Andreas Reif

Publications of Andreas Reif

• An association study of sequence variants in the forkhead box P2 (FOXP2) gene and adulthood attention-deficit/hyperactivity disorder in two European samples.

  Authors: Marta Ribasés, Cristina Sánchez-Mora, Josep Antoni Ramos-Quiroga, Rosa Bosch, Núria Gómez, Mariana Nogueira, Montse Corrales, Gloria Palomar, Christian P Jacob, Silke Gross-Lesch, Susanne Kreiker, Andreas Reif, Klaus Peter Lesch, Bru Cormand, Miquel Casas, Mónica Bayés

  Psychiatric genetics. 04/2012;

  OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder manifesting as symptoms of inattention, hyperactivity, and/or impulsivity. Learning disabilities co-occurOBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder manifesting as symptoms of inattention, hyperactivity, and/or impulsivity. Learning disabilities co-occur with ADHD in 20-30% of cases and this high co-occurrence raises the possibility of a common etiological background. Forkhead box P2 (FOXP2) encodes a transcription factor involved in speech and language impairment and in the control of the corticobasal ganglia circuits known to be relevant in ADHD, suggesting a possible role of FOXP2 in ADHD. Our aim was to carry out an association study between FOXP2 and adulthood ADHD. METHODS: We carried out a case-control association study in 643 adult ADHD patients and 619 controls from Germany and in 361 adult ADHD patients and 442 controls from Spain with 12 tagging single nucleotide polymorphisms covering the FOXP2 gene. RESULTS: The single-marker and multiple-marker analyses showed an association between FOXP2 and combined ADHD in the German cohort [rs12533005: P=0.0033; odds ratio=1.30 (1.09-1.56); rs12533005/rs1229761: P=4.1e-04; odds ratio=1.38 (1.15-1.66)]. These positive results, however, were not confirmed in the Spanish sample. CONCLUSION: Although these preliminary findings provide a tentative evidence for the contribution of FOXP2 to ADHD and suggest common genetic factors for this psychiatric disorder and learning disabilities, they should be interpreted with caution. Further studies in larger samples are needed to clarify the role of this transcription factor in ADHD.

• Monoamine oxidase A gene DNA hypomethylation - a risk factor for panic disorder?

  Authors: Katharina Domschke, Nicola Tidow, Henriette Kuithan, Kathrin Schwarte, Benedikt Klauke, Oliver Ambrée, Andreas Reif, Hartmut Schmidt, Volker Arolt, Anette Kersting, Peter Zwanzger, Jürgen Deckert

  The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). 03/2012;

  The monoamine oxidase A (MAOA) gene has been suggested as a prime candidate in the pathogenesis of panic disorder. In the present study, DNA methylation patterns in the MAOA regulatory and exonThe monoamine oxidase A (MAOA) gene has been suggested as a prime candidate in the pathogenesis of panic disorder. In the present study, DNA methylation patterns in the MAOA regulatory and exon 1/intron 1 region were investigated for association with panic disorder with particular attention to possible effects of gender and environmental factors.Sixty-five patients with panic disorder (44 females, 21 males) and 65 healthy controls were analysed for DNA methylation status at 42 MAOA CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. The occurrence of recent positive and negative life events was ascertained. Male subjects showed no or only very minor methylation with some evidence for relative hypomethylation at one CpG site in intron 1 in patients compared to controls. Female patients exhibited significantly lower methylation than healthy controls at 10 MAOA CpG sites in the promoter as well as in exon/intron 1, with significance surviving correction for multiple testing at four CpG sites (p⩽0.001). Furthermore, in female subjects the occurrence of negative life events was associated with relatively decreased methylation, while positive life events were associated with increased methylation. The present pilot data suggest a potential role of MAOA gene hypomethylation in the pathogenesis of panic disorder particularly in female patients, possibly mediating a detrimental influence of negative life events. Future studies are warranted to replicate the present finding in independent samples, preferably in a longitudinal design.

• Neuropeptide S receptor gene (NPSR) and life events: G × E effects on anxiety sensitivity and its subdimensions.

