Fruhling Rijsdijk

Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples

CONTEXT The use of endophenotypes, biological traits that increase the liability to a disorder, represents one strategy to facilitate the detection of susceptibility genes for complex behavioral disorders such as schizophrenia. Establishing that a candidate trait is both heritable and linked genetically to schizophrenia is integral to its validity as an endophenotypic marker. Neurocognitive deficits are among the most promising indicators of increased risk for schizophrenia; however, it is not clear to what extent these deficits are genetically linked to the disorder. OBJECTIVES To quantify the genetic and environmental contributions to the variability of selected neurocognitive measures and to estimate the genetic relationship between these and schizophrenia. DESIGN Genetic model fitting to monozygotic and dizygotic twin data. SETTING United Kingdom psychiatric research institute. PARTICIPANTS Two hundred sixty-seven monozygotic and dizygotic twins concordant and discordant for schizophrenia, and healthy monozygotic and dizygotic control twin pairs. MAIN OUTCOME MEASURES The heritabilities of intelligence, working memory, processing speed, perceptual organization, and verbal comprehension were estimated, and the genetic relationship between each of these and schizophrenia was quantified. RESULTS Genetic influences contributed substantially to all of the cognitive domains, but intelligence and working memory were the most heritable. A significant correlation was found between intelligence and schizophrenia (r = -0.61; 95% confidence interval, -0.71 to -0.48), with shared genetic variance accounting for 92% of the covariance between the two. Genetic influences also explained most of the covariance between working memory and schizophrenia. Significant but lesser portions of covariance between the other cognitive domains and schizophrenia were also found to be genetically shared. Environmental effects, although separately linked to neurocognition and schizophrenia, did not generally contribute to their covariance. CONCLUSION Genomewide searches using factorial designs stratifying for levels of intelligence and working memory will assist in the search for finding quantitative trait loci for schizophrenia.

An estimate of amyotrophic lateral sclerosis heritability using twin data

Background Causative gene mutations have been identified in about 2% of those with amyotrophic lateral sclerosis (ALS), often, but not always, when there is a strong family history. There is an assumption that there is a genetic component to all ALS, but genome-wide association studies have yet to produce a robustly replicated result. A definitive estimate of ALS heritability is therefore required to determine whether ongoing efforts to find susceptibility genes are worth while. Methods The authors performed two twin studies, one population- and one clinic-based. The authors used structural equation modelling to perform a meta-analysis of data from these studies and an existing twin study to estimate ALS heritability, and identified 171 twin pairs in which at least one twin had ALS. Results and discussion Five monozygotic twin pairs were concordant-affected, and 44 discordant-affected. No dizygotic twin pairs were concordant-affected, and 122 discordant-affected. The heritability of sporadic ALS was estimated as 0.61 (0.38 to 0.78) with the unshared environmental component 0.39 (0.22 to 0.62). ALS has a high heritability, and efforts to find causative genes should continue.

Heritability of Autism Spectrum Disorder in a UK Population-Based Twin Sample

IMPORTANCE Most evidence to date highlights the importance of genetic influences on the liability to autism and related traits. However, most of these findings are derived from clinically ascertained samples, possibly missing individuals with subtler manifestations, and obtained estimates may not be representative of the population. OBJECTIVES To establish the relative contributions of genetic and environmental factors in liability to autism spectrum disorder (ASD) and a broader autism phenotype in a large population-based twin sample and to ascertain the genetic/environmental relationship between dimensional trait measures and categorical diagnostic constructs of ASD. DESIGN, SETTING, AND PARTICIPANTS We used data from the population-based cohort Twins Early Development Study, which included all twin pairs born in England and Wales from January 1, 1994, through December 31, 1996. We performed joint continuous-ordinal liability threshold model fitting using the full information maximum likelihood method to estimate genetic and environmental parameters of covariance. Twin pairs underwent the following assessments: the Childhood Autism Spectrum Test (CAST) (6423 pairs; mean age, 7.9 years), the Development and Well-being Assessment (DAWBA) (359 pairs; mean age, 10.3 years), the Autism Diagnostic Observation Schedule (ADOS) (203 pairs; mean age, 13.2 years), the Autism Diagnostic Interview-Revised (ADI-R) (205 pairs; mean age, 13.2 years), and a best-estimate diagnosis (207 pairs). MAIN OUTCOMES AND MEASURES Participants underwent screening using a population-based measure of autistic traits (CAST assessment), structured diagnostic assessments (DAWBA, ADI-R, and ADOS), and a best-estimate diagnosis. RESULTS On all ASD measures, correlations among monozygotic twins (range, 0.77-0.99) were significantly higher than those for dizygotic twins (range, 0.22-0.65), giving heritability estimates of 56% to 95%. The covariance of CAST and ASD diagnostic status (DAWBA, ADOS and best-estimate diagnosis) was largely explained by additive genetic factors (76%-95%). For the ADI-R only, shared environmental influences were significant (30% [95% CI, 8%-47%]) but smaller than genetic influences (56% [95% CI, 37%-82%]). CONCLUSIONS AND RELEVANCE The liability to ASD and a more broadly defined high-level autism trait phenotype in this large population-based twin sample derives primarily from additive genetic and, to a lesser extent, nonshared environmental effects. The largely consistent results across different diagnostic tools suggest that the results are generalizable across multiple measures and assessment methods. Genetic factors underpinning individual differences in autismlike traits show considerable overlap with genetic influences on diagnosed ASD.

