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Chunhui Chen,
Wen Chen,
Chuansheng Chen, Robert Moyzis,
Qinghua He,
Xuemei Lei,
Jin Li,
Yunxin Wang,
Bin Liu,
Daiming Xiu,
Bi Zhu,
Qi Dong
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ABSTRACT: Obesity has become a worldwide health problem in the past decades. Human and animal studies have implicated serotonin in appetite regulation, and behavior genetic studies have shown that body mass index (BMI) has a strong genetic component. However, the roles of genes related to the serotoninergic (5-hydroxytryptamine,5-HT) system in obesity/BMI are not well understood, especially in Chinese subjects.
With a sample of 478 healthy Chinese volunteers, this study investigated the relation between BMI and genetic variations of the serotoninergic system as characterized by 136 representative polymorphisms. We used a system-level approach to identify SNPs associated with BMI, then estimated their overall contribution to BMI by multiple regression and verified it by permutation.
We identified 12 SNPs that made statistically significant contributions to BMI. After controlling for gender and age, four of these SNPs accounted for 7.7% additional variance of BMI. Permutation analysis showed that the probability of obtaining these findings by chance was low (p = 0.015, permuted for 1000 times).
These results showed that genetic variations in the serotoninergic system made a moderate contribution to individual differences in BMI among a healthy Chinese sample, suggesting that a similar approach can be used to study obesity.
PLoS ONE 01/2013; 8(3):e58717. · 4.09 Impact Factor
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Xuemei Lei,
Chuansheng Chen,
Qinghua He, Robert Moyzis,
Gui Xue,
Chunhui Chen,
Zhongyu Cao,
Jin Li,
He Li,
Bi Zhu,
Mingxia Zhang,
Jun Li,
Qi Dong
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ABSTRACT: Response inhibition refers to the suppression of inappropriate or irrelevant responses. It has a central role in executive functions, and has been linked to a wide spectrum of prevalent neuropsychiatric disorders. Increasing evidence from neuropharmacological studies has suggested that gene variants in the norepinephrine neurotransmission system make specific contributions to response inhibition. This study genotyped five tag single-nucleotide polymorphisms covering the whole alpha-2B-adrenergic receptor (ADRA2B) gene and investigated their associations with response inhibition in a relatively large healthy Chinese sample (N=421). The results revealed significant genetic effects of the ADRA2B conserved haplotype polymorphisms on response inhibition as measured by stop-signal reaction time (SSRT) (F(2, 418)=5.938, p=0.003). Individuals with the AAGG/AAGG genotype (n=89; mean SSRT=170.2 ms) had significantly shorter SSRTs than did those with either the CCAC/AAGG genotype (n=216; mean SSRT=182.4 ms; uncorrected p=0.03; corrected p=0.09) or the CCAC/CCAC genotype (n=116; mean SSRT=195.8 ms; corrected p<0.002, Cohen's d=0.51). This finding provides the first evidence from association research in support of a critical role of the norepinephrine neurotransmission system in response inhibition. A better understanding of the genetic basis of response inhibition would allow us to develop more effective diagnosis, treatment, and prevention of deficient or underdeveloped response inhibition as well as its related prevalent neuropsychiatric disorders.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2012; 37(5):1115-21. · 6.99 Impact Factor
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ABSTRACT: Alcohol use is highly heritable and has been associated with many gene variants, including those related to dopamine (DA). However, single gene association studies have shown inconsistent and small effects. Using a system-level approach, the current study aimed to estimate the overall effect of genetic variations in the DA system on alcohol use among male drinkers. One hundred seventy-six male college students who reported to have ever drunk alcohol were enrolled. Alcohol use was measured using the Alcohol Use Disorders Identification Test. Ninety-eight representative polymorphisms in all major DA neurotransmitter genes were genotyped. Using analysis of variance, we identified six single-nucleotide polymorphisms (SNP)s that made statistically significant contributions to alcohol use. Next, main effects and interactions of these SNPs were assessed using multiple regression. The final model accounted for approximately 20% of the variance for alcohol use. Finally, permutation analyses ascertained the probability of obtaining these findings by chance to be low, p ranging from 0.024 to 0.048. These results confirmed that DA-related gene variants made strong contributions to reported alcohol use and suggest that multiple regression can be a promising way to explore the genetic basis for multi-gene-determined human behaviors.
