Henrik Anckarsäter, Lund University

This follow-up of nation-wide twin cohorts at 15 years of age (DOGSS) was designed to identify hereditary and environmental risk factors for the development of childhood neurodevelopmental problems (NDPs; e.g. attention defict/hyperactivity disorder (AD/HD) and autism spectrum disorders (ASDs)) into negative psychosocial outcomes, defined as educational/peer marginalization, substance abuse, criminality, and mental health problems. The project has been supported by FAS (2007-2009), by Riksbankens Jubileumsfond (2007), by the National Research Council (ongoing), by ALF at each study site (ongoing), and by several smaller grants.

Swedish twins born in 1992 and later are assessed by parental telephone interviews and questionnaires in connection with their 9th and/or 12th birthdays (the CATSS study) and by questionnaires at 15 years, yielding a database that has been linked with the Medical Birth Register. Since 2008, children screening positive for AD/HD, ASDs, tics, LD, motor dyscoordination, or eating disturbances have been assessed clinically together with their co-twins and healthy controls when they have reached 15 years (the DOGSS study). The first two year cohorts (1993 and 1994) have yielded 195 twin pairs (390 individuals) who have been assessed by psychologists (who are blind to previous information and to the results of the co-twin) at four research sites, two in Stockholm, and one each in Malmö and Göteborg. For the 1995 cohort being assessed in 2010, due to restricted funding, we were forced to narrow the clinical examinations to the subgroup screening positive for AD/HD, ASDs, and CD and controls (n=50 pairs), yielding a total study cohort of 225 pairs.

Childhood neurodevelopmental problems (NDPs - here used as an umbrella term for attention- deficit/hyperactivity disorder (AD/HD), autism spectrum disorders (ASD, which in turn is a syndromal description including pervasive social interaction deficits, language impairments, and repetitive/stereotyped behaviors), tic disorders, developmental coordination disorder (DCD), and learning disabilities (LD)) may be associated with an increased risk for subsequent psychosocial marginalization defined as one or more of the following "negative outcomes": 1) educational/social maladjustment, 2) substance abuse, 3) criminality, and 4) mental health problems of other types than the NDPs.

NDPs affect at least 5 % of all children in severe forms (Kadesjo 2000), in most cases persisting into adult age with considerable functional and psychosocial impairments (Gillberg 1995), including increased mortality (Jokela et al. 2009). There are good resons to consider the NDPs as a continuum of mental problems related to neurodevelopment across diagnostic delineations. Epidemiological and clinical studies have identified considerable overlaps across the various diagnoses (e.g. between ASDs and AD/HD (Gadow et al. 2006, Reiersen et al. 2007). Behavioural genetic molecular genetic studies have established common genetic factors involved in the development of all the different NDPs, Lichtenstein et al. in press, Miller et al. 2009). On the other hand, problem-specific genetic effects have been identified in "disorders" treated as syndromes, such as the ASDs (Ronald et al. 2008). Based on these considerations, the present project is designed to study both diagnostic and problem-sepecific definitions of the NDPs (e.g. both ASDs lumped and social interaction problems, communication deficits, and lack of flexibility separately).

The NDPs are also shown to carry an increased risk for psychosocial marginalization. About one third of children with hyperactivity and inattention will develop early-onset conduct disorder (CD), a problem combination that leads to a considerable risk for all types of adult mental disorders, substance abuse, and aggressive criminality (Kim-Cohen et al. 2003; Hofvander et al. 2009), and forms the background to the majority of violent crimes in the community, being especially over-represented among perpetrators of extremely severe and partner violent crimes (Moffitt et al. 2002). It is less well established how ASD-related social interaction and communication problems, behavioural stereotypies, DCD, and LD are associated with mental disorders and the risk for substance abuse, marginalization, and criminality in adult age (Gilmour et al. 2004). Relationships between ASD and outcomes such as substance abuse and criminality have only been examined in cross-sectional studies, none of which has specifically included adolescent development (Siponmaa et al. 2001; Anckarsater et al. 2007; Einarsson et al. 2009), and the few longitudinal studies of ASD that are available have not been designed to capture criminality or substance-related disorders (Billstedt et al. 2005; Cederlund et al. 2008). Neither is it clear whether the development of NDPs into psychosocial problems is due to co-occurrence of different susceptibility factors or to common etiological factors in genes, biology, or environment.

Families included in the CATSS with same-sex twins who were screen-positive for ASDs, AD/HD, LD, tic disorders, DCD, CD, OCD, ED (by the algorithm described for the CATSS 9/12 questionnaires above) or controls were contacted and had a clinical examination at one of four sites: two in Stockholm (60 pairs yearly), one in Malmö (15 pairs yearly), and one in Gothenburg (25 pairs yearly). Case and control twin families were assessed by two independent raters (clinical psychologists who were blind to any previous information and to the results of the examination of the co-twin), including the K-SADS for psychiatric diagnostic according to the DSM-IV. Prior to the visit, participants (twins and parents) have filled out self-assessment forms. In addition, each twin is assessed with the QB-Test, a computerized test assessing impulsivity and hyperactivity. Finally, the results of the psychiatric diagnostic interviews were validated by a senior child psychiatrist and compared to lifetime medical records collected from the Center for Epidemiology at the National Board of Health and Welfare and the child and adolescent psychiatric services. Blood and saliva were collected from the twins and saliva from the parents.

Mental disorders were diagnosed in about half the total cohort, which corresponds to the proportion of screen-positive children in relation to their screen-negative co-twins and controls. The male:female ratio is 5:4. A comprehensive database using the File maker PRO 9 software and a special interface to enter data according to the written protocols has been established with 8,000 variables per individual, each entered by two independent data assistants and cross-checked, giving access to very detailed assessments of mental health problems (beyond established diagnostic categories), substance abuse, psychosocial marginalization, and criminality. This data-base was finalized at the end of the 2011 summer break, and is now available for research.

The DOGSS study has not yet yielded specific publications but is thoroughly described in an overview paper by Anckarsäter and co-workers currently in press in Human Genetics and Twin Research. During the years of data collection, a number of papers of relevance for the original research questions have been written up based on data from the CATSS study at 9 and 12 years of age, including a thesis by Sebastian Lundström on Autistic-like traits, defended in May 2011. Currently, three students, two post-docs, two PhD candidates and one senior researcher work on the data generated by the project in addition to the initial group of researchers assembled for the project.