A quantitative genetic analysis of schizotypal personality traits

BACKGROUND Previous twin studies investigating the heritability of schizotypy have often had limited power and have failed to measure the disorganization/social anxiety component. METHOD Seven hundred and thirty-three female twin pairs, drawn from the Institute of Psychiatry Volunteer Twin Register, completed the Oxford-Liverpool Inventory of Feelings and Experiences and the Peters et al. Delusions Inventory. Structural equation modelling was carried out on scores for MZ and DZ twin pairs. RESULTS The best fitting models for all scales comprised additive genetic and unique environmental effects. Heritability was estimated at approximately 50% for most scales, although it was lower at 37% for the PDI scale. Multivariate structural equation model fitting revealed a best-fitting model in which additive genetic and unique environmental influences act through a single common pathway for Cognitive Disorganization, Unusual Experiences and the PDI, and through a separate common pathway for Cognitive Disorganization and Introvertive Anhedonia. CONCLUSIONS The various components of schizotypy are moderately heritable. Multivariate model fitting indicates that at least two latent factor structures are required to account for the covariation between the various components of schizotypy. The positive and negative components of schizotypy are relatively genetically independent, although each in turn may be related to Cognitive Disorganization.

Associations Between Sleep Problems, Anxiety, and Depression in Twins at 8 Years of Age

OBJECTIVES. Associations between sleep and internalizing problems are complex and poorly understood. To better understand these covarying difficulties, genetic and environmental influences were estimated by using a twin design. METHODS. Three hundred 8-year-old twin pairs reported on their anxiety and depression by completing the Screen for Childhood Anxiety Related Emotional Disorders and the Childrens Depression Inventory. Parents reported on their childrens sleep problems by completing the Child Sleep Habits Questionnaire. RESULTS. Children reported by their parents to have different types of sleep problems self-reported more depression symptoms than those without. The correlation between total sleep-problem score and depression was moderate. That between sleep problems and anxiety was smaller and was not examined further. The association between sleep problems and depression was mainly explained by genes, and there was substantial overlap between the genes influencing sleep problems and those influencing depression. There was smaller influence from environmental factors making family members alike, and environmental factors making family members different decreased the association between sleep problems and depression. CONCLUSIONS. A range of sleep difficulties are associated with depression in school-aged children, and the overall association between the 2 difficulties may be largely influenced by genes.

Brain MRI abnormalities in schizophrenia : same genes or same environment ?

BACKGROUND Structural brain volume abnormalities are among the most extensively studied endophenotypes in schizophrenia. Bivariate genetic model fitting (adjusted to account for selection) was used to quantify the genetic relationship between schizophrenia and brain volumes and to estimate the heritability of these volumes. METHOD We demonstrated by simulation that the adjusted genetic model produced unbiased estimates for endophenotype heritability and the genetic and environmental correlations. The model was applied to brain volumes (whole brain, hippocampus, third and lateral ventricles) in a sample of 14 monozygotic (MZ) twin pairs concordant for schizophrenia, 10 MZ discordant pairs, 17 MZ control pairs, 22 discordant sibling pairs, three concordant sibling pairs, and 114 healthy control subjects. RESULTS Whole brain showed a substantial heritability (88%) and lateral ventricles substantial common environmental effects (67%). Whole brain showed a significant genetic correlation with schizophrenia, whereas lateral ventricles showed a significant individual specific correlation with schizophrenia. There were significant familial effects for hippocampus and third ventricle, but the analyses could not resolve whether these were genetic or environmental in origin (around 30%each). CONCLUSIONS Using genetic model fitting on twin and sibling data we have demonstrated differential sources of covariation between schizophrenia and brain volumes, genetic in the case of whole brain volume and individual specific environment in the case of lateral ventricles.

