Eva Carlström

The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood

OBJECTIVE Autism spectrum disorders are considered to be among the most heritable mental disorders, a notion based on surprisingly sparse data from small clinical studies. Population-based studies of the heritability of other neuropsychiatric disorders and comorbidities among them have also been sparse. The authors sought to address both of these issues. METHOD Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2000 (N=10,895) were interviewed regarding autism spectrum disorders and associated conditions (response rate, 80%). Concordance rates and structural equation modeling were used for evaluating causes for familial aggregation and overlap between conditions. RESULTS Monozygotic twins had higher concordance rates than dizygotic twins for autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), developmental coordination disorder, and tic disorder. Genetic effects accounted for 80% (95% CI=29-91) of the variation in liability for autism spectrum disorders, 79% (95% CI=61-88) for ADHD, 70% (95% CI=35-83) for developmental coordination disorder, and 56% (95% CI=37-68) for tic disorder. Among monozygotic co-twins of children with autism spectrum disorders, the probability of having a diagnosis of ADHD was 44%, compared with 15% for dizygotic co-twins. Differences in cross-disorder effects between monozygotic and dizygotic twins were observed for most other comorbidities, and substantial proportions of the genetic variance for autism spectrum disorders was shared with each of the other disorders. CONCLUSIONS Different neuropsychiatric disorders seem to have a common genetic etiology, suggesting caution in the use of diagnostic entities and proband status in efforts to uncover genes predisposing to autism spectrum disorders.

The Swedish Twin Registry in the Third Millennium: An Update

The Swedish Twin Registry was first established in the late 1950s. Today it includes more than 170,000 twins--in principle, all twins born in Sweden since 1886. In this article we describe some ongoing and recently completed projects based on the registry. In particular, we describe recent efforts to screen all twins born between 1959 and 1985, and young twin pairs when they turn 9 and 12 years of age. For these studies, we present initial frequencies of common conditions and exposures.

The Autism - Tics, AD/HD and other Comorbidities inventory (A-TAC): further validation of a telephone interview for epidemiological research

BackgroundReliable, valid, and easy-to-administer instruments to identify possible caseness and to provide proxies for clinical diagnoses are needed in epidemiological research on child and adolescent mental health.The aim of this study is to provide further validity data for a parent telephone interview focused on Autism - Tics, Attention-deficit/hyperactivity disorder (AD/HD), and other Comorbidities (A-TAC), for which reliability and preliminary validation data have been previously reported.MethodsParents of 91 children clinically diagnosed at a specialized Child Neuropsychiatric Clinic, 366 control children and 319 children for whom clinical diagnoses had been previously assigned were interviewed by the A-TAC over the phone. Interviewers were blind to clinical information. Different scores from the A-TAC were compared to the diagnostic outcome.ResultsAreas under ROC curves for interview scores as predictors of clinical diagnoses were around 0.95 for most disorders, including autism spectrum disorders (ASDs), attention deficit/hyperactivity disorder (AD/HD), tic disorders, developmental coordination disorders (DCD) and learning disorders, indicating excellent screening properties. Screening cut-off scores with sensitivities above 0.90 (0.95 for ASD and AD/HD) were established for most conditions, as well as cut-off scores to identify proxies to clinical diagnoses with specificities above 0.90 (0.95 for ASD and AD/HD).ConclusionsThe previously reported validity of the A-TAC was supported by this larger replication study using broader scales from the A-TAC-items and a larger number of diagnostic categories. Short versions of algorithms worked as well as larger. Different cut-off levels for screening versus identifying proxies for clinical diagnoses are warranted. Data on the validity for mood problems and oppositional defiant/conduct problems are still lacking. Although the A-TAC is principally intended for epidemiological research and general investigations, the instrument may be useful as a tool to collect information in clinical practice as well.