  Authors: Benedikt Klauke, Jürgen Deckert, Peter Zwanzger, Christian Baumann, Volker Arolt, Paul Pauli, Andreas Reif, Katharina Domschke

  The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. 03/2012;

  Objectives. The pathogenesis of anxiety is assumed to be interactively influenced by genetic and environmental factors. Thus, a gene-environment interaction (G × E) study of the neuropeptide SObjectives. The pathogenesis of anxiety is assumed to be interactively influenced by genetic and environmental factors. Thus, a gene-environment interaction (G × E) study of the neuropeptide S receptor gene (NPSR) A/T polymorphism (rs324981) and life events was conducted with respect to anxiety sensitivity (AS) as an intermediate phenotype of anxiety disorders. Methods. A sample of 475 healthy German subjects was genotyped for NPSR and assessed for AS, childhood maltreatment (CTQ) and recent life events (LTE). Influences on AS and its subdimensions were determined by a step-wise hierarchical regression and a multiple indicator multiple cause (MIMIC) model. Results. Significant main effects of NPSR and CTQ as well as significant G × E were observed, with T/T homozygosity and a high CTQ score resulting in increased anxiety sensitivity. MIMIC modelling yielded association of AS subfactor "concern about mental/cognitive incapacitation" and the basal somatic subdimension "concern about physical sensations" to be associated with CTQ and its interaction with NPSR, while the acute somatic subfactor "concern about heart/lung failure" was associated with NPSR and its interaction with LTE. Conclusions. Results indicate G × E effects of the more active NPSR rs324981 T allele and life events on AS with differential effects of temporally proximal and distal factors on specific AS subdimensions.

• Candidate system analysis in ADHD: Evaluation of nine genes involved in dopaminergic neurotransmission identifies association with DRD1.

  Authors: Marta Ribasés, Josep Antoni Ramos-Quiroga, Amaia Hervás, Cristina Sánchez-Mora, Rosa Bosch, Anna Bielsa, Xavier Gastaminza, Klaus-Peter Lesch, Andreas Reif, Tobias J Renner, Marcel Romanos, Andreas Warnke, Susanne Walitza, Christine Freitag, Jobst Meyer, Haukur Palmason, Miquel Casas, Mònica Bayés, Bru Cormand

  The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. 03/2012;

  Objectives. Several pharmacological and genetic studies support the involvement of the dopamine neurotransmitter system in the aetiology of attention-deficit hyperactivity disorder (ADHD). Based onObjectives. Several pharmacological and genetic studies support the involvement of the dopamine neurotransmitter system in the aetiology of attention-deficit hyperactivity disorder (ADHD). Based on this information we evaluated the contribution to ADHD of nine genes involved in dopaminergic neurotransmission (DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, TH, DBH and COMT). Methods. We genotyped a total of 61 tagging single nucleotide polymorphisms (SNPs) in a sample of 533 ADHD patients (322 children and 211 adults), 533 sex-matched unrelated controls and additional 196 nuclear ADHD families from Spain. Results. The single- and multiple-marker analysis in both population and family-based approaches provided preliminary evidence for the contribution of DRD1 to combined-type ADHD in children (P = 8.8e-04; OR = 1.50 (1.18-1.90) and P = 0.0061; OR = 1.73 (1.23-2.45)) but not in adults. Subsequently, we tested positive results for replication in an independent sample of 353 German families with combined-type ADHD children and replicated the initial association between DRD1 and childhood ADHD (P = 8.4e-05; OR = 3.67 (2.04-6.63)). Conclusions: The replication of the association between DRD1 and ADHD in two European cohorts highlights the validity of our finding and supports the involvement of DRD1 in childhood ADHD.

• Modification of caffeine effects on the affect-modulated startle by neuropeptide S receptor gene variation.

