Regulation of 38 genes was found to be altered more than 30% (P < 0.01, n = 8), and seven of these genes were studied with additional quantitative experiments. A large portion of the altered genes encoded molecules involved in calcium signaling, including calcium channel components, calcium-binding proteins and calcium-calmodulin-dependent protein kinase II subunits. At the protein level, we further evaluated some genes in the calcium pathway that were altered in GluR1 KO mice. Protein levels of two key molecules in the calcium pathway - GluR, ionotropic, N-methyl-d-aspartate-1 and calcium/calmodulin-dependent protein kinase II alpha - showed similar changes to those observed in mRNA levels. These findings raise the possibility that calcium signaling and other plasticity molecules may contribute to the hippocampal plasticity and behavioral deficits observed in GluR1 KO mice.

Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers.

MicroRNAs (miRNAs) regulate messenger RNA (mRNA) translation in a sequence-specific manner and are emerging as critical regulators of central nervous system plasticity. We found hippocampal miRNA level changes following chronic treatment with mood stabilizers (lithium and valproate (VPA)). Several of these miRNAs were then confirmed by quantitative PCR: let-7b, let-7c, miR-128a, miR-24a, miR-30c, miR-34a, miR-221, and miR-144. The predicted effectors of these miRNAs are involved in neurite outgrowth, neurogenesis, and signaling of PTEN, ERK, and Wnt/beta-catenin pathways. Interestingly, several of these effector-coding genes are also genetic risk candidates for bipolar disorder. We provide evidence that treatment with mood stabilizers increases these potential susceptibility genes in vivo: dipeptidyl-peptidase 10, metabotropic glutamate receptor 7 (GRM7), and thyroid hormone receptor, beta. Treatment of primary cultures with lithium- or VPA-lowered levels of miR-34a and elevated levels of GRM7, a predicted effector of miR-34a. Conversely, miR-34a precursor treatment lowered GRM7 levels and treatment with a miR-34a inhibitor enhanced GRM7 levels. These data confirm that endogenous miR-34a regulates GRM7 levels and supports the notion that miR-34a contributes to the effects of lithium and VPA on GRM7. These findings are the first to demonstrate that miRNAs and their predicted effectors are targets for the action of psychotherapeutic drugs.

BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments.

Recent microarray studies with stringent validating criteria identified Bcl-2-associated athanogene (BAG1) as a target for the actions of medications that are mainstays in the treatment of bipolar disorder (BPD). BAG1 is a Hsp70/Hsc70-regulating cochaperone that also interacts with glucocorticoid receptors (GRs) and attenuates their nuclear trafficking and function. Notably, glucocorticoids are one of the few agents capable of triggering both depressive and manic episodes in patients with BPD. As a nexus for the actions of glucocorticoids and bipolar medications, we hypothesized that the level of BAG1 expression would play a pivotal role in regulating affective-like behaviors. This hypothesis was investigated in neuron-selective BAG1 transgenic (TG) mice and BAG1 heterozygous knockout (+/-) mice. On mania-related tests, BAG1 TG mice recovered much faster than wild-type (WT) mice in the amphetamine-induced hyperlocomotion test and displayed a clear resistance to cocaine-induced behavioral sensitization. In contrast, BAG1+/- mice displayed an enhanced response to cocaine-induced behavioral sensitization. The BAG1 TG mice showed less anxious-like behavior on the elevated plus maze test and had higher spontaneous recovery rates from helplessness behavior compared with WT mice. In contrast, fewer BAG1+/- mice recovered from helplessness behavior compared with their WT controls. BAG1 TG mice also exhibited specific alterations of hippocampal proteins known to regulate GR function, including Hsp70 and FKBP51. These data suggest that BAG1 plays a key role in affective resilience and in regulating recovery from both manic-like and depression-like behavioral impairments.