Addiction Biology 08/2011; 17(2):479-89. · 4.83 Impact Factor
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ABSTRACT: Previous research has shown inconsistent findings regarding the relations between the functional Val158Met polymorphisms of the catechol-O-methyltransferase (COMT) gene and individual differences in personality traits. This study attempts to overcome some of the weaknesses of previous research, namely, small sample sizes, clinical samples, ethnic stratification, wide age ranges, neglecting sex differences, and single measures of personality traits. A large sample (n = 556, 250 male, 306 female) of healthy Chinese college students (mean age = 20.5 ± 1 years) was given a battery of personality scales, including the temperament and character inventory-revised, the behavioral inhibition system and behavioral approach system scale, the Beck depression inventory, and the Beck anxiety inventory. Factor analysis of the affect-related personality traits revealed two factors that corresponded to positive (PEM) and negative emotionality (NEM). We found a consistent COMT-by-sex interaction effect on affect-related personality traits. Compared with males with Met/Met alleles, males with Val/Val alleles showed significantly higher scores on NEM, but lower scores on PEM. Females, however, showed an opposite but nonsignificant pattern. Our results supported the role of the COMT gene in personality traits for males and contributed to the growing literature on sex differences in gene-behavior connections.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2011; 36(8):1593-8. · 6.99 Impact Factor
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ABSTRACT: Traditional behavioral genetic studies (e.g., twin, adoption studies) have shown that human personality has moderate to high heritability, but recent molecular behavioral genetic studies have failed to identify quantitative trait loci (QTL) with consistent effects. The current study adopted a multi-step approach (ANOVA followed by multiple regression and permutation) to assess the cumulative effects of multiple QTLs. Using a system-level (dopamine system) genetic approach, we investigated a personality trait deeply rooted in the nervous system (the Highly Sensitive Personality, HSP). 480 healthy Chinese college students were given the HSP scale and genotyped for 98 representative polymorphisms in all major dopamine neurotransmitter genes. In addition, two environment factors (stressful life events and parental warmth) that have been implicated for their contributions to personality development were included to investigate their relative contributions as compared to genetic factors. In Step 1, using ANOVA, we identified 10 polymorphisms that made statistically significant contributions to HSP. In Step 2, these polymorphism's main effects and interactions were assessed using multiple regression. This model accounted for 15% of the variance of HSP (p<0.001). Recent stressful life events accounted for an additional 2% of the variance. Finally, permutation analyses ascertained the probability of obtaining these findings by chance to be very low, p ranging from 0.001 to 0.006. Dividing these loci by the subsystems of dopamine synthesis, degradation/transport, receptor and modulation, we found that the modulation and receptor subsystems made the most significant contribution to HSP. The results of this study demonstrate the utility of a multi-step neuronal system-level approach in assessing genetic contributions to individual differences in human behavior. It can potentially bridge the gap between the high heritability estimates based on traditional behavioral genetics and the lack of reproducible genetic effects observed currently from molecular genetic studies.
PLoS ONE 01/2011; 6(7):e21636. · 4.09 Impact Factor
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ABSTRACT: The developmental trajectory of attention-deficit hyperactivity disorder (ADHD) is variable. Utilizing a longitudinally assessed sample, we investigated the contribution of susceptibility gene variants, previously implicated through pooled or meta-analyses, to the developmental course of Attention-Deficit Hyperactivity Disorder over time.
151 children (aged 6-12) who met diagnostic criteria for ADHD were assessed using research diagnostic interviews during childhood and 5 years later in adolescence. Severity was defined as total number of ADHD symptoms at baseline and reassessment. Association with variants at DRD4, DRD5, and the dopamine transporter gene, DAT was analyzed using linear regression.
As expected, affected individuals showed a decline in ADHD severity over time. The DRD4 48 bp VNTR 7-repeat and DRD5 CA(n) microsatellite marker 148 bp risk alleles were associated with persistent ADHD. Those possessing the DRD4 7 repeat risk allele showed less of a decline in severity at reassessment than those without the risk allele.
Those carrying the DRD4 7 risk allele showed greater symptom severity at follow-up and less ADHD reduction over time. These findings support the hypothesis that some susceptibility genes for ADHD also influence its developmental course.