  Authors: Katharina Domschke, Benedikt Klauke, Bernward Winter, Agnes Gajewska, Martin J Herrmann, Bodo Warrings, Andreas Mühlberger, Katherina Wosnitza, Andrea Dlugos, Swantje Naunin, Kathrin Nienhaus, Manfred Fobker, Christian Jacob, Volker Arolt, Paul Pauli, Andreas Reif, Peter Zwanzger, Jürgen Deckert

  Psychopharmacology. 03/2012;

  RATIONALE/OBJECTIVES: Both the neuropeptide S (NPS) system and antagonism at the adenosine A2A receptor (e.g., by caffeine) were found to play a crucial role in the mediation of arousal andRATIONALE/OBJECTIVES: Both the neuropeptide S (NPS) system and antagonism at the adenosine A2A receptor (e.g., by caffeine) were found to play a crucial role in the mediation of arousal and anxiety/panic in animal and human studies. Furthermore, a complex interaction of the neuropeptide S and the adenosinergic system has been suggested with administration of the adenosine A2A receptor antagonist caffeine downregulating NPS levels (Lage et al., 2006) and attenuating the stimulatory effects of NPS in rodents (Boeck et al., 2010). METHODS: Thus, in the present study, the impact of the functional neuropeptide S receptor (NPSR) A/T (Asn(107)Ile; rs324981) variant on affect-modulated (neutral, unpleasant, and pleasant IAPS pictures) startle response depending on the administration of 300 mg caffeine citrate was investigated in a sample of 124 (m = 58, f = 66) healthy probands using a double-blind, placebo-controlled design. RESULTS: ANOVA revealed a significant interaction between NPSR genotype, challenge condition, and picture valence. Comparing startle magnitudes upon stimulation with neutral or emotional pictures between the placebo and caffeine condition, in AA/AT non-risk genotype carriers no significant difference was discerned, while TT risk genotype carriers showed a significantly increased startle magnitude in response to neutral stimuli (p = .02) and a significantly decreased startle magnitude in response to unpleasant stimuli (p = .02) in the caffeine condition as compared to the placebo condition. CONCLUSIONS: In summary, the present findings - extending previous evidence from rodent studies - for the first time provide support for a complex, non-linear interaction of the neuropeptide S and adenosinergic systems affecting the affect-modulated startle response as an intermediate phenotype of anxiety in humans.

• DIRAS2 is Associated with Adult ADHD, Related Traits, and Co-Morbid Disorders.

  Authors: Andreas Reif, T Trang Nguyen, Lena Weißflog, Christian P Jacob, Marcel Romanos, Tobias J Renner, Henriette N Buttenschon, Sarah Kittel-Schneider, Alexandra Gessner, Heike Weber [......] Per M Knappskog, Ole B Fasmer, Phil Asherson, Andreas Warnke, Hans-Jörgen Grabe, Jessie Mahler, Alexander Teumer, Henry Völzke, Ole N Mors, Helmut Schäfer

  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 03/2012; 37(4):1076.

• Human IgG directed against amphiphysin induces anxiety behavior in a rat model after intrathecal passive transfer.

  Authors: Christian Geis, Benedikt Grünewald, Andreas Weishaupt, Thomas Wultsch, Klaus V Toyka, Andreas Reif, Claudia Sommer

  Journal of neural transmission (Vienna, Austria : 1996). 02/2012;

  Stiff person syndrome with auto-antibodies against amphiphysin is characterized by muscular stiffness, spasms, and anxiety which is a less appreciated core symptom. Here, we report that intrathecalStiff person syndrome with auto-antibodies against amphiphysin is characterized by muscular stiffness, spasms, and anxiety which is a less appreciated core symptom. Here, we report that intrathecal application of purified immunoglobulin G-antibodies against amphiphysin from one patient induce anxiety behavior in rats. Immunostaining demonstrated binding of anti-amphiphysin antibodies to brain structures which are associated with anxiety disorders, such as the amygdala. We propose that antibody-mediated amphiphysin deficiency may account for anxiety behavior in stiff person syndrome via presynaptic dysregulation of GABAergic pathways.

• Behavioral Genetics of Affective and Anxiety Disorders.