The monoamine oxidase B gene exhibits significant association to ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition with strong genetic basis. Recent work in China indicated that ADHD may be linked to Xp1-2 in the Han Chinese population. The gene encoding monoamine oxidase B (MAOB), the main enzyme degrading dopamine in the human brain, is located in this region. The current study sequenced the exons and the 5' and 3' flanking regions of the MAOB gene and found four common variants including 2276C>T and 2327C>T in exon 15, rs1799836 in intron 13 and rs1040399 in 3'-UTR. We assessed the association of these variants with ADHD in 548 trios collected from 468 males and 80 females probands. TDT analysis showed that alleles of each polymorphism were preferentially transmitted to probands (rs1799836, P = 3.28E-15; rs1040399, P = 1.87E-6; 2276T>C or 2327T>C, P = 2.20E-6) and haplotype-based TDT analyses also found distorted transmission. In conclusion, this study provides the strongest evidence for the involvement of MAOB gene in the etiology of ADHD to date, at least in Han Chinese population.

[Association between serotonin 1D gene polymorphisms and attention deficit hyperactivity disorder comorbid or not comorbid learning disorder].

OBJECTIVE: To investigate the relationship between two HTR1D gene polymorphisms, 1350T>C and 1236A>G polymorphisms, and attention deficit hyperactivity disorder (ADHD) comorbid or not comorbid learning disorder (LD). METHODS: Blood samples were taken from 91 trios with probands of ADHD comorbid LD and 181 trios with probands of ADHD not comorbid LD. DNA was extracted. 1350T>C and 1236A>G were genotyped by restriction fragment length polymorphism analysis. Transmit/disequilibrium test and haplotype analysis were used to test the association between the two polymorphisms of HTR1D gene and ADHD comorbid or not comorbid LD separately. RESULTS: 1236A allele (chi2=5.306, P=0.021) was over transmitted to probands of ADHD without LD. No biased transmissions of any allele and haplotype were found in families with probands of ADHD with LD. CONCLUSION: whether ADHD comorbid LD or not comorbid LD makes difference at the level of HTR1D gene polymorphism of 1236A>G.

[Association between serotonin 2C gene polymorphisms and attention deficit hyperactivity disorder in children with or without comorbidity of disruptive behavior disorder].

OBJECTIVE: Disruptive behavior disorder (DBD) is one of the main comorbidity of attention deficit hyperactivity disorder (ADHD). Previous studies showed significantly different serotonin function between ADHD children with and without the comorbidity of DBD. Therefore, it is needed to compare these two groups in terms of serotonin receptor gene polymorphisms, which may provide further evidence for the previous studies. The current study aimed to investigate the relationship between two serotonin receptor 2C (HTR2C) gene polymorphisms, that are C-759T and G-697C polymorphisms, and ADHD with or without concomitant DBD. METHOD: Blood samples were taken from 237 trios with probands of ADHD with DBD comorbidity and 251 trios with probands of ADHD without comorbidity of DBD. All the subjects were from the ADHD clinic of Peking University Sixth Hospital. DNA was extracted and PCR was performed to amplify the fragments containing both C-759T and G-697C polymorphisms. AciI was used to detect different alleles of the two polymorphisms. Both allele-based and haplotype-based TDT analyses were used to test the association of the two polymorphisms of HTR2C gene and ADHD with or without comorbidity of DBD. RESULTS: The haplotypes -759C (chi(2) = 4.25, P = 0.04), -697G(chi(2) = 3.21, P = 0.07), as well as -759C/-697G were over-transmitted (chi(2) = 4.31, P = 0.04) to the probands of ADHD without DBD. No biased transmission of any allele and haplotype were found in families with probands of ADHD with DBD. CONCLUSION: ADHD with or without the comorbidity DBD was different at the level of HTR2C gene polymorphisms of C-759T and G-697C. HTR2C is related to ADHD without DBD, while not related to ADHD with DBD. The results suggested that the two groups may have different genetic background, at least in HTR2C.

[Association between serotonin 4 gene polymorphisms and attention deficit hyperactivity disorder comorbid or not comorbid disruptive behavioral disorder].

