Laboratory for Molecular Genetics

In the Laboratory of Molecular Genetics we investigate whether and in what way genetic variations influence the development and expression of neuropsychiatric disorders, in particular autism spectrum disorder, ADHD, conduct disorder and anxiety disorder. Among other things, we analyse how common and rare genetic markers such as single nucleotide polymorphisms and copy number variants or how epigenetic patterns influence the risk and severity of the respective disorders. To further understand the functional aspects of potential risk factors, we investigate their mechanistic effects in neuronal cell models. By integrating knowledge from the neuronal cell models and the genetic markers of patients, we aim to generate a more comprehensive understanding of the underlying pathomechanisms, which will ultimately serve to identify and characterize clinically relevant biomarkers.

Selected publications

Research projects

Team

Yousaf A, Waltes R, Haslinger D, Klauck SM, Duketis E, Sachse M, Voran A, Biscaldi M, Schulte-Rüther M, Cichon S, Nöthen M, Ackermann J, Koch I, Freitag CM, Chiocchetti AG. Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder. Transl Psychiatry. 2020 Jul 5;10(1):215. https://doi.org/10.1038/s41398-020-00906-2

Doan RN, Lim ET, De Rubeis S, Betancur C, Cutler DJ, Chiocchetti AG, Overman LM, Soucy A, Goetze S; Autism Sequencing Consortium, Freitag CM, Daly MJ, Walsh CA, Buxbaum JD, Yu TW. Recessive gene disruptions in autism spectrum disorder. Nat Genet. 2019 Jul;51(7):1092-1098. https://doi.org/10.1038/s41588-019-0433-8

Waltes R, Freitag CM, Herlt T, Lempp T, Seitz C, Palmason H, Meyer J, Chiocchetti AG. Impact of autism-associated genetic variants in interaction with environmental factors on ADHD comorbidities: an exploratory pilot study. J Neural Transm (Vienna). 2019 Dec;126(12):1679-1693. https://doi.org/10.1007/s00702-019-02101-0

Haslinger D, Waltes R, Yousaf A, Lindlar S, Schneider I, Lim CK, Tsai MM, Garvalov BK, Acker-Palmer A, Krezdorn N, Rotter B, Acker T, Guillemin GJ, Fulda S, Freitag CM, Chiocchetti AG. Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model. Mol Autism. 2018 Nov 6;9:56. https://doi.org/10.1186/s13229-018-0239-z 

Chiocchetti AG, Yousaf A, Bour HS, Haslinger D, Waltes R, Duketis E, Jarczok T, Sachse M, Biscaldi M, Degenhardt F, Herms S, Cichon S, Ackermann J, Koch I, Klauck SM, Freitag CM. Common functional variants of the glutamatergic system in Autism spectrum disorder with high and low intellectual abilities. J Neural Transm (Vienna). 2018 Feb;125(2):259-271. https://doi.org/10.1007/s00702-017-1813-9 . Epub 2017 Nov 16.

Chiocchetti AG, Haslinger D, Stein JL, de la Torre-Ubieta L, Cocchi E, Rothämel T, Lindlar S, Waltes R, Fulda S, Geschwind DH, Freitag CM. Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders. Transl Psychiatry. 2016 Aug 2;6(8):e864. https://doi.org/10.1038/tp.2016.119

Waltes R, Chiocchetti AG, Freitag CM. The neurobiological basis of human aggression: A review on genetic and epigenetic mechanisms. Am J Med Genet B Neuropsychiatr Genet. 2016 Jul;171(5):650-75. https://doi.org/10.1002/ajmg.b.32388

Chiocchetti AG, Kopp M, Waltes R, Haslinger D, Duketis E, Jarczok TA, Poustka F, Voran A, Graab U, Meyer J, Klauck SM, Fulda S, Freitag CM. Variants of the CNTNAP2 5' promoter as risk factors for autism spectrum disorders: a genetic and functional approach. Mol Psychiatry. 2015 Jul;20(7):839-49. https://doi.org/10.1038/mp.2014.103

The list of the respective publications can be viewed via Researchgate or pubmed under the names of the respective researchers.