Heritability of autism spectrum disorders: a meta‐analysis of twin studies

Background The etiology of Autism Spectrum Disorder (ASD) has been recently debated due to emerging findings on the importance of shared environmental influences. However, two recent twin studies do not support this and instead re‐affirm strong genetic effects on the liability to ASD, a finding consistent with previous reports. This study conducts a systematic review and meta‐analysis of all twin studies of ASD published to date and explores the etiology along the continuum of a quantitative measure of ASD. Methods A PubMed Central, Science Direct, Google Scholar, Web of Knowledge structured search conducted online, to identify all twin studies on ASD published to date. Thirteen primary twin studies were identified, seven were included in the meta‐analysis by meeting Systematic Recruitment criterion; correction for selection and ascertainment strategies, and applied prevalences were assessed for these studies. In addition, a quantile DF extremes analysis was carried out on Childhood Autism Spectrum Test scores measured in a population sample of 6,413 twin pairs including affected twins. Results The meta‐analysis correlations for monozygotic twins (MZ) were almost perfect at .98 (95% Confidence Interval, .96–.99). The dizygotic (DZ) correlation, however, was .53 (95% CI .44–.60) when ASD prevalence rate was set at 5% (in line with the Broad Phenotype of ASD) and increased to .67 (95% CI .61–.72) when applying a prevalence rate of 1%. The meta‐analytic heritability estimates were substantial: 64–91%. Shared environmental effects became significant as the prevalence rate decreased from 5–1%: 07–35%. The DF analyses show that for the most part, there is no departure from linearity in heritability. Conclusions We demonstrate that: (a) ASD is due to strong genetic effects; (b) shared environmental effects become significant as a function of lower prevalence rate; (c) previously reported significant shared environmental influences are likely a statistical artefact of overinclusion of concordant DZ twins.

The Early Auditory Gamma-Band Response Is Heritable and a Putative Endophenotype of Schizophrenia

BACKGROUND Reduced power and phase locking of the early auditory gamma-band response (EAGBR) have been reported in schizophrenia, but findings are equivocal. Further, little is known about genetic (heritability) and environmental influences on the EAGBR or its potential as an endophenotype of schizophrenia. The present study used a twin design to examine whether EAGBR power and phase locking are heritable and reduced in schizophrenic patients and their unaffected co-twins and thus putative endophenotypes of schizophrenia. METHODS The study sample included a total of 194 individuals, consisting of 15 monozygotic [MZ] twin pairs concordant for schizophrenia, 9 MZ twin pairs discordant for schizophrenia, and 42 MZ and 31 dizygotic (DZ) control pairs. Evoked power and phase-locking factor of the EAGBR were computed on Morlet wavelet-transformed electroencephalogram responses to standard tones during an auditory oddball target detection task. Structural equation modeling was applied to estimate heritability and genetic and environmental correlations with schizophrenia for the EAGBR measures. RESULTS Both evoked power and phase-locking phenotypes were heritable traits (power: h(2) = 0.65; phase locking: h(2) = 0.63). Impaired EAGBR measures were significantly associated with schizophrenia. Patients with schizophrenia and their unaffected identical co-twins exhibited significantly reduced EAGBR power compared with control subjects. In each phenotype, shared genetic factors were likely the source of the observed associations with schizophrenia. CONCLUSIONS Our results support EAGBR measures as putative endophenotypes of schizophrenia, likely reflecting an ubiquitous local cortical circuit deficit.

A common genetic factor explains the association between psychopathic personality and antisocial behavior

BACKGROUND Both psychopathic personality traits and antisocial behavior are influenced by genetic as well as environmental factors. However, little is known about how genetic and environmental factors contribute to the associations between the psychopathic personality traits and antisocial behavior. METHOD Data were drawn from a longitudinal population-based twin sample including all 1480 twin pairs born in Sweden between May 1985 and December 1986. The twins responded to mailed self-report questionnaires at two occasions: 1999 (twins 13-14 years old), and 2002 (twins 16-17 years old). RESULTS A common genetic factor loaded substantially on both psychopathic personality traits and antisocial behavior, whereas a common shared environmental factor loaded exclusively on antisocial behavior. CONCLUSIONS The genetic overlap between psychopathic personality traits and antisocial behavior may reflect a genetic vulnerability to externalizing psychopathology. The finding of shared environmental influences only in antisocial behavior suggests an etiological distinction between psychopathic personality dimensions and antisocial behavior. Knowledge about temperamental correlates to antisocial behavior is important for identification of susceptibility genes, as well as for possible prevention through identification of at-risk children early in life.

Application of hierarchical genetic models to Raven and WAIS subtests: a Dutch twin study

Hierarchical models of intelligence are highly informative and widely accepted. Application of these models to twin data, however, is sparse. This paper addresses the question of how a genetic hierarchical model fits the Wechsler Adult Intelligence Scale (WAIS) subtests and the Raven Standard Progressive test score, collected in 194 18-year-old Dutch twin pairs. We investigated whether first-order group factors possess genetic and environmental variance independent of the higher-order general factor and whether the hierarchical structure is significant for all sources of variance. A hierarchical model with the 3 Cohen group-factors (verbal comprehension, perceptual organisation and freedom-from-distractibility) and a higher-order g factor showed the best fit to the phenotypic data and to additive genetic influences (A), whereas the unique environmental source of variance (E) could be modeled by a single general factor and specifics. There was no evidence for common environmental influences. The covariation among the WAIS group factors and the covariation between the group factors and the Raven is predominantly influenced by a second-order genetic factor and strongly support the notion of a biological basis of g.