OPUS 4 | Universitätspublikationen

Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders (2012)

Claire S. Leblond Jutta Heinrich Richard Delorme Christian Proepper Catalina Betancur Guillaume Huguet Marina Konyukh Pauline Chaste Elodie Ey Maria Rastam Henrik Anckarsäter Gudrun Nygren I. Carina Gillberg Jonas Melke Roberto Toro Beatrice Regnault Fabien Fauchereau Oriane Mercati Nathalie Lemière David Skuse Martin Poot Richard Holt Anthony P. Monaco Irma Järvelä Katri Kantojärvi Raija Vanhala Sarah Curran David A. Collier Patrick Bolton Andreas Chiocchetti Sabine M. Klauck Fritz Poustka Christine M. Freitag Regina Waltes Marnie Kopp Eftichia Duketis Elena Bacchelli Fiorella Minopoli Liliana Ruta Agatino Battaglia Luigi Mazzone Elena Maestrini Ana F. Sequeira Barbara Oliveira Astrid Vicente Guiomar Oliveira Dalila Pinto Stephen W. Scherer Diana Zelenika Marc Delepine Mark Lathrop Dominique Bonneau Vincent Guinchat Françoise Devillard Brigitte Assouline Marie-Christine Mouren Marion Leboyer Christopher Gillberg Tobias M. Boeckers Thomas Bourgeron

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Autistic traits and autism spectrum disorders: the clinical validity of two measures presuming a continuum of social communication skills (2010)

Sven Bölte Eva Westerwald Martin Holtmann Christine M. Freitag Fritz Poustka

Research indicates that autism is the extreme end of a continuously distributed trait. The Social Responsiveness Scale (SRS) and the Social and Communication Disorders Checklist (SCDC) aim to assess autistic traits. The objective of this study was to compare their clinical validity. The SRS showed sensitivities of .74 to .80 and specificities of .69 to 1.00 for autism. Sensitivities were .85 to .90 and specificities .28 to.82 for the SCDC. Correlations with the ADI-R, ADOS and SCQ were higher for the SRS than for the SCDC. The SCDC seems superior to the SRS to screen for unspecific social and communicative deficits including autism. The SRS appears more suitable than the SCDC in clinical settings and for specific autism screening.

Peer-victimization and mental health problems in adolescents: are parental and school support protective? (2010)

Christina Stadler Julia Feifel Sonja Rohrmann Robert Vermeiren Fritz Poustka

The aim of this study was to investigate the frequency and effects of peer-victimization on mental health problems among adolescents. Parental and school support were assumed as protective factors that might interact with one another in acting as buffers for adolescents against the risk of peer-victimization. Besides these protective factors, age and gender were additionally considered as moderating factors. The Social and Health Assessment survey was conducted among 986 students aged 11-18 years in order to assess peer-victimization, risk and protective factors and mental health problems. For mental health problems, the Strengths and Difficulties Questionnaire (SDQ) was used. Effects of peer-victimization on mental health problems were additionally compared with normative SDQ data in order to obtain information about clinically relevant psychopathology in our study sample. Results of this study show that peer-victimization carries a serious risk for mental health problems in adolescents. School support is effective in both male and female adolescents by acting as a buffer against the effect of victimization, and school support gains increasing importance in more senior students. Parental support seems to be protective against maladjustment, especially in peer-victimized girls entering secondary school. Since the effect of peer-victimization can be reduced by parental and school support, educational interventions are of great importance in cases of peer-victimization.

Differences in zinc status and the leptin axis in anorexic and recovered adolescents and young adults: a pilot study (2012)

Florian Daniel Zepf Idil Sungurtekin Franziska Glass Linda Elstrodt Dirk Peetz Gudrun Hintereder Jürgen Kratzsch Caroline Sarah Biskup Fritz Poustka Lars Wöckel

