TY  - JOUR
A1  - Jain, M.
A1  - Vélez, J. I.
A1  - Acosta, M. T.
A1  - Palacio, L. G.
A1  - Balog, J.
A1  - Roessler, E.
A1  - Pineda, D.
A1  - Londoño, A. C.
A1  - Palacio, J. D.
A1  - Arbelaez, A.
A1  - Lopera, F.
A1  - Elia, J.
A1  - Hakonarson, H.
A1  - Seitz, C.
A1  - Freitag, C. M.
A1  - Palmason, H.
A1  - Meyer, J.
A1  - Romanos, M.
A1  - Walitza, S.
A1  - Hemminger, U.
A1  - Warnke, A.
A1  - Romanos, J.
A1  - Renner, T.
A1  - Jacob, C.
A1  - Lesch, K.-P.
A1  - Swanson, J.
A1  - Castellanos, F. X.
A1  - Bailey-Wilson, J. E.
A1  - Arcos-Burgos, M.
A1  - Muenke, M.
T1  - A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD
JF  - Molecular Psychiatry
N2  - 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.
KW  - ADHD
KW  - genetic interaction
KW  - LPHN3
KW  - NCAM1
KW  - DRD2
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125128
VL  - 17
ER  - 
TY  - JOUR
A1  - Jarick, I.
A1  - Volckmar, A. L.
A1  - Pütter, C.
A1  - Pechlivanis, S.
A1  - Nguyen, T. T.
A1  - Dauvermann, M. R.
A1  - Beck, S.
A1  - Albayrak, Ö.
A1  - Scherag, S.
A1  - Gilsbach, S.
A1  - Cichon, S.
A1  - Hoffmann, P.
A1  - Degenhardt, F.
A1  - Nöthen, M. M.
A1  - Schreiber, S.
A1  - Wichmann, H. E.
A1  - Jöckel, K. H.
A1  - Heinrich, J.
A1  - Tiesler, C. M. T.
A1  - Faraone, S. V.
A1  - Walitza, S.
A1  - Sinzig, J.
A1  - Freitag, C.
A1  - Meyer, J.
A1  - Herpertz-Dahlmann, B.
A1  - Lehmkuhl, G.
A1  - Renner, T. J.
A1  - Warnke, A.
A1  - Romanos, M.
A1  - Lesch, K. P.
A1  - Reif, A.
A1  - Schimmelmann, B. G.
A1  - Hebebrand, J.
A1  - Scherag, A.
A1  - Hinney, A.
T1  - Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder
JF  - Molecular Psychiatry
N2  - 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.
KW  - children
KW  - ADHD
KW  - CNVs
KW  - GWAS
KW  - PARK2
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121131
VL  - 19
IS  - 19
ER  - 
TY  - JOUR
A1  - Neufang, S.
A1  - Akhrif, A.
A1  - Herrmann, C.G.
A1  - Drepper, C.
A1  - Homola, G.A.
A1  - Nowak, J.
A1  - Waider, J.
A1  - Schmitt, A.G.
A1  - Lesch, K.-P.
A1  - Romanos, M.
T1  - Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans
JF  - Translational Psychiatry
N2  - In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies.
KW  - Clinical Genetics
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164418
IS  - 6
ER  - 
TY  - JOUR
A1  - Lechermeier, Carina G.
A1  - Zimmer, Frederic
A1  - Lüffe, Teresa M.
A1  - Lesch, Klaus-Peter
A1  - Romanos, Marcel
A1  - Lillesaar, Christina
A1  - Drepper, Carsten
T1  - Transcript analysis of zebrafish GLUT3 genes, slc2a3a and slc2a3b, define overlapping as well as distinct expression domains in the zebrafish (Danio rerio) central nervous system
JF  - Frontiers in Molecular Neuroscience
N2  - The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders.
KW  - glucose transporter
KW  - nervous system
KW  - brain disorders
KW  - psychiatric disorders
KW  - brain development
KW  - GABA
KW  - GAD1
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201797
VL  - 12
IS  - 199
ER  - 
TY  - JOUR
A1  - Ziegler, Georg C.
A1  - Ehlis, Ann-Christine
A1  - Weber, Heike
A1  - Vitale, Maria Rosaria
A1  - Zöller, Johanna E. M.
A1  - Ku, Hsing-Ping
A1  - Schiele, Miriam A.
A1  - Kürbitz, Laura I.
A1  - Romanos, Marcel
A1  - Pauli, Paul
A1  - Kalisch, Raffael
A1  - Zwanzger, Peter
A1  - Domschke, Katharina
A1  - Fallgatter, Andreas J.
A1  - Reif, Andreas
A1  - Lesch, Klaus-Peter
T1  - A Common CDH13 Variant is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD
JF  - Genes
N2  - The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
KW  - ADHD
KW  - CDH13
KW  - neurodevelopment
KW  - executive functions
KW  - working memory
KW  - Big Five
KW  - agreeableness
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245220
SN  - 2073-4425
VL  - 12
IS  - 9
ER  - 
TY  - JOUR
A1  - Taurines, R.
A1  - Fekete, S.
A1  - Preuss-Wiedenhoff, A.
A1  - Warnke, A.
A1  - Wewetzer, C.
A1  - Plener, P.
A1  - Burger, R.
A1  - Gerlach, M.
A1  - Romanos, M.
A1  - Egberts, K. M.
T1  - Therapeutic drug monitoring in children and adolescents with schizophrenia and other psychotic disorders using risperidone
JF  - Journal of Neural Transmission
N2  - Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose–concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20–60 ng/ml) is applicable for minors. In the 64 patients (aged 11–18 years) included, a positive correlation between daily dose and the active moiety (RIS\(_{am}\)) concentration was found (r\(_s\) = 0.49, p = 0.001) with variation in dose explaining 24% (r\(_s\)\(^2\) = 0.240) of the variability in serum concentrations. While the RIS\(_{am}\) concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RIS\(_{am}\) concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RIS\(_{am}\) was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.
KW  - risperidone
KW  - children
KW  - serum concentration
KW  - schizophrenia
KW  - therapeutic drug monitoring
KW  - pharmacovigilance
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324833
VL  - 129
IS  - 5-6
ER  -