Longitudinal Twin Study Research Articles

Whole-cortex mapping of common genetic influences on depression and a social deficits dimension

Social processes are associated with depression, particularly understanding and responding to others, deficits in which can manifest as callousness/unemotionality (CU). Thus, CU may reflect some of the genetic risk to depression. Further, this vulnerability likely reflects the neurological substrates of depression, presenting biomarkers to capture genetic vulnerability of depression severity. However, heritability varies within brain regions, so a high-resolution genetic perspective is needed. We developed a toolbox that maps genetic and environmental associations between brain and behavior at high resolution. We used this toolbox to estimate brain areas that are genetically associated with both depressive symptoms and CU in a sample of 258 same-sex twin pairs from the Colorado Longitudinal Twin Study (LTS). We then overlapped the two maps to generate coordinates that allow for tests of downstream effects of genes influencing our clusters. Genetic variance influencing cortical thickness in the right dorsal lateral prefrontal cortex (DLFPC) sulci and gyri, ventral posterior cingulate cortex (PCC), pre-somatic motor cortex (PreSMA), medial precuneus, left occipital-temporal junction (OTJ), parietal–temporal junction (PTJ), ventral somatosensory cortex (vSMA), and medial and lateral precuneus were genetically associated with both depression and CU. Split-half replication found support for both DLPFC clusters. Meta-analytic term search identified “theory of mind”, “inhibit”, and “pain” as likely functions. Gene and transcript mapping/enrichment analyses implicated calcium channels. CU reflects genetic vulnerability to depression that likely involves executive and social functioning in a distributed process across the cortex. This approach works to unify neuroimaging, neuroinformatics, and genetics to discover pathways to psychiatric vulnerability.

Are changes in ADHD course reflected in differences in IQ and executive functioning from childhood to young adulthood?

Attention-deficit hyperactivity disorder (ADHD) is associated with poorer cognitive functioning. We used a developmental, genetically-sensitive approach to examine intelligence quotient (IQ) from early childhood to young adulthood among those with different ADHD courses to investigate whether changes in ADHD were reflected in differences in IQ. We also examined executive functioning in childhood and young adulthood among different ADHD courses. Study participants were part of the Environmental Risk (E-Risk) Longitudinal Twin Study, a population-based birth cohort of 2232 twins. We assessed ADHD in childhood (ages 5, 7, 10 and 12) and young adulthood (age 18). We examined ADHD course as reflected by remission, persistence and late-onset. IQ was evaluated at ages 5, 12 and 18, and executive functioning at ages 5 and 18. ADHD groups showed deficits in IQ across development compared to controls; those with persistent ADHD showed the greatest deficit, followed by remitted and late-onset. ADHD groups did not differ from controls in developmental trajectory of IQ, suggesting changes in ADHD were not reflected in IQ. All ADHD groups performed more poorly on executive functioning tasks at ages 5 and 18; persisters and remitters differed only on an inhibitory control task at age 18. Differences in ADHD course - persistence, remission and late-onset - were not directly reflected in changes in IQ. Instead, having ADHD at any point across development was associated with lower average IQ and poorer executive functioning. Our finding that individuals with persistent ADHD have poorer response inhibition than those who remitted requires replication.

RELATION BETWEEN ERECTILE DYSFUNCTION AND AMNESTIC MILD COGNITIVE IMPAIRMENT ACROSS TWO TIME POINTS

Previous research by the Vietnam Era Twin Study of Aging (VETSA) demonstrated an association between erectile dysfunction (ED) and cognitive functioning. That finding supports a hypothesis that cardiovascular dysfunction may underlie both ED and problems in cognitive functioning. The purpose of the current research was to extend these findings by investigating a putative association between ED and amnestic and non-amnestic mild cognitive impairment (MCI). MCI is of particular interest because of its relationship with Alzheimer’s disease and other dementing illnesses. VETSA is a longitudinal study of twins who served in the US military during the Vietnam conflict (N= 960) consisting of data collected at age 20 (enlistment), age 55 (VETSA 1), and 61 (VETSA 2). The results of the current analyses show that ED is related to both amnestic MCI (p=.032) and non-amnestic MCI (p=.009) at VETSA 1. At VETSA 2, however, the relationship between ED and non-amnestic MCI was no longer significant (p=.751) while the relationship between ED and amnestic MCI was stronger (p=.001). These results are consistent with ED and MCI sharing, to some extent, a common etiology. Vascular dysfunction, which is associated with both ED and MCI, is a plausible mechanism responsible for the observed relationship. These results also highlight the potential role that may be played by ED as an early indicator of cognitive impairment and, perhaps, pre-symptomatic AD.