OBJECTIVE: To investigate the relationship between three HTR4 gene polymorphisms, 83097 C>T, 83198 A>G as well as -36C>T polymorphisms, and attention deficit hyperactivity disorder (ADHD) comorbid or not comorbid disruptive behavioral disorder (DBD). METHODS: Blood samples were taken from 152 trios with probands of ADHD comorbid DBD and 173 trios with probands of ADHD not comorbid DBD. DNA was extracted. 83097 C>T, 83198 A>G and -36C>T were genotyped by restriction fragment length polymorphism analysis. Transmit/disequilibrium test and haplotype analysis were used to test the association of the three polymorphisms with ADHD comorbid or not comorbid DBD separately. RESULTS: Haplotype T/G/T showed tendency of over transmission (chi(2)=3.470,P=0.062) to probands of ADHD with DBD, while haplotype C/G/T (chi(2)=4.568,P=0.032) and C/G/C (chi(2)=5.333,P=0.021) were under transmitted to probands of ADHD without DBD, No biased transmissions of any allele were found in families with probands of ADHD with and without DBD. CONCLUSION: Whether ADHD comorbid DBD or not comorbid DBD makes difference at the level of HTR4 gene polymorphisms.

Monoamine oxidase A gene polymorphism predicts adolescent outcome of attention-deficit/hyperactivity disorder.

ADHD is generally deemed to be a highly heritable disorder with mean heritability of 0.75. The enzyme monoamine oxidase (MAO), which has both A and B types, has long been considered a candidate pathological substrate for ADHD, and more recently, the genes for both MAO enzymes have been examined as mediators of the illness. Previous studies indicated that 30-50% of children with ADHD will experience symptoms that persist into adolescence and will have more significant impairment in social and neuropsychological functioning compared to those whose symptoms have remitted. Genes may also influence these characteristics of the disorder, and in this context MAO genes may also be candidates for moderating the presentation of ADHD. The current study examined the association between adolescent outcome of ADHD and MAO gene polymorphisms, including the 941T > G polymorphism in exon 8 (rs1799835) and 1460C > T polymorphism in exon 14 (rs1137070) of the MAOA gene, and the A > G polymorphism in intron13 (rs1799836), C > T polymorphism in the 3'UTR (rs1040399), and 2327T > C polymorphism in exon15 of the MAOB gene. Significant associations were observed between the MAOA gene polymorphisms and ADHD remission. Due to the small sample size and the possibility of phenotypic and etiologic heterogeneity of ADHD outcomes across ethnic or geographic groups, these results must be replicated before they can be generalized to other populations.

Association between polymorphisms in serotonin transporter gene and attention deficit hyperactivity disorder in Chinese Han subjects.

Prior work has shown reduced serotonin transmission to be associated with impulsivity and behavioral problems. The current study assessed the association between ADHD and two variants of the serotonin transporter gene: the 44-bp deletion/insertion polymorphism (5-HTTLPR) and the 17 bp-repeat polymorphism in intron 2 (STin2.VNTR). We hypothesized that ADHD phenotypes associated with impulsivity would show an association with these variants. Two-hundred and ninety-three ADHD trios were genotyped and analyzed using transmission disequilibrium test (TDT) analysis and haplotype analysis. We found no association between the STin2.VNTR and ADHD, but did find preferential transmission of the S allele of the 5-HTTLPR polymorphism (chi(2) = 5.751, P = 0.016) to probands with ADHD. Haplotype analysis found the L/10 haplotype was over-transmitted (chi(2) = 6.172, P = 0.013), while L/12 was under-transmitted to probands with ADHD (chi(2) = 4.866, P = 0.027).

Evaluation of potential gene-gene interactions for attention deficit hyperactivity disorder in the Han Chinese population.

Several lines of evidence suggest that attention-deficit/hyperactivity disorder (ADHD) is a polygenic disorder produced by the interaction of several genes with minor effects. To explore potential gene-gene interactions among candidate genes for ADHD, we studied the dopamine D2 receptor (DRD2), dopamine D4 receptor (DRD4), dopamine transporter (DAT1), and catechol-O-methyltransferase (COMT) genes in the Han Chinese population. A sample of 340 children with ADHD was diagnosed according to the DSM-IV criteria. We also recruited 226 unrelated controls. Identified polymorphisms included a 48-base-pair-repeat in Exon 3 of DRD4, a 40-base-pair-repeat in the 3' untranslated region of DAT1, a restriction-fragment-length polymorphism at codon 158 of COMT, and a -241A > G transition in the promoter of DRD2. Associations of polymorphisms with ADHD and its subtypes were examined by comparing allele frequencies between probands and controls. Binary logistic regression analysis was used to examine the potential gene-gene interactions. Binary logistic regression analysis with the sample of refined phenotypes showed that male gender and long-repeat genotypes of DRD4 and DAT1 were independent risk factors for ADHD. We found no evidence for gene-gene interactions among the candidate genes studied. The present study suggests that dopamine candidate genes are associated with increased vulnerability to ADHD in the Han Chinese population.