Familial clustering of suicide risk: A total population study of 11.4 million individuals

Background Research suggests that suicidal behaviour is aggregated in families. However, due to methodological limitations, including small sample sizes, the strength and pattern of this aggregation remains uncertain. Method We examined the familial clustering of completed suicide in a Swedish total population sample. We linked the Cause of Death and Multi-Generation Registers and compared suicide rates among relatives of all 83 951 suicide decedents from 1952–2003 with those among relatives of population controls. Results Patterns of familial aggregation of suicide among relatives to suicide decedents suggested genetic influences on suicide risk; the risk among full siblings (odds ratio 3.1, 95% confidence interval 2.8–3.5, 50% genetic similarity) was higher than that for maternal half-siblings (1.7, 1.1–2.7, 25% genetic similarity), despite similar environmental exposure. Further, monozygotic twins (100% genetic similarity) had a higher risk than dizygotic twins (50% genetic similarity) and cousins (12.5% genetic similarity) had higher suicide risk than controls. Shared (familial) environmental influences were also indicated; siblings to suicide decedents had a higher risk than offspring (both 50% genetically identical but siblings having a more shared environment, 3.1, 2.8–3.5 v. 2.0, 1.9–2.2), and maternal half-siblings had a higher risk than paternal half-siblings (both 50% genetically identical but the former with a more shared environment). Although comparisons of twins and half-siblings had overlapping confidence intervals, they were supported by sensitivity analyses, also including suicide attempts. Conclusions Familial clustering of suicide is primarily influenced by genetic and also shared environmental factors. The family history of suicide should be considered when assessing suicide risk in clinical settings or designing and administering preventive interventions.

Familial Factors Do not Confound the Association Between Birth Weight and Childhood Asthma

OBJECTIVE: Studies have found associations between low birth weight and asthma. However, this association could be due to familial confounding. Our objective was to investigate whether fetal growth and birth weight affect the risk of asthma in childhood, controlling for gestational age (GA), and shared (familial) environment and genetic factors. PATIENT AND METHODS: Information on asthma, zygosity, birth characteristics, and potential confounders was collected for all 9- and 12-year-old twins through the Swedish Twin Register and Medical Birth Register. To obtain an overall effect of birth weight on risk of asthma, we performed cohort analyses on all twins (N = 10918). To address genetic and shared environmental confounding, we performed a co-twin control analysis by using the 157 monozygotic and 289 dizygotic same-sex twin pairs who were discordant for asthma. RESULTS: The overall rate of asthma ever was 13.7%. In the cohort analysis, the adjusted odds ratio (OR) for asthma in relation to a 1000-g decrease in birth weight was 1.57 (95% confidence interval [CI]: 1.38–1.79), and for each reduced gestational week the OR was 1.10 (95% CI: 1.07–1.13). In the co-twin control analyses, a 1000-g decrease in birth weight corresponded to an OR of 1.25 (95% CI: 0.74–2.10) for dizygotic same-sex twins and 2.42 (95% CI: 1.00–5.88) for monozygotic twins. CONCLUSIONS: There is an association between fetal growth and childhood asthma that is independent of GA and shared (familial) environment and genetic factors, which indicates that fetal growth restriction affects lung development, supporting additional studies on the early metabolic and physiologic mechanisms of childhood asthma.

Trajectories leading to autism spectrum disorders are affected by paternal age : findings from two nationally representative twin studies.

BACKGROUND Despite extensive efforts, the causes of autism remain unknown. Advancing paternal age has been associated with various neurodevelopmental disorders. We aim to investigate three unresolved questions: (a) What is the association between paternal age and autism spectrum disorders (ASD)?; (b) Does paternal age moderate the genetic and environmental etiological factors for ASD? (c) Does paternal age affect normal variation in autistic-like traits? METHODS Two nationally representative twin studies from Sweden (n = 11, 122, assessed at age 9 or 12) and the UK (n = 13, 524, assessed at age 9) were used. Categorical and continuous measures of ASD, autistic-like traits and autistic similarity were calculated and compared over paternal age categories. RESULTS Both cohorts showed a strong association between paternal age and the risk for ASD. A U-shaped risk association could be discerned since the offspring of both the youngest and oldest fathers showed an elevation in the risk for ASD. Autistic similarity increased with advancing paternal age in both monozygotic and dizygotic twins. Both cohorts showed significantly higher autistic-like traits in the offspring of the youngest and oldest fathers. CONCLUSIONS Phenomena associated with paternal age are clearly involved in the trajectories leading to autistic-like traits and ASD. Mechanisms influencing the trajectories might differ between older and younger fathers. Molecular genetic studies are now needed in order to further understand the association between paternal age and ASD, as well as normal variation in social, language, and repetitive behaviors in the general population.