Developing an individualized risk calculator for psychopathology among young people victimized during childhood: A population-representative cohort study

BackgroundVictimized children are at greater risk for psychopathology than non-victimized peers. However, not all victimized children develop psychiatric disorders, and accurately identifying which victimized children are at greatest risk for psychopathology is important to provide targeted interventions. This study sought to develop and internally validate individualized risk prediction models for psychopathology among victimized children. MethodsParticipants were members of the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative British birth cohort of 2,232 twins born in 1994–1995. Victimization exposure was measured prospectively between ages 5 and 12 years, alongside a comprehensive range of individual-, family-, and community-level predictors of psychopathology. Structured psychiatric interviews took place at age-18 assessment. Logistic regression models were estimated with Least Absolute Shrinkage and Selection Operator (LASSO) regularization to avoid over-fitting to the current sample, and internally validated using 10-fold nested cross-validation. Results26.5% (n = 591) of E-Risk participants had been exposed to at least one form of severe childhood victimization, and 60.4% (n = 334) of victimized children met diagnostic criteria for any psychiatric disorder at age 18. Separate prediction models for any psychiatric disorder, internalizing disorders, and externalizing disorders selected parsimonious subsets of predictors. The three internally validated models showed adequate discrimination, based on area-under-the-curve estimates (range = =0.66–0.73), and good calibration. LimitationsExternal validation in wholly-independent data is needed before clinical implementation. ConclusionsFindings offer proof-of-principle evidence that prediction modeling can be useful in supporting identification of victimized children at greatest risk for psychopathology. This has the potential to inform targeted interventions and rational resource allocation.

Association of Adverse Experiences and Exposure to Violence in Childhood and Adolescence With Inflammatory Burden in Young People

Childhood stress exposure is associated with inflammation as measured by C-reactive protein (CRP) and interleukin 6 (IL-6). However, findings are inconsistent and effect sizes are small. The addition of soluble urokinase plasminogen activator receptor (suPAR), a new biomarker of chronic inflammation, may improve measurement of stress-related inflammatory burden. To assess whether exposure to adverse experiences, stress, and violence is associated with an increase in suPAR levels in young people and to test the hypothesis that measuring suPAR in addition to CRP or IL-6 levels improves the assessment of the inflammatory burden associated with early-life stress. This cohort study included 1391 participants from a 1994 to 1995 birth cohort of twins from the nationally representative Environmental Risk Longitudinal Twin Study in the United Kingdom. Participants were followed up until 18 years of age (93% retention). Plasma samples were analyzed in July 2018, and statistical analysis was performed from October 1, 2018, to May 31, 2019. Adverse childhood experiences and childhood and adolescent experience of stress and violence exposure. Plasma CRP, IL-6, and suPAR levels at 18 years of age. Among 1391 young people (mean [SD] age, 18.4 [0.36] years; 733 [52.7%] female), those who had been exposed to stressful experiences had elevated suPAR levels by 18 years of age after controlling for sex, body mass index, and smoking: 0.03-ng/mL (95% CI, 0.01-0.05 ng/mL) increase in suPAR per each additional adverse childhood experience, 0.09-ng/mL (95% CI, 0.01-0.17 ng/mL) increase in suPAR per each additional severe childhood experience of stress or violence, and 0.04-ng/mL (95% CI, -0.02 to 0.10 ng/mL) increase in suPAR per each additional severe adolescent experience of stress or violence. Individuals exposed to multiple types of violence in both childhood and adolescence had 0.26-ng/mL (95% CI, 0.07-0.45 ng/mL) higher suPAR levels compared with children who did not experience stress or violence. These stress-exposed young people were significantly more likely to have elevated suPAR levels at 18 years of age even if they did not have elevated CRP or IL-6 levels. Measuring suPAR in addition to CRP or IL-6 increased the association between stress exposure and inflammatory burden. For example, after adjusting for CRP and IL-6 levels, each additional adverse childhood experience was associated with a 0.05-mL (95% CI, 0.03-0.07 ng/mL) increase in suPAR, each additional severe childhood experience of stress or violence was associated with a 0.14-ng/mL (95% CI, 0.06-0.22 ng/mL) increase in suPAR, and each additional severe adolescent experience of stress or violence was associated with a 0.10-ng/mL (95% CI, 0.04-0.16 ng/mL) increase in suPAR. The results suggest that adult inflammation is associated with childhood exposure to stress. Adding information about suPAR to traditional biomarkers of inflammation may improve the measurement of inflammatory burden associated with exposure to stress and violence.

