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B Albrecht,
D Brandeis,
H Uebel,
L Valko,
H Heinrich,
R Drechsler,
A Heise,
U C Müller, H-C Steinhausen,
A Rothenberger,
T Banaschewski
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Patients with attention deficit-hyperactivity disorder (ADHD) exhibit difficulties in multiple attentional functions. Although high heritability rates suggest a strong genetic impact, aetiological pathways from genes and environmental factors to the ADHD phenotype are not well understood. Tracking the time course of deviant task processing using event-related electrophysiological brain activity should characterize the impact of familiality on the sequence of cognitive functions from preparation to response control in ADHD. Method Preparation and response control were assessed using behavioural and electrophysiological parameters of two versions of a cued continuous performance test with varying attentional load in boys with ADHD combined type (n = 97), their non-affected siblings (n = 27) and control children without a family history of ADHD (n = 43). RESULTS: Children with ADHD and non-affected siblings showed more variable performance and made more omission errors than controls. The preparatory Cue-P3 and contingent negative variation (CNV) following cues were reduced in both ADHD children and their non-affected siblings compared with controls. The NoGo-P3 was diminished in ADHD compared with controls whilst non-affected siblings were located intermediate but did not differ from both other groups. No clear familiality effects were found for the Go-P3. Better task performance was further associated with higher CNV and P3 amplitudes. CONCLUSIONS: Impairments in performance and electrophysiological parameters reflecting preparatory processes and to some extend also for inhibitory response control, especially under high attentional load, appeared to be familially driven in ADHD and may thus constitute functionally relevant endophenotypes for the disorder.
Psychological Medicine 12/2012; · 6.16 Impact Factor
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J Kuntsi,
A C Frazier-Wood,
T Banaschewski,
M Gill,
A Miranda,
R D Oades,
H Roeyers,
A Rothenberger, H-C Steinhausen,
J J van der Meere,
S V Faraone,
P Asherson,
F Rijsdijk
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Increased reaction time variability (RTV) on cognitive tasks requiring a speeded response is characteristic of several psychiatric disorders. In attention deficit hyperactivity disorder (ADHD), the association with RTV is strong phenotypically and genetically, yet high RTV is not a stable impairment but shows ADHD-sensitive improvement under certain conditions, such as those with rewards. The state regulation theory proposed that the RTV difference score, which captures change from baseline to a rewarded or fast condition, specifically measures 'state regulation'. By contrast, the interpretation of RTV baseline (slow, unrewarded) scores is debated. We aimed to investigate directly the degree of phenotypic and etiological overlap between RTV baseline and RTV difference scores. Method We conducted genetic model fitting analyses on go/no-go and fast task RTV data, across task conditions manipulating rewards and event rate, from a population-based twin sample (n=1314) and an ADHD and control sibling-pair sample (n=1265). RESULTS: Phenotypic and genetic/familial correlations were consistently high (0.72-0.98) between RTV baseline and difference scores, across tasks, manipulations and samples. By contrast, correlations were low between RTV in the manipulated condition and difference scores. A comparison across two different go/no-go task RTV difference scores (slow-fast/slow-incentive) showed high phenotypic and genetic/familial overlap (r = 0.75-0.83). CONCLUSIONS: Our finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV. Given the statistical shortcomings of difference scores, we recommend the use of RTV baseline scores for most analyses, including genetic analyses.
Psychological Medicine 09/2012; · 6.16 Impact Factor
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A C Wood,
F Rijsdijk,
K A Johnson,
P Andreou,
B Albrecht,
A Arias-Vasquez,
J K Buitelaar,
G McLoughlin,
N N J Rommelse,
J A Sergeant, [......],
I Manor,
A Miranda,
F Mulas,
R D Oades,
H Roeyers,
A Rothenberger, H C Steinhausen,
S V Faraone,
P Asherson,
J Kuntsi
[show abstract]
[hide abstract]
ABSTRACT: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ.
Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI).
Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ.
The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.