Trajectories leading to autism spectrum disorders are affected by paternal age

BACKGROUND Despite extensive efforts, the causes of autism remain unknown. Advancing paternal age has been associated with various neurodevelopmental disorders. We aim to investigate three unresolved questions: (a) What is the association between paternal age and autism spectrum disorders (ASD)?; (b) Does paternal age moderate the genetic and environmental etiological factors for ASD? (c) Does paternal age affect normal variation in autistic-like traits? METHODS Two nationally representative twin studies from Sweden (n = 11, 122, assessed at age 9 or 12) and the UK (n = 13, 524, assessed at age 9) were used. Categorical and continuous measures of ASD, autistic-like traits and autistic similarity were calculated and compared over paternal age categories. RESULTS Both cohorts showed a strong association between paternal age and the risk for ASD. A U-shaped risk association could be discerned since the offspring of both the youngest and oldest fathers showed an elevation in the risk for ASD. Autistic similarity increased with advancing paternal age in both monozygotic and dizygotic twins. Both cohorts showed significantly higher autistic-like traits in the offspring of the youngest and oldest fathers. CONCLUSIONS Phenomena associated with paternal age are clearly involved in the trajectories leading to autistic-like traits and ASD. Mechanisms influencing the trajectories might differ between older and younger fathers. Molecular genetic studies are now needed in order to further understand the association between paternal age and ASD, as well as normal variation in social, language, and repetitive behaviors in the general population.

The Autism—Tics, AD/HD and other Comorbidities (A-TAC) telephone interview: Convergence with the Child Behavior Checklist (CBCL)

Objective: To compare telephone interview screening for child psychiatric/neuropsychiatric disorders using the inventory of Autism—Tics, Attention deficit/hyperactivity disorder (AD/HD) and other Comorbidities (A-TAC) with results from the Child Behavior Checklist (CBCL). Background: The A-TAC is a parent telephone interview focusing on autism spectrum disorders (ASDs) and co-existing problems, developed for lay interviewers. Subjects and methods: A-TAC telephone interviews and CBCL questionnaires were obtained from parents of 106 Swedish twin pairs aged 9 and 12 years. Results: Correlations between A-TAC modules and CBCL scales aimed at measuring similar concepts were generally significant albeit modest, with correlation coefficients ranging from 0.30 through 0.55. Conclusion: The A-TAC has convergent validity with the CBCL in several problem areas, but the A-TAC also provides more detailed and specific assessments of ASD symptoms and related neuropsychiatric problems.

Association between a genetic variant in the serotonin transporter gene (SLC6A4) and suicidal behavior in patients with schizophrenia

BackgroundThe serotonin (5-hydroxytryptamin; 5-HT) system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene (SLC6A4; 5-HTT) is associated with schizophrenia and suicidal behavior. In this study, we wanted to elucidate whether SLC6A4 variations is involved in attempted suicide among patients with schizophrenia in a Scandinavian case–control sample.MethodsPatients diagnosed with schizophrenia from three Scandinavian samples were assessed for presence or absence of suicide attempts, based on record reviews and interview data. Seven SLC6A4 single nucleotide polymorphisms (SNPs) were genotyped in 837 schizophrenia patients and 1,473 control individuals. Association analyses and statistical evaluations were performed with the program UNPHASED (version 3.0.9).ResultsWe observed an allele association between the SNP rs16965628, located in intron one of SLC6A4, and attempted suicide (adjusted p-value 0.01), among patients with schizophrenia. No association was found to a diagnosis of schizophrenia, when patients were compared to healthy control individuals.ConclusionThe gene SLC6A4 appears to be involved in suicidal ideation among patients with schizophrenia. Independent replication is needed before more firm conclusions can be drawn.

The Swedish Version of the Parent-Rated Junior Temperament and Character Inventory (J–TCI)

To evaluate the psychometric characteristics of the Swedish version of the Junior Temperament and Character Inventory (J–TCI), it was sent to parents of 9- and 12-yr.-old twins in Sweden. The final number of responders was 196 parents who rated 92 female and 104 male twin pairs. The inventory of one twin, randomly chosen from each pair, was included in the analyses. Reward Dependence, Persistence, and Cooperativeness were scored higher in girls; Novelty Seeking was higher in the 9-yr.-olds and Persistence in the 12-yr.-olds. Pearsons correlations showed that some dimensions were not statistically independent from each other, even if the covariance was moderate. Internal consistency (Cronbachs alpha) was satisfactory for Harm Avoidance, Novelty Seeking, Self-Directedness, and Cooperativeness (.68–.81), while it was lower in those dimensions that had fewer items. The Swedish parent version of the J–TCI shared about the same psychometric characteristics as found in international samples.