Purper-Ouakil D, Wohl M, Mouren MC, Verpillat P, Ades J, Gorwood P. Meta-analysis of family-based association studies between the dopamine transporter gene and attention deficit hyperactivity disorder. Psychiatr Genet 15: 53-59

ArticleinPsychiatric Genetics 15(1):53-9 · April 2005with16 Reads
DOI: 10.1097/00041444-200503000-00009 · Source: PubMed
Abstract
Molecular genetic research has mainly focused on the D4 dopamine receptor (DRD4) and the dopamine transporter (DAT) genes in attention-deficit hyperactivity disorder (ADHD). A recent meta-analysis showed that the DRD4 gene has a significant role in the vulnerability to ADHD. With an equal number of positive and negative association studies between the 10-repeat of the DAT gene and ADHD, a meta-analysis is required for this other candidate gene. We re-analysed the 13 published family-based association studies between ADHD and the DAT gene. Following recent recommendations, different biases were specifically assessed, such as the sample-size effect and the time effect. The meta-analysis showed no significant association between ADHD and the DAT gene (P = 0.21), but an important between-samples heterogeneity (P = 0.0009). Odds ratios above 1 are mostly observed in studies with a small number of informative transmissions, and decrease with larger sample size. Contrary to what was found for the DRD4 gene, the 10-repeat allele of the DAT gene has at most a minor role in the genetic susceptibility of ADHD. The different biases detected herein probably explain the initial impression of a significant impact of the DAT gene on hyperactivity.
    • "However , the fourth conflicting study was derived from one of the same papers that reported a significant effect in 1373 family-based cohort (Yang et al., 2007), but in this case, the conflicting effect was reported when considering a larger (n ¼ 3594) cohort of casecontrols . Three other studies also reported null effects for this same allele in Asian or Caucasian (or unreported ethnic) cohorts (Li et al., 2006b; Purper-Ouakil et al., 2005) (SupplementaryTable 2). Other variants of focus in ADHD with strongest effects (p < .001) "
    [Show abstract] [Hide abstract] ABSTRACT: Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.
    Full-text · Article · Sep 2014
    • "Association with polymorphisms in the gene encoding the DA D4 receptor (DRD4; Ebstein et al., 1996; LaHoste et al., 1996), the DA D5 receptor (DRD5; Hawi et al., 2002), and the DA transporter gene (DAT/SLC6A3; Cook et al., 1995) have been reported. Most studies of DAT have focused on a 40 base-pair variable number tandem repeat (VNTR) found in the 3 untranslated region (UTR) of the gene (Vandenbergh et al., 1992; Curran et al., 2001; Purper-Ouakil et al., 2005 ). There is also some evidence associating the DA synthesis enzyme Dopamine-beta hydroxylase (DBH) and the disease (Comings et al., 1996). "
    [Show abstract] [Hide abstract] ABSTRACT: Psychiatric disorders are a diverse set of diseases that affect all aspects of mental function including social interaction, thinking, feeling, and mood. Although psychiatric disorders place a large economic burden on society, the drugs available to treat them are often palliative with variable efficacy and intolerable side-effects. The development of novel drugs has been hindered by a lack of knowledge about the etiology of these diseases. It is thus necessary to further investigate psychiatric disorders using a combination of human molecular genetics, gene-by-environment studies, in vitro pharmacological and biochemistry experiments, animal models, and investigation of the non-biological basis of these diseases, such as environmental effects. Many psychiatric disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, mental retardation, and schizophrenia can be triggered by alterations to neural development. The zebrafish is a popular model for developmental biology that is increasingly used to study human disease. Recent work has extended this approach to examine psychiatric disorders as well. However, since psychiatric disorders affect complex mental functions that might be human specific, it is not possible to fully model them in fish. In this review, I will propose that the suitability of zebrafish for developmental studies, and the genetic tools available to manipulate them, provide a powerful model to study the roles of genes that are linked to psychiatric disorders during neural development. The relative speed and ease of conducting experiments in zebrafish can be used to address two areas of future research: the contribution of environmental factors to disease onset, and screening for novel therapeutic compounds.
    Full-text · Article · Apr 2013
    • "A variable number tandem repeat (VNTR) of 7 alleles in the dopamine D4 receptor gene (DRD4) and a 148-bp microsatellite repeat in the dopamine D5 receptor gene (DRD5) have been consistently associated with ADHD [11,12,13,14,15,16] . A VNTR polymorphism in the 39-untrans- lated region (UTR) of DAT1 (also known as SLC6A3), a carrier of dopamine that removes it from the synaptic cleft, has also been repeatedly associated with ADHD [11,12,15,17,18] . More recently , genome-wide association studies (GWAS) have identified SNPs in CDH13, GFOD1, and TLL that may be associated with ADHD, although replication was not present or not attempted in these studies [19,20,21]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Adverse neurodevelopmental sequelae are reported among children who undergo early cardiac surgery to repair congenital heart defects (CHD). APOE genotype has previously been determined to contribute to the prediction of these outcomes. Understanding further genetic causes for the development of poor neurobehavioral outcomes should enhance patient risk stratification and improve both prevention and treatment strategies. Methods: We performed a prospective observational study of children who underwent cardiac surgery before six months of age; this included a neurodevelopmental evaluation between their fourth and fifth birthdays. Attention and behavioral skills were assessed through parental report utilizing the Attention Deficit-Hyperactivity Disorder-IV scale preschool edition (ADHD-IV), and Child Behavior Checklist (CBCL/1.5-5), respectively. Of the seven investigated, three neurodevelopmental phenotypes met genomic quality control criteria. Linear regression was performed to determine the effect of genome-wide genetic variation on these three neurodevelopmental measures in 316 subjects. Results: This genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with three neurobehavioral phenotypes in the postoperative children ADHD-IV Impulsivity/Hyperactivity, CBCL/1.5-5 PDPs, and CBCL/1.5-5 Total Problems. The most predictive SNPs for each phenotype were: a LGALS8 intronic SNP, rs4659682, associated with ADHD-IV Impulsivity (P=1.03 × 10(-6)); a PCSK5 intronic SNP, rs2261722, associated with CBCL/1.5-5 PDPs (P=1.11 × 10(-6)); and an intergenic SNP, rs11617488, 50 kb from FGF9, associated with CBCL/1.5-5 Total Problems (P=3.47 × 10(-7)). 10 SNPs (3 for ADHD-IV Impulsivity, 5 for CBCL/1.5-5 PDPs, and 2 for CBCL/1.5-5 Total Problems) had p<10(-5). Conclusions: No SNPs met genome-wide significance for our three neurobehavioral phenotypes; however, 10 SNPs reached a threshold for suggestive significance (p<10(-5)). Given the unique nature of this cohort, larger studies and/or replication are not possible. Studies to further investigate the mechanisms through which these newly identified genes may influence neurodevelopment dysfunction are warranted.
    Full-text · Article · Sep 2012
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