Psychological Medicine 04/2011; 41(4):861-71. · 6.16 Impact Factor
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J Graham,
T Banaschewski,
J Buitelaar,
D Coghill,
M Danckaerts,
R W Dittmann,
M Döpfner,
R Hamilton,
C Hollis,
M Holtmann, [......],
E Rosenthal,
A Rothenberger,
P Santosh,
J Sergeant,
E Simonoff,
E Sonuga-Barke,
I C K Wong,
A Zuddas, H-C Steinhausen,
E Taylor
[show abstract]
[hide abstract]
ABSTRACT: The safety of ADHD medications is not fully known. Concerns have arisen about both a lack of contemporary-standard information about medications first licensed several decades ago, and signals of possible harm arising from more recently developed medications. These relate to both relatively minor adverse effects and extremely serious issues such as sudden cardiac death and suicidality. A guidelines group of the European Network for Hyperkinetic Disorders (EUNETHYDIS) has therefore reviewed the literature, recruited renowned clinical subspecialists and consulted as a group to examine these concerns. Some of the effects examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations. However, several areas require further study to allow a more precise understanding of these risks.
European Child & Adolescent Psychiatry 11/2010; 20(1):17-37. · 2.82 Impact Factor
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M Aebi,
U C Müller,
P Asherson,
T Banaschewski,
J Buitelaar,
R Ebstein,
J Eisenberg,
M Gill,
I Manor,
A Miranda,
R D Oades,
H Roeyers,
A Rothenberger,
J Sergeant,
E Sonuga-Barke,
M Thompson,
E Taylor,
S V Faraone, H-C Steinhausen
[show abstract]
[hide abstract]
ABSTRACT: Oppositional defiant disorder (ODD) is frequently co-occurring with attention deficit hyperactivity disorder (ADHD) in children and adolescents. Because ODD is a precursor of later conduct disorder (CD) and affective disorders, early diagnostic identification is warranted. Furthermore, the predictability of three recently confirmed ODD dimensions (ODD-irritable, ODD-headstrong and ODD-hurtful) may assist clinical decision making.
Receiver-operating characteristic (ROC) analysis was used in order to test the diagnostic accuracy of the Conners' Parent Rating Scale revised (CPRS-R) and the parent version of the Strength and Difficulties Questionnaire (PSDQ) in the prediction of ODD in a transnational sample of 1093 subjects aged 5-17 years from the International Multicentre ADHD Genetics study. In a second step, the prediction of three ODD dimensions by the same parent rating scales was assessed by backward linear regression analyses.
ROC analyses showed adequate diagnostic accuracy of the CPRS-R and the PSDQ in predicting ODD in this ADHD sample. Furthermore, the three-dimensional structure of ODD was confirmed by confirmatory factor analysis and the CPRS-R emotional lability scale significantly predicted the ODD irritable dimension.
The PSDQ and the CPRS-R are both suitable screening instruments in the identification of ODD. The emotional lability scale of the CPRS-R is an adequate predictor of irritability in youth referred for ADHD.
Psychological Medicine 04/2010; 40(12):2089-100. · 6.16 Impact Factor
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Z. Hawi,
L. Kent,
M. Hill,
R.J.L. Anney,
K.J. Brookes,
E. Barry,
B. Franke,
T. Banaschewski,
J. Buitelaar,
R. Ebstein,
A. Miranda,
R.D. Oades,
H. Roeyers,
A. Rothenberger,
J. Sergeant,
E. Sonuga-Barke, H.-C. Steinhausen,
S.V. Faraone,
P. Asherson,
M. Gill
[show abstract]
[hide abstract]
ABSTRACT: We [Hawi et al. (2005); Am J Hum Genet 77:958–965] reported paternal over-transmission of risk alleles in some ADHD-associated genes. This was particularly clear in the case of the DAT1 3′-UTR VNTR. In the current investigation, we analyzed three new sample comprising of 1,248 ADHD nuclear families to examine the allelic over-transmission of DAT1 in ADHD. The IMAGE sample, the largest of the three-replication samples, provides strong support for a parent of origin effect for allele 6 and the 10 repeat allele (intron 8 and 3′-UTR VNTR, respectively) of DAT1. In addition, a similar pattern of over-transmission of paternal risk haplotypes (constructed from the above alleles) was also observed. Some support is also derived from the two smaller samples although neither is independently significant. Although the mechanism driving the paternal over-transmission of the DAT risk alleles is not known, these finding provide further support for this phenomenon. © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2009; 153B(1):97 - 102. · 3.70 Impact Factor