European Child & Adolescent Psychiatry 07/2008; 18(1):26-32. · 2.82 Impact Factor
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ABSTRACT: The relationship of the dopamine D4 receptor gene (DRD4) to the behavioral trait of novelty seeking has not been uniformly consistent. A methodological shortcoming in previous studies may relate to the way different DRD4 variants were categorized. Because of evolutionary and functional (e.g., diminished potency to reduce cAMP) similarities between the 2- and 7-repeat (2R, 7R) alleles of the DRD4, we suggest grouping of these two alleles together may facilitate detection of biologically meaningful and reproducible association findings with behavioral traits. We measured novelty seeking with the Tridimensional Personality Questionnaire (TPQ) in a community sample of Caucasian, Korean, and Filipino subjects (N = 171) who were subsequently characterized for the DRD4 variable number of tandem repeats (VNTR). In the Korean sample, those with a 2R and/or 7R allele scored significantly higher on novelty seeking scale (P < 0.05). By contrast, grouping the VNTR alleles by size (2, 3, 4 vs. 5, 6, 7), as has been done in similar studies of Asian subjects, was not significant. Using the extreme discordant phenotype (EDP) strategy in the pooled sample and selecting the individuals within the upper and lower decile, we observed a trend for association with higher novelty seeking in individuals who carry the 2R and/or 7R alleles (P = 0.06). We also confirmed that the 2R allele in the Korean and Filipino subjects was the result of a one-step recombination event between the 4R and 7R alleles. This study suggests that genetic association analyses can benefit by consideration of the shared functional and evolutionary attributes of the DRD4 2R and 7R alleles.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2007; 144B(4):453-7. · 3.70 Impact Factor
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James McGough,
James McCracken,
James Swanson,
Mark Riddle,
Scott Kollins,
Laurence Greenhill,
Howard Abikoff,
Mark Davies,
Shirley Chuang,
Tim Wigal,
Sharon Wigal,
Kelly Posner,
Anne Skrobala,
Elizabeth Kastelic,
Jaswinder Ghuman,
Charles Cunningham,
Sharon Shigawa, Robert Moyzis,
Benedetto Vitiello
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ABSTRACT: The authors explored genetic moderators of symptom reduction and side effects in methylphenidate-treated preschool-age children diagnosed with attention-deficit/hyperactivity disorder (ADHD).
DNA was isolated from 81 subjects in a double-blind, placebo-controlled, crossover methylphenidate titration. Parents and teachers completed ADHD symptom scales and side effect ratings for each of five randomly administered weekly conditions that included immediate-release methylphenidate 1.25, 2.5, 5.0, 7.5 mg and placebo given three times daily. Candidate genes hypothesized to influence stimulant effects or individual risks for ADHD were genotyped.
Although the primary analysis did not indicate significant genetic effects, secondary analyses revealed associations between symptom response and variants at the dopamine receptor (DRD4) promoter (p=.05) and synaptosomal-associated protein 25 (SNAP25) allelesT1065G (p=.03) andT1069C (p=.05). SNAP25 variants were also associated with tics (p=.02), buccal-lingual movements (p=.01), and irritability (p=04). DRD4 variants were also associated with picking (p=.03). Increasing dose predicted irritability (p=.05) and social withdrawal (p=.03) with DRD4 variants. There were no significant effects for the dopamine transporter (DAT1).
Emerging evidence suggests the potential for understanding the individual variability of response to and side effects of ADHD medications from the study of genetics, although additional research is required before these findings are proven to have clinical utility.