• EU-funded AIMS-2-TRIALS project to develop tailored therapies for people with autism spectrum disorders
• Functional analysis of autism associated QPRT deletions in the 16p11 locus.
• Validation and characterisation of gene copy polymorphisms in autism in a German cohort.
• Genome-wide association of common polymorphisms with autistic phenotypes: a systems biology study
• Variants of genes of the glutamatergic system as risk factors for ASD.
• EU-funded project FemNAT-CD: Research on social behaviour disorders; genetic and epigenetic markers as risk factors for social behaviour disorders in girls
• Induced pluripotent stem cells as an in-vitro model system of neuronal development
• Characterisation of genetic variants of the MAOA promoter associated with neuropsychiatric disorders during neuronal differentiation.
• ADHD gene-environment interaction study.
• BMBF-funded STAR project "Self-Injury: Treatment, Assessment, Recovery". Sub-project for the identification of genetic risk factors for self-harming behaviour.
• LOEWE-funded project CePTER (Center for personalized and translational epilepsy research) Subproject for the identification and functional characterization of genetic mutations in epilepsy
• BMBF-funded project "RAISE-GENIC" (Rational antiepileptic drug selection by combining gene network and ICT analyses)
• Establishment of a bioinformatics pipeline MAGNET (Mapping the genetics of neuropsychiatric traits to the molecular NETworks of the human brain) to better understand the genetic etiology of a neuropsychiatric trait

One of the most common copy number variations in autism is on chromosome 16p11.2 and involves ~25 genes. Through data from previous studies, we were able to show that one of these genes, QPRT (quinolinate phosphoribosyltransferase), plays a central role during neuronal development. In this study, we investigate the molecular genetic effect of QPRT on neuronal development to obtain a better model of the aetiology of autism. This project is partly conducted in collaboration with Gilles Guillemin and Edwin Lim of Macquarie University Sydney, Australia.

Further information: Denise.Haslinger[at]kgu.de

Gene copy number variations, particularly deletions, affect regions with genes more frequently in patients with autism than in healthy controls. In our cohort we want to replicate this finding and investigate de novo duplications and deletions in relation to clinical appearance in more detail. In doing so, we can draw on a nationally unique cohort of families with autism patients who have been recruited nationwide in years of close cooperation with patients, relatives and clinics.

Further information: Andreas.Chiocchetti[at]kgu.de

Common genetic variants explain up to 50% of the genetic risk in autism. However, it is still unclear to what extent these variants also influence the expression of autistic phenotypes and which biological networks are particularly relevant in this context. In this genome-wide study we test common single nucleotide polymorphisms for association with clinical measures of autism diagnosis and identify the underlying genes. Bioinformatic and graph-theoretical analyses enable us to identify specific processes. We also draw on our unique cohort of families with autism patients, and emphasize the close cooperation with patients, relatives and clinics over many years, and the analysis and validation of the results is based on data from the Autism Genome Project and the SFARI Autism Initiative.

Further information: Afsheen.Yousaf[at]kgu.de

Variants in genes encoding proteins of the glutamatergic pathway are discussed as risk factors for autism. We also draw on our nationwide unique cohort of families with autism, and would like to thank them for the many years of close cooperation, relatives and clinics. The aim of this study is to investigate the modulatory effect of common genetic polymorphisms in these genes on autism specific clinical features.

Further information: Andreas.Chiocchetti[at]kgu.de

Our clinic is currently conducting a Europe-wide study to investigate conduct disorder (CD) in girls. Special focus of this study is on emotion processing, neurobiology and therapy of CD. This disorder can have a negative influence on the development and well-being of affected children and adolescents as well as their families, caregivers and teachers. However, previous research has mostly focused on the investigation of causes, course and treatment options in boys with CD. Although CD is more common in boys than in girls, about one to three percent of girls also suffer from it, and the number of girls with CD in Western societies such as the EU has increased significantly in recent years. A total of 17 research institutes from eight EU countries are participating in this large-scale study. The aim of the study is to gain a better understanding of CD and to identify possible differences between boys and girls with CD and healthy control subjects in order to develop improved treatment options.