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Z Hawi,
L Kent,
M Hill,
R J L Anney,
K J Brookes,
E Barry,
B Franke,
T Banaschewski,
J Buitelaar,
R Ebstein,
A Miranda,
R D Oades,
H Roeyers,
A Rothenberger,
J Sergeant,
E Sonuga-Barke, H-C Steinhausen,
S V Faraone,
P Asherson,
M Gill
[show abstract]
[hide abstract]
ABSTRACT: We [Hawi et al. (2005); Am J Hum Genet 77:958-965] reported paternal over-transmission of risk alleles in some ADHD-associated genes. This was particularly clear in the case of the DAT1 3'-UTR VNTR. In the current investigation, we analyzed three new sample comprising of 1,248 ADHD nuclear families to examine the allelic over-transmission of DAT1 in ADHD. The IMAGE sample, the largest of the three-replication samples, provides strong support for a parent of origin effect for allele 6 and the 10 repeat allele (intron 8 and 3'-UTR VNTR, respectively) of DAT1. In addition, a similar pattern of over-transmission of paternal risk haplotypes (constructed from the above alleles) was also observed. Some support is also derived from the two smaller samples although neither is independently significant. Although the mechanism driving the paternal over-transmission of the DAT risk alleles is not known, these finding provide further support for this phenomenon.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 05/2009; 153B(1):97-102. · 3.70 Impact Factor
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X Xu,
E A Duman,
R Anney,
K Brookes,
B Franke,
K Zhou,
C Buschgens,
W Chen,
H Christiansen,
J Eisenberg, [......],
F Mulas,
R D Oades,
H Roeyers,
A Rothenberger,
J Sergeant,
E Sonuga-Barke, H C Steinhausen,
E Taylor,
S V Faraone,
P Asherson
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2009; · 3.70 Impact Factor
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K.J. Brookes,
X. Xu,
R. Anney,
B. Franke,
K. Zhou,
Wai Chen,
T. Banaschewski,
J. Buitelaar,
R. Ebstein,
J. Eisenberg, [......],
A. Miranda,
R.D. Oades,
H. Roeyers,
A. Rothenberger,
J. Sergeant,
E. Sonuga-Barke, H.-C. Steinhausen,
E. Taylor,
S.V. Faraone,
P. Asherson
[show abstract]
[hide abstract]
ABSTRACT: Multiple studies have reported an association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3′-untranslated region (3′UTR) of the dopamine transporter gene (DAT1). Yet, recent meta-analyses of available data find little or no evidence for this association; although there is strong evidence for heterogeneity between datasets. This pattern of findings could arise for several reasons including the presence of relatively rare risk alleles on common haplotype backgrounds or the functional interaction of two or more loci within the gene. We previously described the importance of a specific haplotype at the 3′ end of DAT1, as well as the identification of associated single nucleotide polymorphisms (SNPs) within or close to 5′ regulatory sequences. In this study we replicate the association of SNPs at the 5′ end of the gene and identify a specific risk haplotype spanning the 5′ and 3′ markers. These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. Overall these data provide further evidence that genetic variants of the dopamine transporter gene confer an increased risk for ADHD. © 2008 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2008; 147B(8):1519 - 1523. · 3.70 Impact Factor
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X Xu,
Z Hawi,
K J Brookes,
R Anney,
M Bellgrove,
B Franke,
E Barry,
W Chen,
J Kuntsi,
T Banaschewski, [......],
A Miranda,
R D Oades,
H Roeyers,
A Rothenberger,
J Sergeant,
E Sonuga-Barke, H-C Steinhausen,
S V Faraone,
M Gill,
P Asherson
[show abstract]
[hide abstract]
ABSTRACT: Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHD in a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 11/2008; 147B(8):1564-7. · 3.70 Impact Factor
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X. Xu,
Z. Hawi,
K.J. Brookes,
R. Anney,
M. Bellgrove,
B. Franke,
E. Barry,
W. Chen,
J. Kuntsi,
T. Banaschewski, [......],
A. Miranda,
R.D. Oades,
H. Roeyers,
A. Rothenberger,
J. Sergeant,
E. Sonuga-Barke, H.-C. Steinhausen,
S.V. Faraone,
M. Gill,
P. Asherson
[show abstract]
[hide abstract]