The serotonin 5-HT1D receptor gene and attention-deficit hyperactivity disorder in Chinese Han subjects.

Attention-deficit/hyperactivity disorder (ADHD) is a heritable disease. Serotonin is one of the neurotransmitters involved in the etiology of ADHD. Serotonin-1D receptors are autoreceptors which can regulate the release of serotonin in brain, so the HTR1D gene may be predisposing. The current study genotyped two variants of HTR1D gene in 272 ADHD trios of Chinese ethnicity, that is 1350T > C in the coding region and 1236A > G in 3'-UTR by the use of transmission disequilibrium test (TDT). The A allele of the 1236A > G polymorphism exhibited both a trend toward preferential transmission to ADHD probands (chi2 = 3.815, P = 0.051) and a significant preferential transmission to probands of ADHDC (chi2 = 4.198, P = 0.040). Additional polymorphisms in this gene need to be studied further.

[Association between serotonin 1D gene polymorphisms and attention deficit hyperactivity disorder comorbid or not comorbid disruptive behavior disorder].

OBJECTIVE: To investigate the relationship between two HTR1D gene polymorphisms, that is 1350T > C and 1236A > G polymorphisms, and attention deficit hyperactivity disorder (ADHD) comorbid or not comorbid disruptive behavior disorder (DBD). METHODS: Blood samples were taken from 90 trios with probands of ADHD comrbid DBD and 182 trios with probands of ADHD not comorbid DBD. DNA was extracted. 1350T > C and 1236A > G were genotyped by restriction fragment length polymorphism analysis. Transmit/disequilibrium test and haplotype analysis were used to test the association of the two polymorphisms of HTR1D gene and ADHD comorbid or not comorbid disruptive behavior disorder (DBD) separately. RESULTS: 1350T allele(chi2 = 3.67, P = 0.055)and G/T haplotype(chi2 = 3.84, P = 0.050)were overtransmitted, while 1350C allele(chi2 = 3.67, P = 0.055) and G/C haplotype(chi2 = 5.22, P = 0.022)were undertransmitted to probands of ADHD with DBD. No biased transmission of any allele and haplotype was found in families with probands of ADHD without DBD. CONCLUSION: ADHD comorbid or not comorbid DBD are different at the level of HTR1D gene polymrohisms of 1350T > C and 1236A > G. The current results indicate that ADHD with DBD has more heritable backgrounds when compared with ADHD without DBD.

Association between polymorphisms in serotonin 2C receptor gene and attention-deficit/hyperactivity disorder in Han Chinese subjects.

Attention deficit hyperactivity disorder (ADHD) is much more frequent in males than females, so several genes on the X chromosome (e.g., MAOA and MAOB) have been pursued as candidates for influencing risk for the disorder. HTR2C is also located on the X chromosome. In the current study, we examined the relationship between the C-759T and G-697C polymorphisms of HTR2C and ADHD in 488 Han Chinese families. Transmission Disequilibrium Test (TDT) analysis showed that the -759C allele, the -697G allele, and haplotype -759C/-697G were significantly over-transmitted to affected probands, while haplotypes -759C/-697C and -759T/-697C were under-transmitted. When families were divided into three subtypes according to the diagnosis of probands, the -697G allele and haplotype -759C/-697G were significantly over transmitted to ADHD-C probands, while haplotype -759T/-697C was under-transmitted to these individuals; however, no biased transmission of any allele or haplotype was observed for probands with ADHD-I, suggesting that different subtypes of ADHD have different genetic influences. Our findings highlight the need to explore the role of 5-HT2C receptor dysfunction in the pathogenesis of ADHD.