  Authors: Katharina Domschke, Andreas Reif

  Current topics in behavioral neurosciences. 02/2012;

  As shown by clinical genetic studies, affective and anxiety disorders are complex genetic disorders with genetic and environmental factors interactively determining their respective pathomechanism.As shown by clinical genetic studies, affective and anxiety disorders are complex genetic disorders with genetic and environmental factors interactively determining their respective pathomechanism. Advances in molecular genetic techniques including linkage studies, association studies, and genome-wide association studies allow for the detailed dissection of the genetic influence on the development of these disorders. Besides the molecular genetic investigation of categorical entities according to standardized diagnostic criteria, intermediate phenotypes comprising neurobiological or neuropsychological traits (e.g., neuronal correlates of emotional processing) that are linked to the disease of interest and that are heritable, have been proposed to be closer to the underlying genotype than the overall disease phenotype. These intermediate phenotypes are dimensional and more precisely defined than the categorical disease phenotype, and therefore have attracted much interest in the genetic investigation of affective and anxiety disorders. Given the complex genetic nature of affective and anxiety disorders with an interaction of multiple risk genes and environmental influences, the interplay of genetic factors with environmental factors is investigated by means of gene-environment interaction (GxE) studies. Pharmacogenetic studies aid in the dissection of the genetically influenced heterogeneity of psychotropic drug response and may contribute to the development of a more individualized treatment of affective and anxiety disorders. Finally, there is some evidence for genetic factors potentially shared between affective and anxiety disorders pointing to a possible overlapping phenotype between anxiety disorders and depression.

• Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3.

  Authors: Nigel M Williams, Barbara Franke, Eric Mick, Richard J L Anney, Christine M Freitag, Michael Gill, Anita Thapar, Michael C O'Donovan, Michael J Owen, Peter Holmans [......] Stephen W Scherer, Alexandre Todorov, Susan L Smalley, Sandra Loo, Stanley Nelson, Corina Shtir, Philip Asherson, Andreas Reif, Klaus-Peter Lesch, Stephen V Faraone

  The American journal of psychiatry. 02/2012; 169(2):195-204.

  Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult.Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

• ADORA2A Gene variation, caffeine, and emotional processing: a multi-level interaction on startle reflex.

  Authors: Katharina Domschke, Agnieszka Gajewska, Bernward Winter, Martin J Herrmann, Bodo Warrings, Andreas Mühlberger, Katherina Wosnitza, Evelyn Glotzbach, Annette Conzelmann, Andrea Dlugos, Manfred Fobker, Christian Jacob, Volker Arolt, Andreas Reif, Paul Pauli, Peter Zwanzger, Jürgen Deckert

  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 02/2012; 37(3):759-69.

  There is converging evidence for genetic, biochemical, and neuropsychological factors to increase the risk for anxiety and anxiety disorders. The pathogenesis of anxiety disorders is assumed to beThere is converging evidence for genetic, biochemical, and neuropsychological factors to increase the risk for anxiety and anxiety disorders. The pathogenesis of anxiety disorders is assumed to be influenced by a complex interaction of these individual risk factors on several levels, affecting intermediate phenotypes of anxiety such as the startle reflex. Thus, in the present double-blind, placebo-controlled study we attempted to paradigmatically investigate a multi-level pathogenetic model of anxiety by testing the effect of 300 mg caffeine citrate as an antagonist at the adenosine A2A receptor vs placebo on the emotion-potentiated (unpleasant, neutral, and pleasant International Affective Picture System pictures) startle reflex in 110 healthy individuals (male=56, female=54) stratified for the adenosine A2A receptor (ADORA2A) 1976T>C polymorphism (rs5751876). In addition to the expected main effect of picture category (highest startle amplitude for unpleasant, lowest for pleasant pictures) groups across all ADORA2A 1976T>C genotype and intervention (caffeine vs placebo) groups, an interaction effect of genotype, intervention, and picture category was discerned: In ADORA2A 1976TT risk genotype carriers, highest startle magnitudes were observed after caffeine administration in response to unpleasant pictures, with this effect arising particularly from the female subgroup. Our data point to a complex, multi-level, and potentially gender-specific pathogenetic model of anxiety, with genetic and biochemical factors interactively increasing the risk of maladaptive emotional processing and thereby possibly also anxiety disorders. The present findings may eventually aid in improving primary and secondary prevention by sharpening the risk profiles of anxiety-prone individuals.

• Expression of monoamine transporters, nitric oxide synthase 3, and neurotrophin genes in antidepressant-stimulated astrocytes.

  Authors: Sarah Kittel-Schneider, Gunter Kenis, Julia Schek, Daniel van den Hove, Jos Prickaerts, Klaus-Peter Lesch, Harry Steinbusch, Andreas Reif

  Frontiers in psychiatry / Frontiers Research Foundation. 01/2012; 3:33.