ABSTRACT: Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHD in a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect. © 2008 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2008; 147B(8):1564 - 1567. · 3.70 Impact Factor
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X. Xu,
E. Aysimi,
R. Anney,
K. Brookes,
B. Franke,
K. Zhou,
C. Buschgens,
W. Chen,
H. Christiansen,
J. Eisenberg, [......],
F. Mulas,
R.D. Oades,
H. Roeyers,
A. Rothenberger,
J. Sergeant,
E. Sonuga-Barke, H.-C. Steinhausen,
E. Taylor,
S.V. Faraone,
P. Asherson
[show abstract]
[hide abstract]
ABSTRACT: Several independent studies have reported association between serotonin transporter gene (SLC6A4) polymorphisms and attention deficit hyperactivity disorder (ADHD). Five studies found evidence for association between the long-allele of a 44-bp insertion/deletion polymorphism (5-HTTLPR) and ADHD. Another two studies corroborated this finding while a further six studies did not find such an association. For a second polymorphism within the gene, a variable number tandem repeat (VNTR) within intron 2, one study demonstrated that the 12/12 genotype was significantly less frequent in ADHD cases compared to controls, while a second study found that the 12-allele was preferentially transmitted to offspring affected with ADHD. To provide further clarification of the reported associations, we investigated the association of these two markers with ADHD in a sample of 1,020 families with 1,166 combined type ADHD cases for the International Multi-Centre ADHD Genetics project, using the Transmission Disequilibrium Test. Given the large body of work supporting the association of the promoter polymorphism and mood disorders, we further analyzed the group of subjects with ADHD plus mood disorder separately. No association was found between either of the two markers and ADHD in our large multisite study or with depression within the sample of ADHD cases. © 2008 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2008; 147B(7):1306 - 1309. · 3.70 Impact Factor
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H-C Steinhausen
[show abstract]
[hide abstract]
ABSTRACT: The concept of a behavioural phenotype was first introduced by Nyhan (1972) when he described a characteristic behaviour of self-mutilation in Lesch-Nyhan-Syndrome. Later, Flint and Yule (1994) pointed out that a behavioural phenotype is a characteristic pattern of motor, cognitive, linguistic and social abnormalities that is consistently associated with a biological disorder. In some instances the behavioural phenotype may represent a psychiatric disorder, in others there may be behaviours that usually will not be regarded as a psychiatric disorder. Dykens (1995) added that a behavioural phenotype may best be described as the heightened probability that people with a given syndrome will be characterized by certain behavioural sequelae. The implications of this are (i) that there is a certain amount of within-syndrome variability, (ii) that there is total vs. partial specificity of certain behaviours, (iii) that behavioural phenotypes relate to various behavioural domains, (iv) that behavioural phenotypes have indirect effects on the behaviour of caretakers, and (v) that developmental and contextual factors in addition to genetic factors contribute to behavioural phenotypes (Hodapp & Dykens, 2007). The rather recent interest in the concept of behavioural phenotypes has renewed the interest of Child and Adolescent Psychiatry in intellectual disability issues that had been lost for decades. It also increased interest in the genetic origins of mental disorders and behavioural abnormalities with an interaction of two major recent scientific developments in the field. One of these trends is represented by the rapid progress in molecular biology that has led to a better understanding of the genetic mechanisms contributing to psychopathology. The other trend is based on the development of more and more refined instruments for the dimensional assessment of adaptive and maladaptive behaviours which have supplemented the classical categorical approach of assessment in child psychopathology. With this theoretical underpinning, the study of behavioural phenotypes has become an attractive research domain in child and adolescent psychiatry. In addition, there are also practical implications in terms of improving communication among experts and lay-person both on assessment and counselling.