The molecular genetics laboratory investigates which genetic and epigenetic factors in girls influence the risk of CD and whether these factors correspond to the risk factors described for boys. On the one hand, we investigate the effect of environmental factors such as smoking during pregnancy in interaction with known genetic variants as a cause of CD. On the other hand, we are looking for patterns of differential DNA methylation (epigenetics) in patients and healthy girls across the genome.

Further information: Andreas.Chiocchetti[at]kgu.de

In order to be able to study the development of human neurons, and in particular to be able to reproduce the neuronal development of a specific person, we use induced pluripotent stem cells. In close cooperation with the Department of Psychiatry, we are currently building up a standardised pipeline in order to be able to use this in future experiments. The aim is to study the development of glutamatergic and dopaminergic neurons of study participants with presumably disease-relevant gene mutations in order to understand the pathomechanism and to gain new insights for the development of personalised therapies.

Further information: Denise.Haslinger[at]kgu.de

MAOA is the central katabolic enzyme of serotonin, dopamine and norepinephrine. Repeated sequences in the promoter of MAOA increase the expression of the gene and have often been associated with neuropsychiatric disorders. However, the functional effect of the number of repeats has not yet been clearly established in the literature and it is not clear whether and when these variants play a role during neuronal development. Therefore, in this study we investigate the activity of the promoter during neuronal differentiation in human neuronal cells.

Further information: Andreas.Chiocchetti[at]kgu.de

Genetic and environmental risk factors for ADHD have previously been identified. However, little research has been done on the interaction of the two factors. Here we are investigating how risk-factors already described, such as smoking or alcohol consumption during pregnancy, are influenced by ADHD or autism associated genetic variants and change the risk of ADHD and ADHD-specific comorbid diseases.

Further information: Regina.Waltes[at]kgu.de

The STAR project aims to identify the factors that contribute to risk, prevention or recovery from non-suicidal self-injurious behaviour. The Molecular Genetics Laboratory is focusing on the genetic factors that can influence the reward system and the pain system in the brain. In particular, we test whether variants of the relevant genes could be related to behaviour and the success of therapy.

Further information: Andreas.Chiocchetti[at]kgu.de

The CePTER research network is concerned with improving the success of epilepsy therapy in the sense of precision medicine, i.e. the development of personalised and, if possible, disease-modifying rather than merely symptomatic treatment. In our subproject we use next generation sequencing technologies to identify relevant mutations in epilepsies and investigate their effect functionally in a neuronal cell model. We are particularly interested in the role of the DEPDC5 gene, which is associated with both epilepsy and autism spectrum disorders.

Further information: Mattson.Jones[at]kgu.de

The RAISE-GENIC research network aims to identify models that allow to predict the drug therapy with the best chances of success for individual epilepsy patients for an individualised selection of anti-epileptic drugs. In our sub-project we analyse RNA expression data of drug treated cells and DNA sequencing data of affected patients and carry out the bioinformatic evaluation of the transcriptome networks and their processing for big-data and machine learning analyses.

Further information: Andreas.birth-Chiocchetti[at]kgu.de

We developed MAGNET to characterise phenotype and genotype relationships and to identify significantly associated variants. Variants can then be mapped to their respective genes and comprehensive information on their function and regulated pathways can be provided. Furthermore, by implementing gene expression data, associated genes can be assigned to developmental stages in the human brain and subsequently be mapped to the respective gene interaction network.

FP7 EU-Project FemNAT-CD No no. 602407 an Christine M. Freitag, (Exp 02 2018)

IMI2 AIMS-2-TRIALS to Christine M. Freitag, Christine Ecker, Andreas G. Chiocchetti [Koordinator Declan Murphy UK]

LOEWE CEPTER to Andreas G. Chiocchetti und Karl Martin Klein  [Coordinator Felix Rosenow, Neurology Uniklinikum Frankfurt]

RAISE-GENIC to Andreas G. Chiocchetti
[Coordinator Felix Rosenow, Neurologie Uniklinikum Frankfurt]

BMBF Projekt STAR; Part Project STAR-NEURO to Christian Schmal, Subtask to Andreas G. Chiocchetti [Koordinator Paul Plener, Ulm]

Paul und Cillie Weill Nachwuchsforscherpreis 2016 to AG Chiocchetti.