Investigating the causal effect of cannabis use on cognitive function with a quasi-experimental co-twin design

BackgroundIt is unclear whether cannabis use causes cognitive decline; several studies show an association between cannabis use and cognitive decline, but quasi-experimental twin studies have found little support for a causal effect. Here, we evaluate the association of cannabis use with general cognitive ability and executive functions (EFs) while controlling for genetic and shared environmental confounds in a longitudinal twin study. MethodsWe first examined the phenotypic associations between cannabis initiation, frequency, and use disorder with cognitive abilities, while also controlling for pre-use general cognitive ability and other substance involvement. We tested the concurrent association between the cannabis use variables and cognitive abilities in late adolescence and young adulthood and the longitudinal association between cannabis use variables during adolescence and young adulthood cognitive abilities. Next, we used multilevel models to test whether these relations reflect between- and/or within-twin pair associations. ResultsPhenotypically, cannabis use was related to poorer cognitive functioning, although most associations were negligible after accounting for other substance use. Nevertheless, there were few significant within-family twin-specific associations, except that age 17 cannabis frequency was associated with worse age 23 Common EF and general cognitive ability. ConclusionsWe found little support for a potential causal effect of cannabis use on cognition, consistent with previous twin studies. Results suggest that cannabis use may not cause decline in cognitive ability among a normative sample of cannabis users.

Development of an individualized risk calculator for poor functioning in young people victimized during childhood: A longitudinal cohort study

BackgroundChildhood victimization elevates the average risk of developing functional impairment in adulthood. However, not all victimized children demonstrate poor outcomes. Although research has described factors that confer vulnerability or resilience, it is unknown if this knowledge can be translated to accurately identify the most vulnerable victimized children. ObjectiveTo build and internally validate a risk calculator to identify those victimized children who are most at risk of functional impairment at age 18 years. ParticipantsWe utilized data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative birth cohort of 2232 UK children born in 1994–95. MethodsVictimization exposure was assessed repeatedly between ages 5 and 12 years along with a range of individual-, family- and community-level predictors. Functional outcomes were assessed at age 18 years. We developed and evaluated a prediction model for psychosocial disadvantage and economic disadvantage using the Least Absolute Shrinkage and Selection Operator (LASSO) regularized regression with nested 10-fold cross-validation. ResultsThe model predicting psychosocial disadvantage following childhood victimization retained 12 of 22 predictors, had an area under the curve (AUC) of 0.65, and was well-calibrated within the range of 40–70% predicted risk. The model predicting economic disadvantage retained 10 of 22 predictors, achieved excellent discrimination (AUC = 0.80), and a high degree of calibration. ConclusionsPrediction modelling techniques can be applied to estimate individual risk for poor functional outcomes in young adulthood following childhood victimization. Such risk prediction tools could potentially assist practitioners to target interventions, which is particularly useful in a context of scarce resources.

Twins Early Development Study: A Genetically Sensitive Investigation into Behavioral and Cognitive Development from Infancy to Emerging Adulthood

The Twins Early Development Study (TEDS) is a longitudinal twin study that recruited over 16,000 twin-pairs born between 1994 and 1996 in England and Wales through national birth records. More than 10,000 of these families are still engaged in the study. TEDS was and still is a representative sample of the population in England and Wales. Rich cognitive and emotional/behavioral data have been collected from the twins from infancy to emerging adulthood, with data collection at first contact and at ages 2, 3, 4, 7, 8, 9, 10, 12, 14, 16, 18 and 21, enabling longitudinal genetically sensitive analyses. Data have been collected from the twins themselves, from their parents and teachers, and from the UK National Pupil Database. Genotyped DNA data are available for 10,346 individuals (who are unrelated except for 3320 dizygotic co-twins). TEDS data have contributed to over 400 scientific papers involving more than 140 researchers in 50 research institutions. TEDS offers an outstanding resource for investigating cognitive and behavioral development across childhood and early adulthood and actively fosters scientific collaborations.

Epigenome-wide association study of leukocyte telomere length.

Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) – the Framingham Heart Study, the Jackson Heart Study, the Women’s Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.

