Meten van kenmerken van autismespectrumstoornissen in gezinnen: een zoektocht naar informatieve fenotypes

Abstract

Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders defined by impairments in social communication and social interaction and by a restricted and repetitive pattern of behaviour and interests with a strong genetic basis. Finding genetic causes of ASDs has been complicated by both genotypic and phenotypic heterogeneity. To overcome these kinds of problems in psychiatry genetics, the concept of endophenotypes, traits that are thought to be intermediate between genes and phenotype, was introduced. In 2007 this concept was broadened to (genetically) informative phenotypes, with three subtypes, each with specific characteristics and ways in which they can be genetically informative. These phenotypes can be of biological, cognitive or behavioural nature. Criteria that should be met for some of these subtypes are, e.g., that it should segregate with the disorder, that it can be measured reliably, and that is present in unaffected family members at a higher frequency than in the general population. In this doctoral dissertation, we describe different studies that aim at defining candidate informative phenotypes for ASDs, focusing on behavioural characteristics in participants with an ASD and their unaffected relatives. All the analyses were based on datanbsp;in 170 families with at least one childnbsp;an ASD. A series of factor analyses on Developmental, Dimensional and Diagnostic Interview (3di) data from participants with an ASD results in a five dimensions solution (Chapter 2). The presence of these underlying constructs cannot be confirmed on 3di data of their unaffected siblings, and the same conclusion resulted from analyses on Social Responsiveness Scale (SRS) data. Based on these results, we conclude that clinical and research instruments that measure ASD traits result in different underlying symptom dimensions in ASD vs. non-ASD samples, and consequently, scores on separate symptom dimensions based on the clinical phenotype in ASD are not readily applicable as informative phenotypes in non-ASD samples (Chapter 3). Another way of searching for informative phenotypes is by studying whether behavioural characteristics of individuals with an ASD are also present in their unaffected relatives. In Chapter 4 we report about atypical sensory processing in adolescents with an ASD using the Adolescent/Adult Sensory Profile. Their unaffected adolescent siblings show a level of sensation seeking that is intermediate between adolescents with an ASD and general population controls. We conclude that, although more research is definitely needed, Sensation Seeking may be a candidate genetically informative phenotype. In a similar vein, we study quantitative autism traits (QAT) as measured by the Social Responsiveness Scale (SRS) of all participating family members. Based on comparisons of SRS total scores of participants with an ASD, their unaffected family members and general population controls, we demonstrate that fathers of children with an ASD show a higher level of QAT compared to controls (Chapter 5). In Chapter 6 we describe the association of QAT levels between family members. These results corroborate the assortative mating theory and possible intergenerational transmission of QAT from both fathers and mothers to their offspring. Combining our results and those of other studies, we can conclude that QAT measures, e.g., the SRS, may serve as a genetically informative phenotype. In our general discussion, the methodological difficulties about the informative phenotype concept are thoroughly discussed. In short, we propose to use the umbrella term genetically informative phenotype, when studying behavioural characteristics in genetic research, since the use of subtypes leads to discussions about terminology, that may be contra productive for further research. Based on our analyses and results, but also on the questions we came across carrying out our studies, we also highlight important methodological issues for both researchers and clinicians. For ASD family studies, a thorough diagnostic screening of all family members appears to be very important since false allocation to an unaffected status can have major consequence on the results. For clinical practice, many questionnaires and interviews have been developed for screening and diagnostic assessment purposes. We discuss however, that clinicians should be aware that the context in which they are used, e.g., screening vs. diagnostic assessment in a psychiatric context vs. family research, can have great influence on their reliability.Dankwoord Summary - Samenvatting Table of content Chapter 1: General introduction 1. Autism spectrum disorders 1.1. Classification and clinical picture 1.2. Epidemiology 1.3. Aetiology 1.3.1. Twin and family studies 1.3.2. Genetics of ASDs 1.3.3. Environmental factors contributing to ASDs 1.3.4. Estimation of recurrence risk 1.3.5. Solutions to overcome the heterogeneity in research 1.4. Informative phenotypes 1.4.1. History of the concept 1.4.2. Component phenotype 1.4.3. Intermediate phenotype 1.4.4. Covariate 