  Background: There is increasing evidence that glial cells play a role in the pathomechanisms of mood disorders and the mode of action of antidepressant drugs. Methods: To examine whether there is aBackground: There is increasing evidence that glial cells play a role in the pathomechanisms of mood disorders and the mode of action of antidepressant drugs. Methods: To examine whether there is a direct effect on the expression of different genes encoding proteins that have been implicated in the pathophysiology of affective disorders, primary astrocyte cell cultures from rats were treated with two different antidepressant drugs, imipramine and escitalopram, and the RNA expression of brain-derived neurotrophic factor (Bdnf), serotonin transporter (5Htt), dopamine transporter (Dat), and endothelial nitric oxide synthase (Nos3) was examined. Results: Stimulation of astroglial cell culture with imipramine, a tricyclic antidepressant, led to a significant increase of the Bdnf RNA level whereas treatment with escitalopram did not. In contrast, 5Htt was not differentially expressed after antidepressant treatment. Finally, neither Dat nor Nos3 RNA expression was detected in cultured astrocytes. Conclusion: These data provide further evidence for a role of astroglial cells in the molecular mechanisms of action of antidepressants.

• Progranulin gene variability and plasma levels in bipolar disorder and schizophrenia.

  Authors: Daniela Galimberti, Bernardo Dell'osso, Chiara Fenoglio, Chiara Villa, Francesca Cortini, Maria Serpente, Sarah Kittel-Schneider, Johannes Weigl, Maria Neuner, Juliane Volkert [......] David G Olmes, Juliane Kopf, Claudia Cantoni, Elisa Ridolfi, Carlotta Palazzo, Laura Ghezzi, Nereo Bresolin, A C Altamura, Elio Scarpini, Andreas Reif

  PloS one. 01/2012; 7(4):e32164.

  Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLDBasing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n = 271) or BPD (n = 237) as compared with 574 age-, gender- and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls.A significantly decreased allelic frequency of the minor versus the wild-type allele was observed for rs2879096 (23.2 versus 34.2%, P<0.001, OR:0.63, 95%CI:0.49-0.80), rs4792938 (30.7 versus 39.7%, P = 0.005, OR: 0.70, 95%CI: 0.55-0.89) and rs5848 (30.3 versus 36.8, P = 0.007, OR: 0.71, 95%CI: 0.56-0.91). Mean±SEM progranulin plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls (89.69±3.97 and 116.14±5.80 ng/ml, respectively, versus 180.81±18.39 ng/ml P<0.001) and were not correlated with age.In conclusion, GRN variability decreases the risk to develop BPD and schizophrenia, and progranulin plasma levels are significantly lower in BPD patients than in controls. Nevertheless, a larger replication analysis would be needed to confirm these preliminary results.

• Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.

  Authors: Josephine Elia, Joseph T Glessner, Kai Wang, Nagahide Takahashi, Corina J Shtir, Dexter Hadley, Patrick M A Sleiman, Haitao Zhang, Cecilia E Kim, Reid Robison [......] Philip Shaw, Marcella Devoto, Peter S White, Struan F A Grant, Joseph D Buxbaum, Judith L Rapoport, Nigel M Williams, Stanley F Nelson, Stephen V Faraone, Hakon Hakonarson

  Nature genetics. 12/2011; 44(1):78-84.

  Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases withAttention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

• Genome-wide association study in German patients with attention deficit/hyperactivity disorder.

  Authors: Anke Hinney, André Scherag, Ivonne Jarick, Özgür Albayrak, Carolin Pütter, Sonali Pechlivanis, Maria R Dauvermann, Sebastian Beck, Heike Weber, Susann Scherag [......] Beate Herpertz-Dahlmann, Judith Sinzig, Gerd Lehmkuhl, Tobias J Renner, Andreas Warnke, Marcel Romanos, Klaus-Peter Lesch, Andreas Reif, Benno G Schimmelmann, Johannes Hebebrand

  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 12/2011; 156B(8):888-97.

  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 theThe 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 × 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 × 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.