Journal of Intellectual Disability Research 10/2008; 52(10):810. · 1.88 Impact Factor
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K J Brookes,
X Xu,
R Anney,
B Franke,
K Zhou,
Wai Chen,
T Banaschewski,
J Buitelaar,
R Ebstein,
J Eisenberg, [......],
A Miranda,
R D Oades,
H Roeyers,
A Rothenberger,
J Sergeant,
E Sonuga-Barke, H-C Steinhausen,
E Taylor,
S V Faraone,
P Asherson
[show abstract]
[hide abstract]
ABSTRACT: Multiple studies have reported an association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'UTR) of the dopamine transporter gene (DAT1). Yet, recent meta-analyses of available data find little or no evidence for this association; although there is strong evidence for heterogeneity between datasets. This pattern of findings could arise for several reasons including the presence of relatively rare risk alleles on common haplotype backgrounds or the functional interaction of two or more loci within the gene. We previously described the importance of a specific haplotype at the 3' end of DAT1, as well as the identification of associated single nucleotide polymorphisms (SNPs) within or close to 5' regulatory sequences. In this study we replicate the association of SNPs at the 5' end of the gene and identify a specific risk haplotype spanning the 5' and 3' markers. These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. Overall these data provide further evidence that genetic variants of the dopamine transporter gene confer an increased risk for ADHD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2008; 147B(8):1519-23. · 3.70 Impact Factor
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X Xu,
E A Duman,
E Aysimi,
R Anney,
K Brookes,
B Franke,
K Zhou,
C Buschgens,
W Chen,
H Christiansen, [......],
F Mulas,
R D Oades,
H Roeyers,
A Rothenberger,
J Sergeant,
E Sonuga-Barke, H-C Steinhausen,
E Taylor,
S V Faraone,
P Asherson
[show abstract]
[hide abstract]
ABSTRACT: Several independent studies have reported association between serotonin transporter gene (SLC6A4) polymorphisms and attention deficit hyperactivity disorder (ADHD). Five studies found evidence for association between the long-allele of a 44-bp insertion/deletion polymorphism (5-HTTLPR) and ADHD. Another two studies corroborated this finding while a further six studies did not find such an association. For a second polymorphism within the gene, a variable number tandem repeat (VNTR) within intron 2, one study demonstrated that the 12/12 genotype was significantly less frequent in ADHD cases compared to controls, while a second study found that the 12-allele was preferentially transmitted to offspring affected with ADHD. To provide further clarification of the reported associations, we investigated the association of these two markers with ADHD in a sample of 1,020 families with 1,166 combined type ADHD cases for the International Multi-Centre ADHD Genetics project, using the Transmission Disequilibrium Test. Given the large body of work supporting the association of the promoter polymorphism and mood disorders, we further analyzed the group of subjects with ADHD plus mood disorder separately. No association was found between either of the two markers and ADHD in our large multisite study or with depression within the sample of ADHD cases.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2008; 147B(7):1306-9. · 3.70 Impact Factor
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P Asherson,
K Zhou,
R J L Anney,
B Franke,
J Buitelaar,
R Ebstein,
M Gill,
M Altink,
R Arnold,
F Boer, [......],
I Manor,
A Miranda,
R D Oades,
H Roeyers,
A Rothenberger,
J Sergeant, H-C Steinhausen,
E Taylor,
M Thompson,
S V Faraone
[show abstract]
[hide abstract]
ABSTRACT: As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.
Molecular psychiatry 05/2008; 13(5):514-21. · 15.05 Impact Factor
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Zeitschrift für Kinder- und Jugendpsychiatrie und Psychotherapie 04/2008; 36(2):77-9. · 0.99 Impact Factor
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K J Brookes,
B Neale,
X Xu,
A Thapar,
M Gill,
K Langley,
Z Hawi,
J Mill,
E Taylor,
B Franke, [......],
J Eisenberg,
I Manor,
A Miranda,
R D Oades,
H Roeyers,
A Rothenberger,
J Sergeant, H C Steinhausen,
S V Faraone,
P Asherson
[show abstract]
[hide abstract]