Background: Evidence from animal studies suggests that leptin metabolism is associated with zinc (Zn) status. However, research investigating this relationship in adolescents and young adults with anorexia nervosa (AN) is scarce; the present study aims to fill that gap. Methods: Serum concentrations of leptin, the soluble leptin receptor (sOB-R) and the free leptin index (FLI) were obtained in healthy control subjects (n=19), acutely ill individuals (n=14) and recovered patients with AN (n=15). Serum Zn concentrations noted in previous research data were also incorporated for all groups. Results: Leptin, FLI and Zn concentrations were higher in recovered subjects with AN when compared with acutely ill AN patients. Remitted patients showed higher sOB-R concentrations but no difference in FLI compared with the control group. Leptin and FLI were lower in the acutely ill patients compared with the control subjects, who showed no differences in Zn concentrations. Zn concentrations were not correlated with leptin, sOB-R or FLI concentrations in any of the three investigated subgroups. Conclusions: The present investigation does not entirely support an association between Zn, Leptin and FLI concentrations in subjects with AN, possibly due to limited statistical power. Further research and replication of the present findings related to the interaction between leptin and Zn is warranted. However, with respect to serum leptin levels the data of the present investigation indicate that acutely ill and remitted patients with AN differ as regards serum leptin concentrations and FLI, which is in line with previous research.

Individual common variants exert weak effects on the risk for autism spectrum disorders (2012)

Richard Anney Lambertus Klei Dalila Pinto Joana Almeida Elena Bacchelli Gillian Baird Nadia Bolshakova Sven Bölte Patrick F. Bolton Thomas Bourgeron Sean Brennan Jessica Brian Jillian Casey Judith Conroy Catarina Correia Christina Corsello Emily L. Crawford Maretha de Jonge Richard Delorme Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A. Fernandez Susan E. Folstein Eric Fombonne John Gilbert Christopher Gillberg Joseph T. Glessner Andrew Green Jonathan Green Stephen J. Guter Elizabeth A. Heron Richard Holt Jennifer L. Howe Gillian Hughes Vanessa Hus Roberta Igliozzi Suma Jacob Graham P. Kenny Cecilia Kim Alexander Kolevzon Vlad Kustanovich Clara M. Lajonchere Janine A. Lamb Miriam Law-Smith Marion Leboyer Ann Le Couteur Bennett L. Leventhal Xiao-Qing Liu Frances Lombard Catherine Lord Linda Lotspeich Linda Lotspeich Sabata C. Lund Tiago R. Magalhaes Carine Mantoulan Christopher J. McDougle Nadine M. Melhem Alison Merikangas Nancy J. Minshew Ghazala K. Mirza Jeff Munson Carolyn Noakes Gudrun Nygren Katerina Papanikolaou Alistair T. Pagnamenta Barbara Parrini Tara Paton Tara Paton Andrew Pickles David J. Posey Fritz Poustka Jiannis Ragoussis Regina Regan Wendy Roberts Kathryn Roeder Bernadette Roge Michael L. Rutter Sabine Schlitt Naisha Shah Val C. Sheffield Latha Soorya Inês Sousa Vera Stoppioni Nuala Sykes Raffaella Tancredi Ann P. Thompson Susanne Thomson Ana Tryfon John Tsiantis Herman Van Engeland John B. Vincent Fred Volkmar JAS Vorstman Simon Wallace Kirsty Wing Kerstin Wittemeyer Shawn Wood Danielle Zurawiecki Lonnie Zwaigenbaum Anthony J. Bailey Agatino Battaglia Rita M. Cantor Hilary Coon Michael L. Cuccaro Geraldine Dawson Sean Ennis Christine M. Freitag Daniel H. Geschwind Jonathan L. Haines Sabine M. Klauck William M. McMahon Elena Maestrini Judith Miller Anthony P. Monaco Stanley F. Nelson John I. Nurnberger Guiomar Oliveira Jeremy R. Parr Margaret A. Pericak-Vance Joseph Piven Gerard D. Schellenberg Stephen W. Scherer Astrid M. Vicente Thomas H. Wassink Ellen M. Wijsman Catalina Betancur Joseph D. Buxbaum Edwin H. Cook Louise Gallagher Michael Gill Joachim Hallmayer Andrew D. Paterson James S. Sutcliffe Peter Szatmari Veronica J. Vieland Hakon Hakonarson Bernie Devlin

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Brief report: the level and nature of autistic intelligence revisited (2009)

Sven Bölte Isabel Dziobek Fritz Poustka

Owing to higher performance on the Raven’s Progressive Matrices (RPM) than on the Wechsler Intelligence Scales (WIS), it has recently been argued that intelligence is underestimated in autism. This study examined RPM and WIS IQs in 48 individuals with autism, a mixed clinical (n = 28) and a neurotypical (n = 25) control group. Average RPM IQ was higher than WIS IQ only in the autism group, albeit to a much lesser degree than previously reported and only for individuals with WIS IQs <85. Consequently, and given the importance of reliable multidimensional IQ estimates in autism, the WIS are recommended as first choice IQ measure in high functioning individuals. Additional testing with the RPM might be required in the lower end of the spectrum.