Genetic and environmental risk factors in the non-medical use of over-the-counter or prescribed analgesics, and their relationship to major classes of licit and illicit substance use and misuse in a population-based sample of young adult twins.

The non-medical use of over-the-counter or prescribed analgesics (NMUA) is a significant public health problem. Little is known about the genetic and environmental etiology of NMUA and how these risks relate to other classes of substance use and misuse. Our aims were to estimate the heritability NMUA and sources of genetic and environmental covariance with cannabis and nicotine use, cannabis and alcohol use disorders and nicotine dependence in Australian twins. Biometrical genetic analyses or twin methods using structural equation univariate and multivariate modeling. Australia. A total of 2007 young adult twins [66% female; μage =25.9, standard deviation (SD)=3.6, range=18-38] from the Brisbane Longitudinal Twin Study retrospectively assessed between 2009 and 2016. Self-reported NMUA (non-opioid or opioid-based), life-time nicotine, cannabis and opioid use, DSM-V cannabis and alcohol use disorders and the Fagerström Test for Nicotine Dependence. Life-time NMUA was reported by 19.4% of the sample. Univariate heritability explained 46% [95% confidence interval (CI)=0.29-0.57] of the risks in NMUA. Multivariate analyses revealed that NMUA is moderately associated genetically with cannabis (rg =0.41) and nicotine (rg =0.45) use and nicotine dependence (rg =0.34). In contrast, the genetic correlations with cannabis (rg =0.15) and alcohol (rg =0.07) use disorders are weak. In young male and female adults in Australia, the non-medical use of over-the-counter or prescribed analgesics appears to have moderate heritability. NMUA is moderately associated with cannabis and nicotine use and nicotine dependence. Its genetic etiology is largely distinct from that of cannabis and alcohol use disorders.

Using discordant twin methods to investigate an environmentally mediated pathway between social support and the reduced likelihood of adolescent psychotic experiences.

Social support has been shown to be associated with a reduced likelihood of developing psychotic experiences in the general population and even amongst those at high risk due to exposure to multiple forms of victimisation (poly-victimised). However, it is unclear whether this association is merely due to the confounding effects of shared environmental and genetic influences, or reverse causality. Therefore, we investigated whether social support has a unique environmentally mediated effect on adolescent psychotic experiences after accounting for familial factors, including genetic factors, and also prior psychopathology. Participants were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 UK-born twins. Adolescents were interviewed at age 18 about psychotic experiences and victimisation exposure since age 12, and their perceptions of social support. Prior childhood mental health problems and psychotic symptoms were assessed at age 12. The discordant twin method was used to disentangle the relative family-wide and unique-environmental effects of social support on psychotic experiences in the general population and among poly-victimised adolescents. Perceived social support, particularly from friends, was found to have a unique environmentally mediated buffering effect on adolescent psychotic experiences in the whole sample and in the high-risk poly-victimised group. The protective effects of social support on adolescent psychotic experiences cannot be accounted for by shared environmental or genetic factors, nor by earlier psychopathology. Our findings suggest that early intervention programmes focused on increasing perceptions of social support have the potential to prevent the emergence of psychotic experiences amongst adolescents.

Association of Genetic and Environmental Risks for Attention-Deficit/Hyperactivity Disorder With Hypomanic Symptoms in Youths

Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder are highly comorbid, with significantly associated symptoms. The mechanisms that account for their co-occurrence are not known. To examine the degree to which genetic and environmental risk factors for ADHD traits, across childhood and adolescence, are associated with adolescent hypomanic symptoms. This study used data on 13 532 twin pairs from the Child and Adolescent Twin Study in Sweden, a prospective, longitudinal twin study. Their parents provided ADHD data when children were 9 or 12 years of age. Of those who reached 15 years of age, 3784 participated. Of those who reached 18 years of age, 3013 participated. The study was performed from December 20, 2017, to December 5, 2018. Data analysis was performed at the Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden, from March 1, 2018, to October 31, 2018. Attention-deficit/hyperactivity disorder traits and hypomanic symptoms were assessed using parent-rated instruments. Associations between ADHD and adolescent hypomanic symptoms across childhood and adolescence were investigated using generalized estimating equations. Multivariate twin models were used to examine the extent to which genetic and environmental risk factors for ADHD were associated with hypomania. Among 3784 15-year-old twin pairs and 3013 18-year-old twin pairs, ADHD and hypomanic symptoms were significantly associated (age 15 years: β = 0.30; 95% CI, 0.24-0.34; P < .001; age 18 years: β = 0.19; 95% CI, 0.16-0.22; P < .001), especially for the hyperactivity-impulsivity ADHD symptom domain (age 15 years: β = 0.53; 95% CI, 0.46-0.60; P < .001; age 18 years: β = 0.36; 95% CI, 0.30-0.42; P < .001) compared with the inattention domain (age 15 years: β = 0.40; 95% CI, 0.34-0.47; P < .001; age 18 years: β = 0.24; 95% CI, 0.19-0.29; P < .001). Between 13% and 29% of the genetic risk factors for hypomania were also associated with ADHD, with higher estimates detected for symptoms of hyperactivity-impulsivity (10%-25%) compared with inattention (6%-16%). Environmental factors played a negligible role in the associations. Genetic factors unique to adolescent hypomania were associated with 25% to 42% of its variance, suggesting some etiologic distinction between these forms of psychopathology. More than a quarter of the genetic risk factors for adolescent hypomanic traits were also associated with ADHD symptoms in childhood and adolescence, with hypomania-specific genetic risk factors detected. These findings suggest that ADHD and hypomanic symptoms are associated with shared genetic factors, which should be the focus of further research.

Genetic and environmental influences on functional connectivity within and between canonical cortical resting-state networks throughout adolescent development in boys and girls

The human brain is active during rest and hierarchically organized into intrinsic functional networks. These functional networks are largely established early in development, with reports of a shift from a local to more distributed organization during childhood and adolescence. It remains unknown to what extent genetic and environmental influences on functional connectivity change throughout adolescent development. We measured functional connectivity within and between eight cortical networks in a longitudinal resting-state fMRI study of adolescent twins and their older siblings on two occasions (mean ages 13 and 18 years). We modelled the reliability for these inherently noisy and head-motion sensitive measurements by analyzing data from split-half sessions. Functional connectivity between resting-state networks decreased with age whereas functional connectivity within resting-state networks generally increased with age, independent of general cognitive functioning. Sex effects were sparse, with stronger functional connectivity in the default mode network for girls compared to boys, and stronger functional connectivity in the salience network for boys compared to girls. Heritability explained up to 53% of the variation in functional connectivity within and between resting-state networks, and common environment explained up to 33%. Genetic influences on functional connectivity remained stable during adolescent development. In conclusion, longitudinal age-related changes in functional connectivity within and between cortical resting-state networks are subtle but wide-spread throughout adolescence. Genes play a considerable role in explaining individual variation in functional connectivity with mostly stable influences throughout adolescence.

Mental Health and Functional Outcomes in Young Adulthood of Children With Psychotic Symptoms: A Longitudinal Cohort Study.

BackgroundChildhood psychotic symptoms have been associated with various psychiatric disorders in adulthood but their role as early markers of poor outcomes during the crucial transition to adulthood is largely unknown. Therefore, we investigated associations between age-12 psychotic symptoms and a range of mental health problems and functional outcomes at age 18. MethodsData were used from the Environmental Risk Longitudinal Twin Study, a nationally representative birth cohort of 2232 twins born in 1994–1995 in England and Wales, followed to age 18 with 93% retention. Childhood psychotic symptoms were assessed in structured interviews at age 12. At age 18, study members’ mental health problems, functional outcomes, risky behaviors, and offending were measured using self-reports and official records. ResultsChildren with psychotic symptoms (N = 125, 5.9%) were more likely to experience a range of mental health problems in young adulthood than children without such symptoms. They were also more likely to be obese, smoke cigarettes, be lonely, be parents, and report a lower quality of life, but not more likely to commit crimes. Childhood psychotic symptoms predicted these poor outcomes over and above other emotional and behavioral problems during childhood. Nevertheless, twin analyses indicated that these associations were largely accounted for by shared family factors. ConclusionsPsychotic symptoms in childhood signal risk for pervasive mental health and functional difficulties in young adulthood and thus may provide a useful screen for an array of later problems. However, early psychotic symptoms and poor outcomes may be manifestations of shared environmental and genetic risks.