• Reduced prefrontal oxygenation during object and spatial visual working memory in unpolar and bipolar depression.

  Authors: Martin Schecklmann, Thomas Dresler, Stefanie Beck, Johanna T Jay, Richard Febres, Julia Haeusler, Tomasz A Jarczok, Andreas Reif, Michael M Plichta, Ann-Christine Ehlis, Andreas J Fallgatter

  Psychiatry research. 11/2011; 194(3):378-84.

  Altered prefrontal brain activity (e.g. hypofrontality) during cognitive tasks such as working memory is a core neuroimaging marker in unipolar (UNI) and bipolar (BI) depression. The present studyAltered prefrontal brain activity (e.g. hypofrontality) during cognitive tasks such as working memory is a core neuroimaging marker in unipolar (UNI) and bipolar (BI) depression. The present study investigated for the first time UNI (n=16) and BI patients (n=14) in a working memory task including different processes (storage and matching) and components (object and spatial visual) with functional near-infrared spectroscopy (fNIRS) over the prefrontal cortex. In healthy controls (n=15) comparable to both patient groups, changes of oxygenated and deoxygenated haemoglobin indicated increased ventro-lateral, dorso-lateral prefrontal and superior frontal cortex activity for object and spatial visual working memory storage as compared to the control condition. In contrast, both patient groups showed diminished brain activity in all working memory conditions. Results revealed unspecific deficits that did not allow the differentiation between unipolar and bipolar depression in dependence of working memory processes or components. However, fNIRS can be considered as a valid, easy manageable, low cost and rapid tool for measuring (diminished) prefrontal cortex functions.

• Serotonergic modulation in executive functioning: linking genetic variations to working memory performance.

  Authors: Sören Enge, Monika Fleischhauer, Klaus-Peter Lesch, Andreas Reif, Alexander Strobel

  Neuropsychologia. 11/2011; 49(13):3776-85.

  Emerging evidence from studies using, for example, acute tryptophan depletion or investigating genetic variation of genes related to the serotonin signaling pathway suggest a role of serotonin inEmerging evidence from studies using, for example, acute tryptophan depletion or investigating genetic variation of genes related to the serotonin signaling pathway suggest a role of serotonin in executive functions such as top-down attention, working memory and inhibitory control. In the current study, we aimed at extending this evidence by using the n-back task to examine working memory performance of 130 participants via behavioral and neurophysiological indices and by focusing on variations within genes encoding key regulators of the serotonergic system: the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and a repeat polymorphism in the transcriptional control region of the monoamine-oxidase gene (MAOA-uVNTR). Because serotonin and norepinephrine systems have been shown to be structurally and functionally highly interrelated, we also examined a novel polymorphism in the promoter region of the norepinephrine transporter gene (NET -3081) in anticipation of epistatic effects. We found that carriers of 5-HTTLPR and MAOA-uVNTR alleles recently implicated in executive processing showed a more efficient executive control of working memory-related performance as evidenced by reaction time, error rate as well as N2 and P3b event-related potential measures. This impact was further supported by interactions with the NET polymorphism. Linking serotonergic influence to mechanisms of inhibitory response control implicated in working memory, our results provide further support for and add new evidence concerning the importance of serotonergic neuromodulation in executive functioning.

• Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.

  Authors: Pamela Sklar, Stephan Ripke, Laura J Scott, Ole A Andreassen, Sven Cichon, Nick Craddock, Howard J Edenberg, John I Nurnberger, Marcella Rietschel, Douglas Blackwood [......] Grant W Montgomery, Mark Lathrop, Högni Oskarsson, Michael Bauer, Adam Wright, Philip B Mitchell, Martin Hautzinger, Andreas Reif, John R Kelsoe, Shaun M Purcell

  Nature genetics. 09/2011; 43(10):977-83.

  We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication studyWe conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

• NOS1 ex1f-VNTR polymorphism affects prefrontal oxygenation during response inhibition tasks.