1.4.5. Difficulties in the search for informative phenotypes 1.5. Broad autism phenotype 1.6. Quantitative autism traits in the general population 1.7. Conclusion 2. Aims of this PhD research 2.1. To search for candidate informative phenotypes for ASD 2.1.1. Social and communicative reciprocity 2.1.2. Constructs underlying the categorical ASD phenotype 2.1.3. Symptoms of sensory hyper- and/or hyposensitivity 2.2. To search for patterns of familial transmission of QAT in ASD families 2.3. To define individual and familial characteristics that influence both the presence and transmission of these traits 2.3.1. Gender 2.3.2. Relation to the child with an ASD 2.3.3. Type of family: simplex vs. multiplex 3. Methodology of the PhD research 3.1. Ethical approval 3.2. Participants 3.3. Instruments and procedures 3.3.1. Sensory Profile (SP) and Adult and Adolescent Sensory Profile 3.3.2. Developmental, Dimensional and Diagnostic Interview 3.3.3. Other procedures References Chapter 2: The underlying symptom structure of autism spectrum disorders: A factor analytic approach using the Developmental, Dimensional and Diagnostic Interview Abstract 1. Introduction 2. Methods 2.1. Participants 2.2. Instruments 2.3. Statistical analyses 3. Results 3.1. Confirmatory factor analyses 3.2. Exploratory factor analyses 4. Discussion 5. Conclusion Acknowledgements References Chapter 3: No replication of the autism spectrum disorder symptom structure in unaffected siblings Abstract 1. Introduction 2. Methods 3. Results 4. Additional analyses and results 5. Conclusion References Chapter 4: Atypical sensory processing in adolescents with an autism spectrum disorder and their non-affected siblings Abstract 1. Introduction 2. Methods 2.1. Sample 2.1.1. Participants with an ASD and siblings 2.1.2. Controls 2.1.3. Total sample 2.2. Measures 2.2.1. Adolescent/Adult Sensory Profile (AASP) 2.2.2. Developmental, Dimensional and Diagnostic Interview (3di) 2.2.3. Social Responsiveness Scale (SRS) 2.3. Statistical analyses 3. Results 4. Discussion 4.1. Limitations 4.2. Clinical Implications 5. Conclusion Acknowledgements References Chapter 5: Quantitative autism traits in first degree relatives: Evidence for the broader autism phenotype in fathers, but not in mothers and siblings Abstract 1. Introduction 1.1. Aims of the study 2. Methods 2.1. Research population 2.1.1. Children with an ASD, their siblings and parents 2.1.2. General population controls 2.1.3. Adults with an ASD 2.1.4. Total sample 2.2. Instruments 2.2.1. Social Responsiveness Scale (SRS) 2.2.2. Developmental, Dimensional and Diagnostic Interview (3di) 2.3. Statistical analysis 3. Results 3.1. Children 3.2. Adults 4. Discussion 4.1. Children 4.2. Adults 4.3. Limitations 5. Conclusion Acknowledgements References Chapter 6: Measuring quantitative autism traits in families: Informant effect or intergenerational transmission? Abstract 1. Introduction 2. Methods 2.1. Participants 2.2. Instruments 2.2.1. Social Responsiveness Scale (SRS) 2.3. Statistical analyses 3. Results 3.1. Do mother, father and teacher reports yield similar SRS ratings for children? 3.2. Do self- and other-reports yield similar SRS ratings for adults? 3.3. How are parental and offspring QAT related in ASD families, while accounting for possible informant effects? 4. Discussion 4.1. Inter-informant agreement in children 4.2. Inter-informant agreement in adults 4.3. Relatedness of parental and offspring QAT in families, accounting for informant effects 4.4. Limitations 5. Conclusion Acknowledgments References Chapter 7: General discussion 1. Background and research goals 2. Answers to our research questions 2.1. Candidate informative phenotypes? 2.1.1. A milder expression of ASD traits: evidence for the Broader Autism Phenotype in fathers but not in mothers and siblings 2.1.2. Constructs underlying the categorical ASD phenotype 2.1.3. Symptoms of sensory hyper- and/or hyposensitivity: Sensation Seeking as a candidate informative phenotype. 2.2. Familial transmission of QAT? 2.3. Patient and family characteristics that influence both the presence and transmission of the possible informative phenotypes presented earlier 2.3.1. Influence on the BAP in unaffected family members 2.3.2. Influence on atypical sensory processing in unaffected family members 2.3.3. Influence on familial transmission of QAT 2.4. Building an interesting database of well phenotyped ASD families for further research 2.5. Conclusions 2.6. Discussion 3. Reflections about methodology: limitations to our (and other) studies 3.1. Participants: who do we include? 3.1.1. ASD: who is affected and who is not? 3.1.2. Simplex or Multiplex? 3.1.3. Research sample reflecting the full spectrum? 3.2. Diagnostic instruments: what do we (want to) measure? 3.2.1. Questionnaires 3.2.2. Interviews 3.2.3. Direct observations 4. Recommendations for future research 5. Reflections for clinicians 5.1. Diagnostic assessment 5.2. Diagnostic stability 5.3. Broader Autism Phenotype? 5.4. Recurrence risk and intergenerational transmission References Appendix A: list of publications based on the dataset gathered during this PhD research Curriculum vitae & publicationsstatus: publishe