Journal of the American Academy of Child & Adolescent Psychiatry 12/2006; 45(11):1314-22. · 6.44 Impact Factor
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01/2006; , ISBN: 9780470018866
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Patrick W L Leung,
C C Lee,
S F Hung,
T P Ho,
C P Tang,
S L Kwong,
S Y Leung,
S T Yuen,
F Lieh-Mak,
Jaap Oosterlaan,
Deborah Grady,
Ante Harxhi,
Y C Ding,
H C Chi,
Pamela Flodman,
Sabrina Schuck,
M Anne Spence, Robert Moyzis,
James Swanson
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ABSTRACT: There is an increased prevalence of the 7-repeat (7R) allele of the dopamine receptor D4 (DRD4) gene in attention-deficit/hyperactivity disorder (ADHD). However, the population prevalence of the 7R allele varies considerably across ethnicity and is very low in Asians. To test whether this 7R allele/ADHD association still held in a Chinese clinical sample, 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate-responders were genotyped. None of them had a DRD4 7R allele. Instead, we observed a significantly increased prevalence of the 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically-matched controls (20%) (chi(2)(1d.f.) = 5.90, P = 0.015). This approximately 1.65-fold increase of the 2R allele in our probands is close to the observed increase of the 7R allele in European-ancestry ADHD children. Recent genetic studies have indicated that the 2R allele in Asians is likely derived from the 7R allele. Further, available biochemical data indicate that both the 2R and 7R protein have blunted responses to dopamine compared to the 4R protein. Based on these results, we propose that the observed increased prevalence of the 2R allele in our Han Chinese ADHD probands is still consistent with the 7R allele hypothesis of ADHD in European-ancestry children. Recent studies have suggested that any variant from the conserved ancestral 4R allele might potentially alter biochemistry/phenotype. We hypothesize that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD that holds across ethnicity. The present findings, however, obtained with a small ADHD sample size, should be replicated.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2005; 133B(1):54-6. · 3.70 Impact Factor
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Patrick W.L. Leung,
C.C. Lee,
S.F. Hung,
T.P. Ho,
C.P. Tang,
S.L. Kwong,
S.Y. Leung,
S.T. Yuen,
F. Lieh-Mak,
Jaap Oosterlaan,
Deborah Grady,
Ante Harxhi,
Y.C. Ding,
H.C. Chi,
Pamela Flodman,
Sabrina Schuck,
M. Anne Spence, Robert Moyzis,
James Swanson
[show abstract]
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ABSTRACT: There is an increased prevalence of the 7-repeat (7R) allele of the dopamine receptor D4 (DRD4) gene in attention-deficit/hyperactivity disorder (ADHD). However, the population prevalence of the 7R allele varies considerably across ethnicity and is very low in Asians. To test whether this 7R allele/ADHD association still held in a Chinese clinical sample, 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate-responders were genotyped. None of them had a DRD4 7R allele. Instead, we observed a significantly increased prevalence of the 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically-matched controls (20%) (χ2(1d.f.) = 5.90, P = 0.015). This approximately 1.65-fold increase of the 2R allele in our probands is close to the observed increase of the 7R allele in European-ancestry ADHD children. Recent genetic studies have indicated that the 2R allele in Asians is likely derived from the 7R allele. Further, available biochemical data indicate that both the 2R and 7R protein have blunted responses to dopamine compared to the 4R protein. Based on these results, we propose that the observed increased prevalence of the 2R allele in our Han Chinese ADHD probands is still consistent with the 7R allele hypothesis of ADHD in European-ancestry children. Recent studies have suggested that any variant from the conserved ancestral 4R allele might potentially alter biochemistry/phenotype. We hypothesize that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD that holds across ethnicity. The present findings, however, obtained with a small ADHD sample size, should be replicated. © 2004 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2005; 133B(1):54 - 56. · 3.70 Impact Factor
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ABSTRACT: Rather than starting with traits and speculating whether selective forces drove evolution in past environments, we propose starting with a candidate gene associated with a trait and testing first for patterns of selection at the DNA level. This can provide limitations on the number of traits to be evaluated subsequently by adaptationism as described by Andrews et al.
Behavioral and Brain Sciences 07/2002; 25(04):530 - 531. · 25.06 Impact Factor
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ABSTRACT: A research program at UC Irvine has investigated the molecular genetic basis of ADHD by focusing on one candidate gene (DRD4) and the highly variable 48 bp VNTR polymorphism in exon 3. Initial studies revealed that the 7R variant is over-represented in ADHD samples, and a subsequent study suggested that the 7R allele is associated with clear excesses in behavior but not with some cognitive deficits thought to be core feature of the disorder. The next phase of this research program showed that (1) the common 7R allele was the product of positive selection, (2) other variation in and around the DRD4 gene is in tight linkage disequilibrium with the 7R allele but not the 4R allele, and (3) more rare 7R variants in the ADHD clinical sample than expected. Based on this program of research, we suggest that the 7R VNTR variant is responsible for the observed association of the DRD4 gene with ADHD, and that a challenge for the future is understanding what other genetic and/or environmental factors influence this association and affect clinical outcome of the disorder.