Polymorphisms in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in populations of European ancestry (2010)

Inês Sousa Taane Gregrory Clark Richard Holt Alistair T. Pagnamenta Erik J. Mulder Ruud B. Minderaa Anthony J. Bailey Agatino Battaglia Sabine Klauck Fritz Poustka Anthony P. Monaco

Background: Autism spectrum disorders (ASDs) are a group of highly heritable neurodevelopmental disorders which are characteristically comprised of impairments in social interaction, communication and restricted interests/behaviours. Several cell adhesion transmembrane leucine-rich repeat (LRR) proteins are highly expressed in the nervous system and are thought to be key regulators of its development. Here we present an association study analysing the roles of four promising candidate genes - LRRTM1 (2p), LRRTM3 (10q), LRRN1 (3p) and LRRN3 (7q) - in order to identify common genetic risk factors underlying ASDs. Methods: In order to gain a better understanding of how the genetic variation within these four gene regions may influence susceptibility to ASDs, a family-based association study was undertaken in 661 families of European ancestry selected from four different ASD cohorts. In addition, a case-control study was undertaken across the four LRR genes, using logistic regression in probands with ASD of each population against 295 ECACC controls. Results: Significant results were found for LRRN3 and LRRTM3 (P< 0.005), using both single locus and haplotype approaches. These results were further supported by a case-control analysis, which also highlighted additional SNPs in LRRTM3. Conclusions: Overall, our findings implicate the neuronal leucine-rich genes LRRN3 and LRRTM3 in ASD susceptibility.

A genome-wide scan for common alleles affecting risk for autism (2010)

Richard Anney Lambertus Klei Dalila Pinto Regina Regan Judith Conroy Tiago R. Magalhaes Catarina Correia Brett S. Abrahams Nuala Sykes Alistair T. Pagnamenta Joana Almeida Elena Bacchelli Anthony J. Bailey Gillian Baird Agatino Battaglia Tom Berney Nadia Bolshakova Sven Bölte Patrick F. Bolton Thomas Bourgeron Sean Brennan Jessica Brian Andrew R. Carson Guillermo Casallo Jillian Casey Su H. Chu Lynne Cochrane Christina Corsello Emily L. Crawford Andrew Crossett Geraldine Dawson Maretha de Jonge Richard Delorme Irene Drmic Eftichia Duketis Frederico Duque Annette Estes Penny Farrar Bridget A. Fernandez Susan E. Folstein Eric Fombonne Christine M. Freitag John Gilbert Christopher Gillberg Joseph T. Glessner Jeremy Goldberg Jonathan Green Stephen J. Guter Hakon Hakonarson Elizabeth A. Heron Matthew Hill Richard Holt Jennifer L. Howe Gillian Hughes Vanessa Hus Roberta Igliozzi Cecilia Kim Sabine M. Klauck Alexander Kolevzon Olena Korvatska Vlad Kustanovich Clara M. Lajonchere Janine A. Lamb Magdalena Laskawiec Marion Leboyer Ann Le Couteur Bennett L. Leventhal Anath C. Lionel Xiao-Qing Liu Catherine Lord Linda Lotspeich Sabata C. Lund Elena Maestrini William Mahoney Carine Mantoulan Christian R. Marshall Helen McConachie Christopher J. McDougle Jane McGrath William M. McMahon Nadine M. Melhem Alison Merikangas Ohsuke Migita Nancy J. Minshew Ghazala K. Mirza Jeff Munson Stanley F. Nelson Carolyn Noakes Abdul Noor Gudrun Nygren Guiomar Oliveira Katerina Papanikolaou Jeremy R. Parr Barbara Parrini Tara Paton Andrew Pickles Joseph Piven David J. Posey Annemarie Poustka Fritz Poustka Aparna Prasad Jiannis Ragoussis Katy Renshaw Jessica Rickaby Wendy Roberts Kathryn Roeder Bernadette Roge Michael L. Rutter Laura J. Bierut John P. Rice Jeff Salt Katherine Sansom Daisuke Sato Ricardo Segurado Lili Senman Naisha Shah Val C. Sheffield Latha Soorya Ines Sousa Vera Stoppioni Christina Strawbridge Raffaella Tancredi Katherine Tansey Bhooma Thiruvahindrapduram Ann P. Thompson Susanne Thomson Ana Tryfon John Tsiantis Herman Van Engeland John B. Vincent Fred Volkmar Simon Wallace Kai Wang Zhouzhi Wang Thomas H. Wassink Kirsty Wing Kerstin Wittemeyer Shawn Wood Brian L. Yaspan Danielle Zurawieck Lonnie Zwaigenbaum Catalina Betancur Joseph D. Buxbaum Rita M. Cantor Edwin H. Cook Hilary Coon Michael L. Cuccaro Louise Gallagher Daniel H. Geschwind Michael Gill Jonathan L. Haines Judith Miller Anthony P. Monaco John I. Jr. Nurnberger Andrew D. Paterson Margaret A. Pericak-Vance Gerard D. Schellenberg Stephen W. Scherer James S. Sutcliffe Peter Szatmari Astrid M. Vicente Veronica J. Vieland Ellen M. Wijsman Bernie Devlin Sean Ennis Joachim Hallmayer

