The heritability of the brain’s structure and function in schizophrenia remains elusive

To assess the influence of genetic and environmental factors on executive function in schizophrenia.

A twin-sibling study of 206 subjects; 163 twins, varying in their zygosity and concordance for schizophrenia, and 43 singletons from sibling clusters varying in their concordance for schizophrenia. We assessed performance and regional brain activation using functional magnetic resonance imaging, during a phonological verbal fluency task.

Patients and their unaffected relatives developed greater activation in the left inferior frontal gyrus, and greater deactivation in the middle temporal gyri bilaterally. These features were maximally evident in subjects with schizophrenia. When the analysis was restricted to the unaffected relatives and healthy controls, a similar pattern was evident. Heritability was greatest in the left hippocampus and the right middle temporal gyrus. Genetic modelling indicated a phenotypic correlation between schizophrenia and increased activity in the inferior frontal gyrus and reduced activity in the left middle temporal gyrus and left hippocampus, which appeared principally due to shared genetic effects.

Both schizophrenia and its familial vulnerability were associated with altered frontal, parahippocampal and temporal activation during verbal fluency. The altered left inferior frontal activity was particularly associated with schizophrenia, while altered left medial temporal and right middle temporal activity were more heritable. The latter was more intimately linked to the genetic risk for schizophrenia, and thus the better candidate intermediate phenotype.

A bidirectional association between type 2 diabetes and depression has been consistently reported. It is associated with worse biomedical outcomes and increased mortality. One possible question is whether the co-occurrence of type 2 diabetes and depression is due to genetic and/or environmental vulnerabilities in common to the two traits.

To examine the genetic relationship between type 2 diabetes and depression at a population level.

To quantify the genetic overlap between type 2 diabetes and depression using the Swedish Twin Registry.

The study included 43,565 twin pairs (12,363 monozygotic pairs and 31,202 dizygotic pairs). The primary outcomes were lifetime diagnosis of type 2 diabetes and depression from the Swedish National Hospital Discharge Registry. Standard bivariate twin models were fitted to the raw data to estimate the genetic and environmental (co)variance of the two traits.

Heritability estimates for lifetime diagnoses of type 2 diabetes and depression were similar to previous estimates, at 77% and 42% respectively. The phenotypic correlation between type 2 diabetes and depression was 0.14 (95%CI: 0.11-0.17), of which 58% was due to shared genetic influences. When covariates (age and gender) were included, the genetic contribution to the phenotypic correlation reduced to 51%.

This is the first study to demonstrate a small but significant genetic overlap between type 2 diabetes and depression at a population level, using hospital-registry records.

Only a minority of trauma-exposed individuals go on to develop post traumatic stress disorder (PTSD). Previous studies in high-income countries suggest that maladaptive family functioning adversities (MFFA) in childhood may partially ex-plain individual variation in vulnerability to PTSD following trauma. We test in a lower middle income setting (Sri Lanka) whether: (1) MFFA moderates the association between exposure to trauma and later (a) PTSD (b) other psychiatric diagnoses; (2) any moderation by MFFA is explained by experiences of interpersonal violence, cumulative trauma exposure or other psychopathology.

We conducted a population study of 3995 twins and 2019 singletons residing in Colombo, Sri Lanka. Participants completed the composite international diagnostic interview, including nine traumatic exposures and a questionnaire on MFFA.

In total, 23.4% of participants reported exposure to MFFA. We found that (1) MFFA moderates the association between trauma exposure and both (a) PTSD and (b) non-PTSD diagnosis. (2) This was not explained by interpersonal violence, cumulative trauma exposure or other psychopathology.

In our sample MFFA moderates the association between trauma and PTSD, and the association between trauma and non-PTSD psychopathology.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

Abnormalities in early social development and personality are present in patients with schizophrenia and their unaffected relatives. This study aimed to establish the degree to which these childhood and adolescent developmental abnormalities are genetically determined.

We used a combined twin and family study design (n=531) to assess childhood and adolescent social adjustment and schizotypal personality traits in 98 twin pairs (n=196) varying in their zygosity and concordance for schizophrenia and 156 sibling clusters (n=335) varying in their concordance for schizophrenia.

Schizophrenia was significantly associated with childhood and adolescent deficits in social adjustment and personality, with additive genetic effects being the main source of these phenotypic correlations.

Abnormalities of social adjustment and personality are present in children and adolescents who later develop schizophrenia, reflecting the influence of common genetic risk.

Impaired P300 auditory response has been reported in patients with psychotic bipolar disorder (BPD) and unaffected relatives of psychotic bipolar patients. Deficits in mismatch negativity (MMN), however, have not been observed in bipolar patients. To our knowledge, no family study of MMN in BPD has been reported. The current study combined the Maudsley twin and bipolar family samples using genetic model fitting analyses to: (1) assess the relationship between BPD and MMN, (2) substantiate the association between psychotic BPD and P300 variables, (3) verify the genetic overlap of BPD with P300 amplitude previously reported in the twin sample, and (4) examine the shared genetic influences between BPD and bilateral temporal scalp locations of P300 components.

A total of 301 subjects were included in this study, including 94 twin pairs, 31 bipolar families, and 39 unrelated healthy controls. Statistical analyses were based on structural equation modelling.

Both P300 and MMN are heritable, with heritability estimates of 0.58 for MMN, 0.68–0.80 for P300 amplitude, and 0.21–0.56 for P300 latency. The bipolar patients and their relatives showed normal MMN. No significant association, either genetic or environmental, was found with BPD. BPD was significantly associated with reduced P300 amplitude and prolonged latency on midline and bilateral temporal-posterior scalp areas. Shared genetic factors were the main source of these associations.

The results confirm that MMN is not an endophenotype for psychotic BPD whereas P300 amplitude and latency components are valid endophenotypes for psychotic BPD.