  Authors: Juliane Kopf, Martin Schecklmann, Tim Hahn, Alica C Dieler, Martin J Herrmann, Andreas J Fallgatter, Andreas Reif

  Human brain mapping. 09/2011;

  Impulsivity is a trait shared by many psychiatric disorders and therefore a suitable intermediate phenotype for their underlying biological mechanisms. One of the molecular determinants involved isImpulsivity is a trait shared by many psychiatric disorders and therefore a suitable intermediate phenotype for their underlying biological mechanisms. One of the molecular determinants involved is the NOS1 ex1f-VNTR, whose short variants are associated with a variety of impulsive behaviors. Fifty-six healthy controls were stratified into homozygous long (LL) (30 probands) and short (SS) (26 probands) allele groups. Subjects completed a combined stop-signal go/nogo task, while the oxygenation in the prefrontal cortex was measured with functional near-infrared spectroscopy. Electromyography was recorded to control for differences in muscle activity in the two inhibition tasks. Two questionnaires on impulsive traits were completed. Differences between the two tasks are shown by distinct activation patterns within the prefrontal cortex. The nogo task resulted mainly in the activation of the dorsolateral prefrontal cortex (dlPFC), whereas successful and unsuccessful inhibition in the stop-signal task elicited the predicted activity in the inferior frontal cortex (IFC). Although significant differences were found in neither the scores obtained on impulsivity-related questionnaires nor the behavioral data, the LL group displayed increased dlPFC activity during nogo trials and the predicted activation in the IFC during successful inhibition in the stop-signal task, while no significant activation was found in the SS group. Our data confirm an influence of NOS1 ex1f-VNTR on impulsivity, as carriers of the short risk allele exhibited diminished activity of (pre-)frontal brain regions during the inhibition in a stop-signal task. Impairment of prefrontal control with consecutive failure of inhibitory processes might underlie association findings reported previously. Hum Brain Mapp, 2011. © 2011 Wiley-Liss, Inc.

• DIRAS2 is associated with adult ADHD, related traits, and co-morbid disorders.

  Authors: Andreas Reif, T Trang Nguyen, Lena Weissflog, Christian P Jacob, Marcel Romanos, Tobias J Renner, Henriette N Buttenschon, Sarah Kittel-Schneider, Alexandra Gessner, Heike Weber [......] Jessie Mahler, Alexander Teumer, Henry Völzke, Ole N Mors, Helmut Schäfer, Josep Antoni Ramos-Quiroga, Bru Cormand, Jan Haavik, Barbara Franke, Klaus-Peter Lesch

  Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 07/2011; 36(11):2318-27.

  Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locusSeveral linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008-0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.

• Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: a meta-analysis in four European populations.

  Authors: Cristina Sánchez-Mora, Marta Ribasés, Miquel Casas, Mònica Bayés, Rosa Bosch, Noelia Fernàndez-Castillo, Lucas Brunso, Kaya K Jacobsen, Elisabeth T Landaas, Astri J Lundervold [......] J J Sandra Kooij, Eric Mick, Phil Asherson, Stephen V Faraone, Barbara Franke, Andreas Reif, Stefan Johansson, Jan Haavik, Josep Antoni Ramos-Quiroga, Bru Cormand

  American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 07/2011; 156B(5):600-12.

  Attention-deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting about 4-8% of children. ADHD persists into adulthood in around 65% of cases, either as the full condition orAttention-deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting about 4-8% of children. ADHD persists into adulthood in around 65% of cases, either as the full condition or in partial remission with persistence of symptoms. Pharmacological, animal and molecular genetic studies support a role for genes of the dopaminergic system in ADHD due to its essential role in motor control, cognition, emotion, and reward. Based on these data, we analyzed two functional polymorphisms within the DRD4 gene (120 bp duplication in the promoter and 48 bp VNTR in exon 3) in a clinical sample of 1,608 adult ADHD patients and 2,352 controls of Caucasian origin from four European countries that had been recruited in the context of the International Multicentre persistent ADHD CollaboraTion (IMpACT). Single-marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiple-marker meta-analysis showed a nominal association (P = 0.02) of the L-4R haplotype (dup120bp-48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. Since we previously described association between adulthood ADHD and the dopamine transporter SLC6A3 9R-6R haplotype (3'UTR VNTR-intron 8 VNTR) in the same dataset, we further tested for gene × gene interaction between DRD4 and SLC6A3. However, we detected no epistatic effects but our results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene.