Reciprocal links between anxiety sensitivity and obsessive-compulsive symptoms in youth: a longitudinal twin study.

BACKGROUND: Anxiety sensitivity, the tendency to fear the symptoms of anxiety, is a key risk factor for the development anxiety disorders. Although obsessive-compulsive disorder was previously classified as an anxiety disorder, the prospective relationship between anxiety sensitivity and obsessive-compulsive symptoms (OCS) has been largely overlooked. Furthermore, a lack of genetically informative studies means the aetiology of the link between anxiety sensitivity and OCS remains unclear. METHODS: Adolescent twins and siblings (N = 1,579) from the G1219 study completed self-report questionnaires two years apart assessing anxiety sensitivity, OCS, anxiety and depression. Linear regression models tested prospective associations between anxiety sensitivity and OCS, with and without adjustment for anxiety and depressive symptoms. A phenotypic cross-lagged model assessed bidirectional influences between anxiety sensitivity and OCS over time, and a genetic version of this model examined the aetiology of these associations. RESULTS: Anxiety sensitivity was prospectively associated with changes in OCS, even after controlling for comorbid anxiety and depressive symptoms. The longitudinal relationship between anxiety sensitivity and OCS was bidirectional, and these associations were predominantly accounted for by nonshared environmental influences. CONCLUSIONS: Our findings are consistent with the notion that anxiety sensitivity is a risk factor for OCS during adolescence, but also suggest that experiencing OCS confers risk for heightened anxiety sensitivity. The reciprocal links between OCS and anxiety sensitivity over time are likely to be largely mediated by nonshared environmental experiences, as opposed to common genes. Our findings raise the possibility that interventions aimed at ameliorating anxiety sensitivity could reduce risk for OCS, and vice versa.

Are punitive parenting and stressful life events environmental risk factors for obsessive-compulsive symptoms in youth? A longitudinal twin study.

BACKGROUND: Punitive parenting and stressful life events are associated with obsessive-compulsive symptoms (OCS). However, the lack of longitudinal, genetically-informative studies means it remains unclear whether these factors represent environmentally-mediated risks for the development of OCS. METHODS: Twins and siblings from the Genesis1219 study completed self-report questionnaires two years apart (Time 1: N = 2616, mean age = 15.0; Time 2: N = 1579, mean age = 17.0 years) assessing OCS, maternal and paternal punitive parenting, and dependent stressful life events. Multiple regression models tested cross-sectional and longitudinal associations between the putative environmental risk factors and obsessive-compulsive symptoms using: (a) individual scores; and (b) monozygotic twin difference scores. The aetiologies of significant phenotypic associations between putative risk factors and OCS were further examined using multivariate genetic models. RESULTS: At a phenotypic level, maternal and paternal punitive parenting and stressful life events were all associated with OCS both cross-sectionally and longitudinally. However, only stressful life events predicted the subsequent development of OCS, after controlling for earlier symptoms. Genetic models indicated that the association between life events and change in OCS symptoms was due to both genetic (48%) and environmental (52%) influences. Overall, life events associated with change in OCS accounted for 1.2% of variation in OCS at Time 2. CONCLUSIONS: Stressful life events, but not punitive parenting, predict OCS change during adolescence at a phenotypic level. This association exists above and beyond genetic confounding, consistent with the hypothesis that stressful life events play a causal role in the development of obsessive-compulsive symptoms.

Shared genetic influences do not explain the association between parent-offspring relationship quality and offspring internalizing problems: results from a Children-of-Twins study.

BACKGROUND: Associations between parenting and child outcomes are often interpreted as reflecting causal, social influences. However, such associations may be confounded by genes common to children and their biological parents. To the extent that these shared genes influence behaviours in both generations, a passive genetic mechanism may explain links between them. Here we aim to quantify the relative importance of passive genetic v. social mechanisms in the intergenerational association between parent-offspring relationship quality and offspring internalizing problems in adolescence. METHODS: We used a Children-of-Twins (CoT) design with data from the parent-based Twin and Offspring Study of Sweden (TOSS) sample [909 adult twin pairs and their offspring; offspring mean age 15.75 (2.42) years], and the child-based Swedish Twin Study of CHild and Adolescent Development (TCHAD) sample [1120 adolescent twin pairs; mean age 13.67 (0.47) years]. A composite of parent-report measures (closeness, conflict, disagreements, expressions of affection) indexed parent-offspring relationship quality in TOSS, and offspring self-reported internalizing symptoms were assessed using the Child Behavior Checklist (CBCL) in both samples. RESULTS: A social transmission mechanism explained the intergenerational association [r = 0.21 (0.16-0.25)] in our best-fitting model. A passive genetic transmission pathway was not found to be significant, indicating that parental genetic influences on parent-offspring relationship quality and offspring genetic influences on their internalizing problems were non-overlapping. CONCLUSION: These results indicate that this intergenerational association is a product of social interactions between children and parents, within which bidirectional effects are highly plausible. Results from genetically informative studies of parenting-related effects should be used to help refine early parenting interventions aimed at reducing risk for psychopathology.

Advantageous developmental outcomes of advancing paternal age.

Advanced paternal age (APA) at conception has been associated with negative outcomes in offspring, raising concerns about increasing age at fatherhood. Evidence from evolutionary and psychological research, however, suggests possible link between APA and a phenotypic advantage. We defined such advantage as educational success, which is positively associated with future socioeconomic status. We hypothesised that high IQ, strong focus on the subject of interest and little concern about 'fitting in' will be associated with such success. Although these traits are continuously distributed in the population, they cluster together in so-called 'geeks'. We used these measures to compute a 'geek index' (GI), and showed it to be strongly predictive of future academic attainment, beyond the independent contribution of the individual traits. GI was associated with paternal age in male offspring only, and mediated the positive effects of APA on education outcomes, in a similar sexually dimorphic manner. The association between paternal age and GI was partly mediated by genetic factors not correlated with age at fatherhood, suggesting contribution of de novo factors to the 'geeky' phenotype. Our study sheds new light on the multifaceted nature of the APA effects and explores the intricate links between APA, autism and talent.

Cannabis and Depression: A Twin Model Approach to Co-morbidity.

Cannabis use disorder (CUD) co-occurs with major depressive disorder (MDD) more frequently than would be expected by chance. However, studies to date have not produced a clear understanding of the mechanisms underlying this co-morbidity. Genetically informative studies can add valuable insight to this problem, as they allow the evaluation of competing models of co-morbidity. This study uses data from the Australian Twin Registry to compare 13 co-morbidity twin models initially proposed by Neale and Kendler (Am J Hum Genet 57:935-953, 1995). The analysis sample comprised 2410 male and female monozygotic and dizygotic twins (average age 32) who were assessed on CUD and MDD using the SSAGA-OZ interview. Data were analyzed in OpenMx. Of the 13 different co-morbidity models, two fit equally well: CUD causes MDD and Random Multiformity of CUD. Both fit substantially better than the Correlated Liabilities model. Although the current study cannot differentiate between them statistically, these models, in combination, suggest that CUD risk factors may causally influence the risk to develop MDD, but only when risk for CUD is high.

Developmental changes in genetic and environmental influences on Chinese child and adolescent anxiety and depression.

BACKGROUND: Twin and family studies using Western samples have established that child and adolescent anxiety and depression are under substantial genetic, modest shared environmental, and substantial non-shared environmental influences. Generalizability of these findings to non-Western societies remains largely unknown, particularly regarding the changes of genetic and environmental influences with age. The current study examined changes in genetic and environmental influences on self-reported anxiety and depression from late childhood to mid-adolescence among a Chinese twin sample. Sex differences were also examined. METHOD: Self-reported anxiety and depression were collected from 712 10- to 12-year-old Chinese twins (mean = 10.88 years, 49% males) and again 3 years later. Quantitative genetic modeling was used to examine developmental changes in genetic and environmental influences on anxiety and depression, and sex differences. RESULTS: Heritability of anxiety and depression in late childhood (23 and 20%) decreased to negligible in mid-adolescence, while shared environmental influences increased (20 and 27% to 57 and 60%). Shared environmental factors explained most of the continuity of anxiety and depression (75 and 77%). Non-shared environmental factors were largely time-specific. No sex differences were observed. CONCLUSIONS: Shared environmental influences might be more pronounced during the transition period of adolescence in non-Western societies such as China. Future research should examine similarities and differences in the genetic and environmental etiologies of child and adolescent internalizing and other psychopathology in development between Western and non-Western societies.

Genetic overlap between type 2 diabetes and depression in Swedish and Danish twin registries.

A bidirectional association between type 2 diabetes (T2DM) and depression has been consistently reported. Depression is associated with worse biomedical outcomes and increased mortality. The mechanisms underlying the association of T2DM with depression remain unclear. One possible question we can address is the extent to which the co-occurrence of diabetes and depression is due to correlated genetic and/or environmental risk factors. In this study, we performed structural equation model fitting to population-level data from the Swedish (n=68 606) and Danish (n=95 403) twin registries. The primary outcomes were clinical diagnosis of T2DM and depression using national hospital discharge registries. The phenotypic correlation between T2DM and depression is modest in both samples. In the Swedish sample, unique environmental effects explain a greater proportion of the covariance in males, whereas the association is primarily attributed to genetic effects in females. In the Danish sample, genetic effects account for the majority of the covariance in both males and females. Qualitative genetic sex differences are observed in both samples. We believe this is the first study to demonstrate significant genetic overlap between T2DM and depression.

Genetic and environmental aetiology of the dimensions of Callous-Unemotional traits.

BACKGROUND: A Callous-Unemotional trait specifier (termed 'Limited Prosocial Emotions') was added to the diagnosis of conduct disorder in DSM-5. The Inventory of Callous-Unemotional Traits (ICU) is a comprehensive measure of these traits assessing three distinct, yet correlated dimensions--Callousness, Uncaring, and Unemotional--all thought to reflect the general Callous-Unemotional construct. The present study was the first to examine the degree to which the aetiology of these dimensions is shared v. independent. METHOD: Parent-reported ICU data from 5092 16-year-old twin pairs from the Twins Early Development Study were subjected to confirmatory factor analysis. Multivariate genetic modelling was applied to the best-fitting structure. RESULTS: A general-specific structure, retaining a general factor and two uncorrelated specific factors (Callousness-Uncaring, Unemotional), provided the best fit to the data. The general factor was substantially heritable (h2 = 0.58, 95% CI 0.51-0.65). Unusually, shared environmental influences were also important in accounting for this general factor (c2 = 0.26, 95% CI 0.22-0.31), in addition to non-shared environmental influences. The Unemotional dimension appeared phenotypically and genetically distinct as shown by the substantial loadings of unemotional items on a separate dimension and a low genetic correlation between Unemotional and Callousness-Uncaring. CONCLUSIONS: A general factor, indicative of a shared phenotypic structure across the dimensions of the ICU was under substantial common genetic and more modest shared environment influences. Our findings also suggest that the relevance of the Unemotional dimension as part of a comprehensive assessment of CU traits should be investigated further.

The relationship between parental depressive symptoms and offspring psychopathology: evidence from a children-of-twins study and an adoption study.

BACKGROUND: Parental depressive symptoms are associated with emotional and behavioural problems in offspring. However, genetically informative studies are needed to distinguish potential causal effects from genetic confounds, and longitudinal studies are required to distinguish parent-to-child effects from child-to-parent effects. METHOD: We conducted cross-sectional analyses on a sample of Swedish twins and their adolescent offspring (n = 876 twin families), and longitudinal analyses on a US sample of children adopted at birth, their adoptive parents, and their birth mothers (n = 361 adoptive families). Depressive symptoms were measured in parents, and externalizing and internalizing problems measured in offspring. Structural equation models were fitted to the data. RESULTS: Results of model fitting suggest that associations between parental depressive symptoms and offspring internalizing and externalizing problems remain after accounting for genes shared between parent and child. Genetic transmission was not evident in the twin study but was evident in the adoption study. In the longitudinal adoption study child-to-parent effects were evident. CONCLUSIONS: We interpret the results as demonstrating that associations between parental depressive symptoms and offspring emotional and behavioural problems are not solely attributable to shared genes, and that bidirectional effects may be present in intergenerational associations.

Different heritabilities but shared etiological influences for parent, teacher and self-ratings of ADHD symptoms: an adolescent twin study.

BACKGROUND: Parent and teacher ratings of attention deficit hyperactivity disorder (ADHD) symptoms yield high estimates of heritability whereas self-ratings typically yield lower estimates. To understand why, the present study examined the etiological overlap between parent, teacher and self-ratings of ADHD symptoms in a population-based sample of 11-12-year-old twins. Method Participants were from the Twins Early Development Study (TEDS). ADHD symptoms were assessed using the Strengths and Difficulties Questionnaire (SDQ) hyperactivity scale completed by parents, teachers and children. Structural equation modeling was used to examine genetic and environmental contributions to phenotypic variance/covariance. RESULTS: The broad-sense heritability of ADHD symptoms was 82% for parent ratings, 60% for teacher ratings and 48% for self-ratings. Post-hoc analyses revealed significantly higher heritability for same-teacher than different-teacher ratings of ADHD (76% v. 49%). A common pathway model best explained the relationship between different informant ratings, with common genetic influences accounting for 84% of the covariance between parent, teacher and self-rated ADHD symptoms. The remaining variance was explained by rater-specific genetic and non-shared environmental influences. CONCLUSIONS: Despite different heritabilities, there were shared genetic influences for parent, teacher and self-ratings of ADHD symptoms, indicating that different informants rated some of the same aspects of behavior. The low heritability estimated for self-ratings and different-teacher ratings may reflect increased measurement error when different informants rate each twin from a pair, and/or greater non-shared environmental influences. Future studies into the genetic influences on ADHD should incorporate informant data in addition to self-ratings to capture a pervasive, heritable component of ADHD symptomatology.

Genetic analysis of reaction time variability: room for improvement?

BACKGROUND: Increased reaction time variability (RTV) on cognitive tasks requiring a speeded response is characteristic of several psychiatric disorders. In attention deficit hyperactivity disorder (ADHD), the association with RTV is strong phenotypically and genetically, yet high RTV is not a stable impairment but shows ADHD-sensitive improvement under certain conditions, such as those with rewards. The state regulation theory proposed that the RTV difference score, which captures change from baseline to a rewarded or fast condition, specifically measures 'state regulation'. By contrast, the interpretation of RTV baseline (slow, unrewarded) scores is debated. We aimed to investigate directly the degree of phenotypic and etiological overlap between RTV baseline and RTV difference scores. Method We conducted genetic model fitting analyses on go/no-go and fast task RTV data, across task conditions manipulating rewards and event rate, from a population-based twin sample (n=1314) and an ADHD and control sibling-pair sample (n=1265). RESULTS: Phenotypic and genetic/familial correlations were consistently high (0.72-0.98) between RTV baseline and difference scores, across tasks, manipulations and samples. By contrast, correlations were low between RTV in the manipulated condition and difference scores. A comparison across two different go/no-go task RTV difference scores (slow-fast/slow-incentive) showed high phenotypic and genetic/familial overlap (r = 0.75-0.83). CONCLUSIONS: Our finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV. Given the statistical shortcomings of difference scores, we recommend the use of RTV baseline scores for most analyses, including genetic analyses.

Intrauterine environment and cognitive development in young twins.

Intrauterine factors important for cognitive development, such as birth weight, chorionicity and umbilical cord characteristics were investigated. A total of 663 twin pairs completed the Wechsler Intelligence Scale for Children-Revised and scores were available for Performance, Verbal and Total Intelligence Quotient (IQ). The intrauterine factors examined were birth weight, placental weight and morphology, cord knots, cord length and cord insertion. IQ scores for the varying levels of the intrauterine markers adjusting for gender and gestational age were calculated. The heritability of IQ and the association between IQ and intrauterine environment were examined. Twins with lower birth weight and cord knots had lower IQ scores. The aetiology of IQ is largely distinct from that of birth weight and cord knots, and non-shared environment may influence the observed relationships.

Bigger families fare better: a novel method to estimate rater contrast effects in parental ratings on ADHD symptoms.

Many twin studies on parental ratings of attention deficit hyperactivity disorder (ADHD) symptoms report low or negative DZ correlations. The observed differences in MZ and DZ variances indicate sibling contrast effects, which appear to reflect a bias in parent ratings. Knowledge of the factors that contribute to this rater contrast effect is, however, limited. Using parent-rated ADHD symptoms from the Twins' Early Development Study and a novel application of a twin model, we explored a range of socio-demographic variables (ethnicity, socio-economic status, and family size), as potential contributors to contrast effects and their interactive effect with gender composition of twin pairs. Gender did moderate contrast effects but only in DZ opposite-sex twin pairs. Family size also showed a moderating effect on rater contrast effects, which was further modified by gender. We further observed an effect of rating scale, with the DSM-IV ADHD subscale of the Revised Conners' Parent Rating Scale more resistant to contrast effects than shorter scales of ADHD symptoms. The improved identification of situations where the accuracy of the most common informant of childhood ADHD symptoms-parents-is compromised as a result of rater bias, might have implications for future research on ADHD.

Phenotypic and genetic structure of anxiety sensitivity in adolescence and early adulthood.

Anxiety sensitivity is a risk factor for emotional disorders. The structure of anxiety sensitivity was examined using phenotypic and genetic analyses. Self-reported anxiety sensitivity was measured at three time points from adolescence into young adulthood by 2651 individuals from the G1219 twin study. Confirmatory factor analyses revealed comparable statistical support for anxiety sensitivity models consisting of three or four dimensions across all time points. The three-factor model depicting Physical, Social and Mental anxiety-related concerns was favoured due to greater interpretability and parsimony. Multivariate quantitative genetic analyses supported a hierarchical structure with general genetic (.09-.61) and non-shared environmental (.39-.72) influences acting via a higher-order factor as well as dimension-specific genetic (.09-.21) and non-shared environmental (.23-.68) influences. The findings provide further evidence for a hierarchical structure underlying different dimensions of anxiety sensitivity.

A twin study of body dysmorphic concerns.

BACKGROUND: Dysmorphic concern refers to an excessive preoccupation with a perceived or slight defect in physical appearance. It lies on a continuum of severity from no or minimal concerns to severe concerns over one's appearance. The present study examined the heritability of dysmorphic concerns in a large sample of twins. METHOD: Twins from the St Thomas UK twin registry completed a valid and reliable self-report measure of dysmorphic concerns, which also includes questions about perceived body odour and malfunction. Twin modelling methods (female twins only, n=3544) were employed to decompose the variance in the liability to dysmorphic concerns into additive genetic, shared and non-shared environmental factors. RESULTS: Model-fitting analyses showed that genetic factors accounted for approximately 44% [95% confidence intervals (CI) 36-50%] of the variance in dysmorphic concerns, with non-shared environmental factors and measurement error accounting for the remaining variance (56%; 95% CI 50-63%). Shared environmental factors were negligible. The results remained unchanged when excluding individuals reporting an objective medical condition/injury accounting for their concern in physical appearance. CONCLUSIONS: Over-concern with a perceived or slight defect in physical appearance is a heritable trait, with non-shared environmental factors also playing an important role in its causation. The results are relevant for various psychiatric disorders characterized by excessive concerns in body appearance, odour or function, including but not limited to body dysmorphic disorder.

Parents and teachers make different contributions to a shared perspective on hyperactive-impulsive and inattentive symptoms: a multivariate analysis of parent and teacher ratings on the symptom domains of ADHD.

Attention deficit hyperactivity disorder (ADHD) is characterised by developmentally inappropriate and impairing levels of inattentive and hyperactive-impulsive behaviours. We aimed to investigate the differential effects of parent and teacher ratings on inattention and hyperactivity-impulsivity and the extent of genetic overlap between the two behavioural dimensions. Multivariate structural equation modelling was performed on DSM-IV based ADHD ratings by parents and teachers collected on a general population sample of 672 twin pairs, at ages 7-10 years. This study is the first to simultaneously use parent and teacher ratings in twin modelling to examine the effects of different raters on the two behavioural dimensions of ADHD. The findings indicated that hyperactivity-impulsivity and inattention load on to separate latent factors that represent a common behavioural view for both parents and teachers, although there are additional aspects to the observations of these behaviours that are unique to each type of rater. The findings further indicate some shared aetiology for hyperactivity-impulsivity and inattention as measured by both parent and teacher ratings, in agreement with previous findings on the aetiology of the two symptom dimensions of ADHD.

The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ.

BACKGROUND: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. METHOD: Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS: Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

Genetic overlap between episodic memory deficits and schizophrenia: results from the Maudsley Twin Study.

BACKGROUND: Visual and verbal episodic memory deficits are putative endophenotypes for schizophrenia; however, the extent of any genetic overlap of these with schizophrenia is unclear. In this study, we set out to quantify the genetic and environmental contributions to variance in visual and verbal memory performance, and to quantify their genetic relationship with schizophrenia. METHOD: We applied bivariate genetic modelling to 280 twins in a classic twin study design, including monozygotic (MZ) and dizygotic (DZ) pairs concordant and discordant for schizophrenia, and healthy control twins. We assessed episodic memory using subtests of the Wechsler Memory Scale - Revised (WMS-R). RESULTS: Genetic influences (i.e. heritability) contributed significantly to variance in immediate recall of both verbal memory and visual learning, and the delayed recall of verbal and visual memory. Liability to schizophrenia was associated with memory impairment, with evidence of significant phenotypic correlations between all episodic memory measures and schizophrenia. Genetic factors were the main source of the phenotypic correlations for immediate recall of visual learning material; both immediate and delayed recall of verbal memory; and delayed recall of visual memory that, for example, shared genetic variance with schizophrenia, which accounted for 88% of the phenotypic correlation (rph=0.41) between the two. CONCLUSIONS: Verbal memory and visual learning and memory are moderately heritable, share a genetic overlap with schizophrenia and are valid endophenotypes for the condition. The inclusion of these endophenotypes in genetic association studies may improve the power to detect susceptibility genes for schizophrenia.

Do COMT, BDNF and NRG1 polymorphisms influence P50 sensory gating in psychosis?

BACKGROUND: Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. METHOD: The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. RESULTS: Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. CONCLUSIONS: The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle.

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.