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I Jarick,
A-L Volckmar,
C Pütter,
S Pechlivanis,
T T Nguyen,
M R Dauvermann,
S Beck,
O Albayrak,
S Scherag,
S Gilsbach, [......],
G Lehmkuhl,
T J Renner,
A Warnke,
M Romanos, K-P Lesch,
A Reif,
B G Schimmelmann,
J Hebebrand,
A Scherag,
A Hinney
[show abstract]
[hide abstract]
ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency 1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.161.
Molecular psychiatry 11/2012; · 15.05 Impact Factor
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ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with impairments across the lifespan. The persistence of ADHD is associated with considerable liability to neuropsychiatric co-morbidity such as depression, anxiety and substance use disorder. The substantial heritability of ADHD is well documented and recent genome-wide analyses for risk genes revealed synaptic adhesion molecules (e.g. latrophilin-3, LPHN3; fibronectin leucine-rich repeat transmembrane protein-3, FLRT3), glutamate receptors (e.g. metabotropic glutamate receptor-5, GRM5) and mediators of intracellular signalling pathways (e.g. nitric oxide synthase-1, NOS1). These genes encode principal components of the molecular machinery that connects pre- and postsynaptic neurons, facilitates glutamatergic transmission, controls synaptic plasticity and empowers intersecting neural circuits to process and refine information. Thus, identification of genetic variation affecting molecules essential for the formation, specification and function of excitatory synapses is refocusing research efforts on ADHD pathogenesis to include the long-neglected glutamate system.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 08/2012; · 3.68 Impact Factor
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Molecular psychiatry 05/2012; · 15.05 Impact Factor
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[show abstract]
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ABSTRACT: Das Aufmerksamkeitsdefizit-/Hyperaktivitätssyndrom (ADHS) ist eine klinisch heterogene Störung der Gehirnentwicklung unter
Beteiligung zahlreicher genetischer und umweltbedingter Risikofaktoren. Ziel der interdisziplinär und translational ausgerichteten
neurobiologischen Forschung ist, die wechselseitige Beziehung zwischen molekularen Mechanismen und strukturell-funktionellen
Substraten in der Pathogenese des ADHS und ihre Bedeutung für den Langzeitverlauf der Erkrankung aufzuklären. Die Auseinandersetzung
mit ADHS-spezifischen molekulargenetischen und entwicklungsbiologischen Grundlagen der Gehirnfunktion sowie strukturell-funktionellen
Anlagen des Verhaltens verspricht, zur Entwicklung von Prädiktoren und differenziellen Strategien für die therapeutische Beeinflussung
schwerer und chronischer Verläufe des ADHS beizutragen. Um evolutionär konservierte ADHS-relevante Prinzipien der Funktion
und Struktur des Gehirns sowie des syndromtypischen Verhaltens zu definieren, ist ein integrierter Ansatz zur Aufklärung spezifischer
neuro- und psychobiologischer Mechanismen und damit der systemischen Pathophysiologie des ADHS notwendig. Pathophysiologische
Modelle des ADHS, insbesondere aber die syndromalen und komorbiden Dimensionen, benötigen daher die Kombination von molekulargenetischen,
funktionell-bildgebenden, neuropsychologischen, verhaltensbiologischen und psychosozialen Strategien zur Erklärung vollständiger
Kausalketten unter dem Gesichtspunkt einer gestörten Gehirnentwicklung.
Attention-deficit hyperactivity disorder (ADHD) is defined as a clinically heterogeneous neurodevelopmental syndrome with
the contribution of numerous genetic and environmental risk factors. The goal of interdisciplinary and translational neurobiological
research is to clarify the interdependent relationship between molecular mechanisms and structural-functional substrates in
the pathogenesis of ADHD and its significance to the disorder’s long-term course. Work on ADHD-specific molecular genetic
and developmental biological essentials of brain function and on the structural-functional basis of behavior holds the promise
of developing predictors and differential strategies for effective therapy of severe and chronic courses of ADHD. To define
evolutionary conserved ADHD-relevant principles of structure and function of the brain and behavior typical to the syndrome,
an integrated approach in the elucidation of specific neuro- and psychobiological mechanisms and thus systemic pathophysiology
of ADHD is crucial. Regarding compromised neurodevelopment, pathophysiological models of ADHD, particularly its syndromal
and comorbid dimensions, therefore require the combination of molecular genetic, neuroimaging, neuropsychology, behavioral,
and psychosocial strategies to explain complete causal chains.