Clinical Neuroscience Research 5:265-272. · 0.80 Impact Factor
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J.M Swanson,
Pamela Flodman,
James Kennedy,
M.Anne Spence, Robert Moyzis,
Sabrina Schuck,
Michael Murias,
Joan Moriarity,
Cathy Barr,
Moyra Smith,
Michael Posner
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ABSTRACT: Family, twin, and adoption studies have documented a strong genetic basis for ADHD/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which for a half century have provided the primary pharmacological treatment for ADHD/HKD. Two candidate dopamine genes have been investigated and reported to be associated with ADHD/HKD: the dopamine transporter (DAT1) gene [Cook et al., American Journal of Human Genetics 1995;56:993–998, Gill et al., Molecular Psychiatry 1997;2:311–313] and the dopamine receptor D4 (DRD4) gene [LaHoste et al., Molecular Psychiatry 1996;1:121–124; Smalley et al., 1998;3:427–430; Swanson et al., Molecular Psychiatry 1998;3:38–41]. Speculative hypotheses [Swanson and Castellanos, NIH Consensus Development Conference: Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder, November 1998. p. 37–42] have suggested that specific alleles of these dopamine genes may alter dopamine transmission in the neural networks implicated in ADHD/HKD (e.g. that the 10-repeat allele of the DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7-repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic receptor). These and other variants of the dopamine hypothesis of ADHD will be discussed.
Neuroscience & Biobehavioral Reviews 24(1):21-25. · 8.65 Impact Factor
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J.M Swanson,
Pamela Flodman,
James Kennedy,
M.Anne Spence, Robert Moyzis,
Sabrina Schuck,
Michael Murias,
Joan Moriarity,
Cathy Barr,
Moyra Smith,
Michael Posner
[show abstract]
[hide abstract]
ABSTRACT: Family, twin, and adoption studies have documented a strong genetic basis for ADHD/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which for a half century have provided the primary pharmacological treatment for ADHD/HKD. Two candidate dopamine genes have been investigated and reported to be associated with ADHD/HKD: the dopamine transporter (DAT1) gene [Cook et al., American Journal of Human Genetics 1995;56:993–998, Gill et al., Molecular Psychiatry 1997;2:311–313] and the dopamine receptor D4 (DRD4) gene [LaHoste et al., Molecular Psychiatry 1996;1:121–124; Smalley et al., 1998;3:427–430; Swanson et al., Molecular Psychiatry 1998;3:38–41]. Speculative hypotheses [Swanson and Castellanos, NIH Consensus Development Conference: Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder, November 1998. p. 37–42] have suggested that specific alleles of these dopamine genes may alter dopamine transmission in the neural networks implicated in ADHD/HKD (e.g. that the 10-repeat allele of the DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7-repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic receptor). These and other variants of the dopamine hypothesis of ADHD will be discussed.
Neuroscience & Biobehavioral Reviews.
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James Swanson,
Curtis Deutsch,
Dennis Cantwell,
Michael Posner,
James L. Kennedy,
Cathy L. Barr, Robert Moyzis,
Sabrina Schuck,
Pamela Flodman,
M.Anne Spence,
Michael Wasdell
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ABSTRACT: In a collaborative research program on attention-deficit hyperactivity disorder (ADHD) initiated 20 years ago at UC Irvine, we adopted Cantwell's (1994) approach to define a refined phenotype for use in studies of the biological bases of this disorder. We have used this refined phenotype (ADHD-Combined Type without internalizing comorbidities) in our molecular genetic studies of ADHD, which have paralleled the emerging literature in this new field. In our research program, we used the candidate gene approach, with hypotheses derived from the dopamine theory of ADHD and Posner and Raichle's (1994) theory of attention. We proposed a candidate dopamine gene (DRD4) and discovered an association with ADHD due to an increase prevalence of the ‘7-repeat’ allele defined by a 48-base-pair variable number of tandem repeats in exon III. The DRD4–ADHD association has now been confirmed by multiple groups around the world. In the next steps of our research program, we are evaluating the impact of a putative DRD4 risk allele on cognition, initiating an investigation of DNA sequence variation in DRD4 alleles, and investigating the association of ADHD with other candidate genes. Using our collaborative research program as an example, we will review the history and current status of molecular genetic studies of ADHD.
Clinical Neuroscience Research.