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 3 10 exp -8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner’s curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 3 10 exp -8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

The heterogeneity of disruptive behaviour disorders – implications for neurobiological research and treatment (2010)

Christina Stadler Fritz Poustka Philipp Sterzer

Disruptive behaviour disorders are reflected by a great variety of symptoms ranging from impulsive-hot tempered quarrels to purposeful and goal directed acts of cruelty. A growing body of data indicates that there are neurobiological factors that increase the risk for developing disruptive behaviour disorders. In this review, we give a broad overview of recent studies investigating physiological, neural, genetic factors, and specific neurotransmitter systems. We also discuss the impact of psychosocial risk and consider the effects of gene-environment interactions. Due to the heterogeneity of disruptive behaviour disorders, it is concluded that specific subtypes of disruptive behaviour should be considered both in terms their biological basis and in regard to specific treatment needs.

Cognitive behavioral therapy of socially phobic children focusing on cognition: a randomised wait-list control study (2011)

Siebke Melfsen Martina Kühnemund Judith Schwieger Andreas Warnke Christina Stadler Fritz Poustka Ulrich Stangier

Background: Although literature provides support for cognitive behavioral therapy (CBT) as an efficacious intervention for social phobia, more research is needed to improve treatments for children. Methods: Forty four Caucasian children (ages 8-14) meeting diagnostic criteria of social phobia according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; APA, 1994) were randomly allocated to either a newly developed CBT program focusing on cognition according to the model of Clark and Wells (n = 21) or a wait-list control group (n = 23). The primary outcome measure was clinical improvement. Secondary outcomes included improvements in anxiety coping, dysfunctional cognitions, interaction frequency and comorbid symptoms. Outcome measures included child report and clinican completed measures as well as a diagnostic interview. Results: Significant differences between treatment participants (4 dropouts) and controls (2 dropouts) were observed at post test on the German version of the Social Phobia and Anxiety Inventory for Children. Furthermore, in the treatment group, significantly more children were free of diagnosis than in wait-list group at post-test. Additional child completed and clinician completed measures support the results. Discussion: The study is a first step towards investigating whether CBT focusing on cognition is efficacious in treating children with social phobia. Future research will need to compare this treatment to an active treatment group. There remain the questions of whether the effect of the treatment is specific to the disorder and whether the underlying theoretical model is adequate. Conclusion: Preliminary support is provided for the efficacy of the cognitive behavioral treatment focusing on cognition in socially phobic children. Active comparators should be established with other evidence-based CBT programs for anxiety disorders, which differ significantly in their dosage and type of cognitive interventions from those of the manual under evaluation (e.g. Coping Cat).

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