Der Nervenarzt 04/2012; 79(7):771-781. · 0.68 Impact Factor
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B Franke,
S V Faraone,
P Asherson,
J Buitelaar,
C H D Bau,
J A Ramos-Quiroga,
E Mick,
E H Grevet,
S Johansson,
J Haavik, K-P Lesch,
B Cormand,
A Reif
[show abstract]
[hide abstract]
ABSTRACT: The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.
Molecular psychiatry 11/2011; 17(10):960-87. · 15.05 Impact Factor
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B Franke,
S V Faraone,
P Asherson,
J Buitelaar,
C H D Bau,
J A Ramos-Quiroga,
E Mick,
E H Grevet,
S Johansson,
J Haavik, K-P Lesch,
B Cormand,
A Reif
[show abstract]
[hide abstract]
ABSTRACT: The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30–40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.Keywords: persistent ADHD; molecular genetics; heritability; endophenotype; IMpACT
Molecular Psychiatry 11/2011; 17(10):960-987. · 13.67 Impact Factor
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[show abstract]
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ABSTRACT: Noradrenergic neurotransmission influences executive functions, attentional performance, and general alertness, involving neuronal networks affected in attention deficit/hyperactivity disorder (ADHD). The norepinephrine transporter facilitates the reuptake of norepinephrine and dopamine in the prefrontal cortex and represents the main target of atomoxetine, an effective drug in the treatment of ADHD. Due to its influence on catecholaminergic signaling, variants of the coding gene (SLC6A2) have been widely investigated in ADHD. Several previous studies report an association between single nucleotide polymorphisms located in SLC6A2 and ADHD; however, the findings are inconsistent. The variant A-3081T (rs28386840) has been shown to have major influence on the expression levels of SLC6A2 due to sequence alteration at a repressor binding site, with the T-allele being associated with ADHD. We tested this potential association of A-3081T in a German family-based ADHD sample of 235 children from 162 families, which has a power >99% based on the previously reported odds ratios. There was no evidence for an overtransmission of the risk allele T (transmission rate: 48.5%, P = 0.55). We conclude that A-3081T is not a major risk variant in our ADHD sample, though SLC6A2 remains an interesting candidate gene in ADHD, especially for the inattentive subtype.
ADHD Attention Deficit and Hyperactivity Disorders 09/2011; 3(3):285-9.
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M Jain,
J I Vélez,
M T Acosta,
L G Palacio,
J Balog,
E Roessler,
D Pineda,
A C Londoño,
J D Palacio,
A Arbelaez, [......],
A Warnke,
J Romanos,
T Renner,
C Jacob, K-P Lesch,
J Swanson,
F X Castellanos,
J E Bailey-Wilson,
M Arcos-Burgos,
M Muenke
[show abstract]
[hide abstract]
ABSTRACT: In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10(-8)) and 11q and 17p (P<1 × 10(-6)). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q-11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.
Molecular psychiatry 05/2011; 17(7):741-7. · 15.05 Impact Factor
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M Jain,
J I V|[eacute]|lez,
M T Acosta,
L G Palacio,
J Balog,
E Roessler,
D Pineda,
A C Londo|[ntilde]|o,
J D Palacio,
A Arbelaez, [......],
A Warnke,
J Romanos,
T Renner,
C Jacob, K-P Lesch,
J Swanson,
F X Castellanos,
J E Bailey-Wilson,
M Arcos-Burgos,
M Muenke
[show abstract]
[hide abstract]
ABSTRACT: In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10−8) and 11q and 17p (P<1 × 10−6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q–11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome.Keywords: ADHD; genetic interaction; LPHN3; NCAM1; DRD2
Molecular Psychiatry 05/2011; 17(7):741-747. · 13.67 Impact Factor
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[show abstract]
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ABSTRACT: Norepinephrine and serotonin involvement in nociceptive functions is supported by observations of analgesic effects of norepinephrine transporter (NET) and serotonin transporter (SERT) inhibitors such as amitriptyline. However, the relative contribution of NET and SERT to baseline nociception, as well as amitriptyline analgesia, is unclear. Amitriptyline and morphine analgesia in wild-type (WT) mice and littermates with gene knockout (KO) of SERT, NET or both transporters was conducted using the hotplate and tail-flick tests. Hypoalgesia was observed in NET KO mice, and to a lesser extent in SERT KO mice. The magnitude of this hypoalgesia in NET KO mice was so profound that it limited the assessment of drug-induced analgesia. Nonetheless, the necessary exclusion of these subjects because of profound baseline hypoalgesia strongly supports the role of norepinephrine and NET in basal nociceptive behavior while indicating a much smaller role for serotonin and SERT. To further clarify the role of NET and SERT in basal nociceptive sensitivity further experiments were conducted in SERT KO and NET KO mice across a range of temperatures. NET KO mice were again found to have pronounced thermal hypoalgesia compared to WT mice in both the hotplate and tail-flick tests, while only limited effects were observed in SERT KO mice. Furthermore, in the acetic acid writhing test of visceral nociception pronounced hypoalgesia was again found in NET KO mice, but no change in SERT KO mice. As some of these effects may have resulted from developmental consequences of NET KO, the effects of the selective NET blocker nisoxetine and the selective SERT blocker fluoxetine were also examined in WT mice: only nisoxetine produced analgesia in these mice. Collectively these data suggest that NET has a far greater role in determining baseline analgesia, and perhaps other analgesic effects, than SERT in mice.
Neuroscience 02/2011; 175:315-27. · 3.38 Impact Factor
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R Stark,
E Bauer,
C J Merz,
M Zimmermann,
M Reuter,
M M Plichta,
P Kirsch, K P Lesch,
A J Fallgatter,
D Vaitl,
M J Herrmann
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[hide abstract]
ABSTRACT: Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) suggest dysfunctional reward processing, with hypo-responsiveness during reward anticipation in the reward system including the nucleus accumbens (NAcc). In this study, we investigated the association between ADHD related behaviors and the reward system using functional magnetic resonance imaging in a non-clinical sample. Participants were 31 healthy, female undergraduate students with varying levels of self-reported ADHD related behaviors measured by the adult ADHD self-report scale. The anticipation of different types of reward was investigated: monetary reward, punishment avoidance, and verbal feedback. All three reward anticipation conditions were found to be associated with increased brain activation in the reward system, with the highest activation in the monetary reward anticipation condition, followed by the punishment avoidance anticipation condition, and the lowest activation in the verbal feedback anticipation condition. Most interestingly, in all three conditions, NAcc activation was negatively correlated with ADHD related behaviors. In conclusion, our results from a non-clinical sample are in accordance with reported deficits in the reward system in ADHD patients: the higher the number and severity of ADHD related behaviors, the lower the neural responses in the dopaminergic driven reward anticipation task. Thus, our data support current aetiological models of ADHD which assume that deficits in the reward system might be responsible for many of the ADHD related behaviors.
Neuropsychologia 02/2011; 49(3):426-34. · 3.64 Impact Factor
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A. Hinney,
A. Scherag,
I. Jarick,
O. Albayrak,
C. Putter,
S. Pechlivanis,
M. R. Dauvermann,
S. Beck,
H. Weber,
S. Scherag, [......],
B. Herpertz-Dahlmann,
J. Sinzig,
G. Lehmkuhl,
T. J. Renner,
A. Warnke,
M. Romanos, K. P. Lesch,
A. Reif,
B. G. Schimmelmann,
J. Hebebrand
[show abstract]
[hide abstract]
ABSTRACT: The heritability of attention deficit hyperactivity disorder (ADHD) is approximately 0.8. Despite several larger scale attempts, genome-wide association studies (GWAS) have not led to the identification of significant results. We performed a GWAS based on 495 German young patients with ADHD (according to DSM-IV criteria; Human660W-Quadv1; Illumina, San Diego, CA) and on 1,300 population-based adult controls (HumanHap550v3; Illumina). Some genes neighboring the single nucleotide polymorphisms (SNPs) with the lowest P-values (best P-value: 8.38 x 10(-7) ) have potential relevance for ADHD (e.g., glutamate receptor, metabotropic 5 gene, GRM5). After quality control, the 30 independent SNPs with the lowest P-values (P-values </= 7.57 x 10(-5) ) were chosen for confirmation. Genotyping of these SNPs in up to 320 independent German families comprising at least one child with ADHD revealed directionally consistent effect-size point estimates for 19 (10 not consistent) of the SNPs. In silico analyses of the 30 SNPs in the largest meta-analysis so far (2,064 trios, 896 cases, and 2,455 controls) revealed directionally consistent effect-size point estimates for 16 SNPs (11 not consistent). None of the combined analyses revealed a genome-wide significant result. SNPs in previously described autosomal candidate genes did not show significantly lower P-values compared to SNPs within random sets of genes of the same size. We did not find genome-wide significant results in a GWAS of German children with ADHD compared to controls. The second best SNP is located in an intron of GRM5, a gene located within a recently described region with an infrequent copy number variation in patients with ADHD. (c) 2011 Wiley Periodicals, Inc.
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 01/2011; 156(8):888-97.
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D Hoyle,
G Juhasz,
E Aso,
D Chase,
J del Rio,
V Fabre,
M Hamon,
L Lanfumey, K-P Lesch,
R Maldonado,
M-A Serra,
T Sharp,
R Tordera,
C Toro,
J F W Deakin
[show abstract]
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ABSTRACT: This study aimed to identify whether genetic manipulation of four systems implicated in the pathogenesis of depression converge on shared molecular processes underpinning depression-like behaviour in mice. Altered 5HT function was modelled using the 5-HT transporter knock out mouse, impaired glucocorticoid receptor (GR) function using an antisense-induced knock down mouse, disrupted glutamate function using a heterozygous KO of the vesicular glutamate transporter 1 gene, and impaired cannabinoid signalling using the cannabinoid 1 receptor KO mouse. All 4 four genetically modified mice were previously shown to show exaggerated helpless behaviour compared to wild-type controls and variable degrees of anxiety and anhedonic behaviour. mRNA was extracted from frontal cortex and hybridised to Illumina microarrays. Combined contrast analysis was used to identify genes showing different patterns of up- and down-regulation across the 4 models. 1823 genes were differentially regulated. They were over-represented in gene ontology categories of metabolism, protein handling and synapse. In each model compared to wild-type mice of the same genetic background, a number of genes showed increased expression changes of >10%, other genes showed decreases in each model. Most of the genes showed mixed effects. Several previous array findings were replicated. The results point to cellular stress and changes in post-synaptic remodelling as final common mechanisms of depression and resilience.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 10/2010; 21(1):3-10. · 3.68 Impact Factor
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E T Landaas,
S Johansson,
K K Jacobsen,
M Ribasés,
R Bosch,
C Sánchez-Mora,
C P Jacob,
A Boreatti-Hümmer,
S Kreiker, K-P Lesch, [......],
J K Buitelaar,
S V Faraone,
A Halmøy,
J A Ramos-Quiroga,
B Cormand,
A Reif,
B Franke,
E Mick,
P M Knappskog,
J Haavik
[show abstract]
[hide abstract]
ABSTRACT: Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting children and adults. It has been suggested that gene variants related to serotonin neurotransmission are associated with ADHD. We tested the functional promoter polymorphism 5-HTTLPR and seven single nucleotide polymorphisms in SLC6A4 for association with ADHD in 448 adult ADHD patients and 580 controls from Norway. Replication attempts were performed in a sample of 1454 Caucasian adult ADHD patients and 1302 controls from Germany, Spain, the Netherlands and USA, and a meta-analysis was performed also including a previously published adult ADHD study. We found an association between ADHD and rs140700 [odds ratio (OR ) = 0.67; P = 0.01] and the short (S) allele of the 5-HTTLPR (OR = 1.19; P = 0.06) in the Norwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females (rs140700: OR = 0.45; P = 0.00084). However, the meta-analysis of 1894 cases and 1878 controls could not confirm the association for rs140700 [OR = 0.85, 95% confidence interval (CI) = 0.67-1.09; P = 0.20]. For 5-HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta-analysis refuted a strong effect (OR = 1.10, 95% CI = 1.00-1.21; P = 0.06). Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety. In conclusion, our results do not support a major role for SLC6A4 common variants in persistent ADHD, although a modest effect of the 5-HTTLPR and a role for rare variants cannot be excluded.
Genes Brain and Behavior 07/2010; 9(5):449-58. · 3.48 Impact Factor
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[hide abstract]
ABSTRACT: Mice deficient of the serotonin transporter (5-HTT ko) mice have a reduced brain serotonin content and develop late-onset obesity. To elucidate the pathophysiology of this obesity, we analyzed the expression of the interrelated weight-regulatory molecules: brain-derived neurotrophic factor (BDNF) and leptin receptor (LR) in brain areas associated with nutrition and activity.