ABSTRACT: Season of birth (SOB) has been associated with attention deficit hyperactivity disorder (ADHD) in two existing studies. One further study reported an interaction between SOB and genotypes of the dopamine D4 receptor (DRD4) gene. It is important that these findings are further investigated to confirm or refute the findings. In this study, we investigated the SOB association with ADHD in four independent samples collected for molecular genetic studies of ADHD and found a small but significant increase in summer births compared to a large population control dataset. We also observed a significant association with the 7-repeat allele of the DRD4 gene variable number tandem repeat polymorphism in exon three with probands born in the winter season, with no significant differential transmission of this allele between summer and winter seasons. Preferential transmission of the 2-repeat allele to ADHD probands occurred in those who were born during the summer season, but did not surpass significance for association, even though the difference in transmission between the two seasons was nominally significant. However, following adjustment for multiple testing of alleles none of the SOB effects remained significant. We conclude that the DRD4 7-repeat allele is associated with ADHD but there is no association or interaction with SOB for increased risk for ADHD. Our findings suggest that we can refute a possible effect of SOB for ADHD.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2008; 147B(1):94-9. · 3.70 Impact Factor
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K.J. Brookes,
B. Neale,
X. Xu,
A. Thapar,
M. Gill,
K. Langley,
Z. Hawi,
J. Mill,
E. Taylor,
B. Franke, [......],
J. Eisenberg,
I. Manor,
A. Miranda,
R.D. Oades,
H. Roeyers,
A. Rothenberger,
J. Sergeant, H.C. Steinhausen,
S.V. Faraone,
P. Asherson
[show abstract]
[hide abstract]
ABSTRACT: Season of birth (SOB) has been associated with attention deficit hyperactivity disorder (ADHD) in two existing studies. One further study reported an interaction between SOB and genotypes of the dopamine D4 receptor (DRD4) gene. It is important that these findings are further investigated to confirm or refute the findings. In this study, we investigated the SOB association with ADHD in four independent samples collected for molecular genetic studies of ADHD and found a small but significant increase in summer births compared to a large population control dataset. We also observed a significant association with the 7-repeat allele of the DRD4 gene variable number tandem repeat polymorphism in exon three with probands born in the winter season, with no significant differential transmission of this allele between summer and winter seasons. Preferential transmission of the 2-repeat allele to ADHD probands occurred in those who were born during the summer season, but did not surpass significance for association, even though the difference in transmission between the two seasons was nominally significant. However, following adjustment for multiple testing of alleles none of the SOB effects remained significant. We conclude that the DRD4 7-repeat allele is associated with ADHD but there is no association or interaction with SOB for increased risk for ADHD. Our findings suggest that we can refute a possible effect of SOB for ADHD. © 2007 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2008; 147B(1):94 - 99. · 3.70 Impact Factor
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H Christiansen,
W Chen,
R D Oades,
P Asherson,
E A Taylor,
J Lasky-Su,
K Zhou,
T Banaschewski,
C Buschgens,
B Franke, [......],
M Gill,
A Miranda,
F Mulas,
H Roeyers,
A Rothenberger,
J A Sergeant,
E J S Sonuga-Barke, H-C Steinhausen,
M Thompson,
S V Faraone
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ABSTRACT: Common disorders of childhood and adolescence are attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). For one to two cases in three diagnosed with ADHD the disorders may be comorbid. However, whether comorbid conduct problems (CP) represents a separate disorder or a severe form of ADHD remains controversial. We investigated familial recurrence patterns of the pure or comorbid condition in families with at least two children and one definite case of DSM-IV ADHDct (combined-type) as part of the International Multicentre ADHD Genetics Study (IMAGE). Using case diagnoses (PACS, parental account) and symptom ratings (Parent/Teacher Strengths and Difficulties [SDQ], and Conners Questionnaires [CPTRS]) we studied 1009 cases (241 with ADHDonly and 768 with ADHD + CP), and their 1591 siblings. CP was defined as > or =4 on the SDQ conduct-subscale, and T > or = 65, on Conners' oppositional-score. Multinomial logistic regression was used to ascertain recurrence risks of the pure and comorbid conditions in the siblings as predicted by the status of the cases. There was a higher relative risk to develop ADHD + CP for siblings of cases with ADHD + CP (RRR = 4.9; 95%CI: 2.59-9.41); p < 0.001) than with ADHDonly. Rates of ADHDonly in siblings of cases with ADHD + CP were lower but significant (RRR = 2.9; 95%CI: 1.6-5.3, p < 0.001). Children with ADHD + CP scored higher on the Conners ADHDct symptom-scales than those with ADHDonly. Our finding that ADHD + CP can represent a familial distinct subtype possibly with a distinct genetic etiology is consistent with a high risk for cosegregation. Further, ADHD + CP can be a more severe disorder than ADHDonly with symptoms stable from childhood through adolescence. The findings provide partial support for the ICD-10 distinction between hyperkinetic disorder (F90.0) and hyperkinetic conduct disorder (F90.1).
Acta Neurovegetativa 01/2008; 115(2):163-75. · 2.73 Impact Factor