We investigated feeding behavior, physical activity and metabolic parameters of 5-HTT ko and wild-type mice and measured the expression of BDNF and LR in brain areas associated with nutrition and activity using quantitative real-time PCR. The influence of age, gender and fasting was analyzed.
Male 5-HTT ko mice developed obesity without hyperphagia from the age of 5 months. Physical activity was reduced in old male, but not old female, 5-HTT ko mice. The BDNF gene expression in frontal cortex was elevated in young, but reduced in old 5-HTT ko mice. Fasting failed to increase the BDNF gene expression in frontal cortex of young 5 HTT ko mice and in the hypothalamus in old 5-HTT ko mice. The fasting-induced hypothalamic increase of LR was absent in both young and old 5-HTT ko mice.
We propose that low brain serotonin level due to the 5-HTT ko genotype leads to reduced physical activity and low BDNF, which together with the lack of fasting-induced hypothalamic BDNF and LR production results in late-onset obesity. Although lack of the 5-HTT is a genetic vulnerability factor for obesity, female gender is protective.
International journal of obesity (2005) 04/2010; 34(4):701-11. · 4.34 Impact Factor
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ABSTRACT: Several lines of evidence implicate a dysregulation of the serotonin (5-HT) system in emotional behavior and stress, and point to its relevance for the etiology and pathogenesis of various neuropsychiatric disorders. This is evidenced by behavioral pharmacology as well as genetic studies, yet the impact of genetic variation within the 5-HT system on human disorders remains controversial. The generation of tissue-specific and inducible knockout mice lacking genes belonging to the 5-HT system further established the importance of the 5-HT system for neuronal development and the regulation of emotions. This part of the review provides a summary and critical discussion of genetic, neurobiological and pharmacological studies along with recent clinical research. Together, these data underscore the complex effects of 5-HT on human behavior and psychiatric disorders. Epigenetic mechanisms add to the complexity of the 5-HT system and will be increasingly studied in the coming years. Thus, the serotonergic system still remains in the centre of current hypotheses regarding the pathogenesis of disorders with the shared feature of emotional dysregulation.
Fortschritte der Neurologie · Psychiatrie 03/2010; 78(6):332-42. · 0.74 Impact Factor
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ABSTRACT: As soon as in the 1960's, the role of serotonin (5-Hydroxytryptamin, 5-HT) in psychiatric disorders was realized, which was further substantiated by several lines of evidence amounting to a huge body of knowledge. The indolamine 5-HT belongs to the class of monoamine transmitters and can be found in the serotonergic neurons of the raphe nuclei in the brain stem. In the periphery, it is mainly present in the gastrointestinal system and the pineal gland. 5-HT is implicated in a variety of cognitive, emotional and vegetative behaviors, as well as in the regulation of circadian rhythms. Apart from its role as a neurotransmitter, it has an important function in prenatal development, where its expression pattern is tightly regulated, and in adult neurogenesis. The numerous effects of 5-HT are mediated by specific pre- and postsynaptic receptors, whose localization and functions are further described here. The serotonin transporter (SERT), which accomplishes the re-uptake of 5-HT into the neuron following its release in the synaptic cleft, not only has an important role in the termination of serotonergic neurotransmission but is also an important drug target for antidepressant compounds. In this part of the review, the neurobiological underpinnings of 5-HT synthesis, metabolism, and neurotransmission as well as the corresponding physiological consequences are summarized, while in the second part, an overview on clinical findings is provided and critically discussed.
Fortschritte der Neurologie · Psychiatrie 03/2010; 78(6):319-31. · 0.74 Impact Factor
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K-P Lesch,
S Selch,
T J Renner,
C Jacob,
T T Nguyen,
T Hahn,
M Romanos,
S Walitza,
S Shoichet,
A Dempfle, [......],
T Wultsch,
S Heinzel,
M Fassnacht,
A Fallgatter,
B Allolio,
H Schäfer,
A Warnke,
A Reif,
H-H Ropers,
R Ullmann
[show abstract]
[hide abstract]
ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental syndrome characterized by hyperactivity, inattention and increased impulsivity. To detect micro-deletions and micro-duplications that may have a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNVs) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution array comparative genomic hybridization (aCGH), a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise 4 deletions and 13 duplications with approximate sizes ranging from 110 kb to 3 Mb. Two CNVs occurred de novo and nine were inherited from a parent with ADHD, whereas five are transmitted by an unaffected parent. Candidates include genes expressing acetylcholine-metabolizing butyrylcholinesterase (BCHE), contained in a de novo chromosome 3q26.1 deletion, and a brain-specific pleckstrin homology domain-containing protein (PLEKHB1), with an established function in primary sensory neurons, in two siblings carrying a 11q13.4 duplication inherited from their affected mother. Other genes potentially influencing ADHD-related psychopathology and involved in aberrations inherited from affected parents are the genes for the mitochondrial NADH dehydrogenase 1 α subcomplex assembly factor 2 (NDUFAF2), the brain-specific phosphodiesterase 4D isoform 6 (PDE4D6) and the neuronal glucose transporter 3 (SLC2A3). The gene encoding neuropeptide Y (NPY) was included in a ∼3 Mb duplication on chromosome 7p15.2-15.3, and investigation of additional family members showed a nominally significant association of this 7p15 duplication with increased NPY plasma concentrations (empirical family-based association test, P=0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses elicited by functional magnetic resonance imaging links gene dose-dependent increases in NPY to reward and emotion processing in duplication carriers. These findings implicate CNVs of behaviour-related genes in the pathogenesis of ADHD and are consistent with the notion that both frequent and rare variants influence the development of this common multifactorial syndrome.
Molecular psychiatry 03/2010; 16(5):491-503. · 15.05 Impact Factor
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C. Sánchez-Mora,
M. Ribasés,
J.A. Ramos-Quiroga,
M. Casas,
R. Bosch,
A. Boreatti-Hümmer,
M. Heine,
C.P. Jacob, K-P. Lesch,
O.B. Fasmer, [......],
J.K. Buitelaar,
E. Mick,
P. Asherson,
S.V. Faraone,
B. Franke,
S. Johansson,
J. Haavik,
A. Reif,
M. Bayés,
B. Cormand
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ABSTRACT: Attention-deficit hyperactivity disorder (ADHD) is a multifactorial, neurodevelopmental disorder that often persists into adolescence and adulthood and is characterized by inattention, hyperactivity and impulsiveness. Before the advent of the first genome-wide association studies in ADHD, genetic research had mainly focused on candidate genes related to the dopaminergic and serotoninergic systems, although several other genes had also been assessed. Pharmacological data, analysis of animal models and association studies suggest that Brain-Derived Neurotrophic Factor (BDNF) is also a strong candidate gene for ADHD. Several polymorphisms in BDNF have been reported and studied in psychiatric disorders but the most frequent is the p.Val66Met (rs6265G > A) single nucleotide polymorphism (SNP), with functional effects on the intracellular trafficking and secretion of the protein. To deal with the inconsistency raised among different case–control and family-based association studies regarding the p.Val66Met contribution to ADHD, we performed a meta-analysis of published as well as unpublished data from four different centers that are part of the International Multicentre Persistent ADHD CollaboraTion (IMpACT). A total of 1,445 adulthood ADHD patients and 2,247 sex-matched controls were available for the study. No association between the p.Val66Met polymorphism and ADHD was found in any of the four populations or in the pooled sample. The meta-analysis also showed that the overall gene effect for ADHD was not statistically significant when gender or comorbidity with mood disorders were considered. Despite the potential role of BDNF in ADHD, our data do not support the involvement of p.Val66Met in the pathogenesis of this neuropsychiatric disorder. © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2010; 153B(2):512 - 523. · 3.70 Impact Factor
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M Arcos-Burgos,
M Jain,
M T Acosta,
S Shively,
H Stanescu,
D Wallis,
S Domen|[eacute,
J I V|[eacute]|lez,
J D Karkera,
J Balog, [......],
A Warnke,
J Romanos,
T Renner,
C Jacob, K-P Lesch,
J Swanson,
A Vortmeyer,
J E Bailey-Wilson,
F X Castellanos,
M Muenke
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ABSTRACT: Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD.Keywords: ADHD; complex trait; gene; LPHN3; genetics; latrophilin
Molecular Psychiatry 02/2010; 15(11):1053-1066. · 13.67 Impact Factor