Borderline Symptoms at Age 12 Signal Risk for Poor Outcomes During the Transition to Adulthood: Findings From a Genetically Sensitive Longitudinal Cohort Study

ObjectiveBorderline personality disorder in adolescence remains a controversial construct. We addressed concerns about the prognostic significance of adolescent borderline pathology by testing whether borderline symptoms at age 12 years predict functioning during the transition to adulthood, at age 18 years, in areas critical to life-course development.MethodWe studied members of the Environmental Risk (E-Risk) Longitudinal Twin Study, which tracks the development of a birth cohort of 2,232 British twin children. At age 12, study members' borderline symptoms were measured using mothers’ reports. At age 18, study members’ personality, psychopathology, functional outcomes, and experiences of victimization were measured using self-reports, coinformant reports, and official records.ResultsAt age 18, study members who had more borderline symptoms at age 12 were more likely to have difficult personalities, to struggle with poor mental health, to experience poor functional outcomes, and to have become victims of violence. Reports of poor outcomes were corroborated by coinformants and official records. Borderline symptoms in study members at 12 years old predicted poor outcomes over and above other behavioral and emotional problems during adolescence. Twin analyses showed that borderline symptoms in 12-year-olds were influenced by familial risk, particularly genetic risk, which accounted for associations with most poor outcomes at age 18.ConclusionBorderline symptoms in 12-year-olds signal risk for pervasive poor functioning during the transition to adulthood. This association is driven by genetic influences, suggesting that borderline symptoms and poor outcomes are manifestations of shared genetic risk.

High naevus count and MC1R red hair alleles contribute synergistically to increased melanoma risk.

A high total body naevus count is the highest risk factor for melanoma; the phenotype of red hair colour, freckling and pale skin that burns easily, produced by MC1R R alleles, also predisposes to melanoma. To determine whether the known melanoma risk factors of high naevus count and red hair or MC1R R alleles act synergistically to increase melanoma risk. The Brisbane Naevus Morphology Study involved 1267 participants from volunteers presenting at a melanoma unit, dermatology outpatient clinic, private dermatology clinics, the Brisbane Longitudinal Twin Study and the QSkin Study. We examined pigmentation characteristics, total body naevus ≥ 5 mm count, and MC1R, ASIP and CDKN2A genotype in participants with and without a personal history of melanoma, living in Queensland, Australia, which is an area of high ultraviolet radiation. Cases were older than controls (median 57 vs. 33 years). Compared with individuals with dark brown hair and zero to four naevi, individuals with red hair and ≥ 20 naevi had a melanoma odds ratio of 10·0 (95% confidence interval 4·2-24·3). Individuals with MC1R R/R genotype and ≥ 20 naevi (≥ 5 mm diameter) had a melanoma odds ratio of 25·1 (95% confidence interval 8·4-82·7) compared with wild-type (WT)/WT individuals with zero to four naevi. The highest risk group is Australian men with the MC1R R/R genotype and ≥ 20 moles, who have an absolute risk of melanoma to age 75 years of 23·3%, compared with 0·8% for men with the WT/WT genotype and zero to four naevi. Patients who live in areas of high ultraviolet radiation, and have many large naevi and the red hair colour phenotype, particularly those with the MC1R R/R genotype, have a high risk of melanoma above the threshold recommended for screening in other cancers. Therefore, they should undergo intensive physician-led surveillance. What's already known about this topic? A high number of acquired melanocytic naevi, the red hair phenotype and MC1R R alleles all independently increase melanoma risk. Women with atypical naevi have an increasing melanoma risk gradient from darker hair to lighter hair. Women with many naevi have an increasing melanoma risk gradient from those with no elements of the red hair phenotype, to those with freckles but not red hair, to those with red hair. What does this study add? In Queensland, Australia, people with ≥ 20 naevi (≥ 5 mm diameter) and MC1R R/R genotype have a 25-fold increased melanoma risk, relative to people with zero to four naevi and the MC1R WT/WT genotype. In Queensland, individuals with ≥ 20 naevi and the MC1R R/R genotype have an absolute melanoma risk to age 75years of 23·3% for men and 19·3% for women. This effect is independent of CDKN2A genotype. Further research is required to determine the effect of areas of lower ultraviolet radiation, as this study took place in the Queensland, Australia, which is an area of high ultraviolet radiation. MC1R R/r genotype is associated with increased total body naevus count but this is not the case for R/R. What is the translational message? Patients with many large naevi and the red hair colour phenotype, particularly those with an MC1R R/R genotype, have an unusually high risk of melanoma. In a high ultraviolet environment, this risk exceeds the threshold recommended for screening in other cancers, and such individuals should undergo intensive, regular, physician-led surveillance. Patients with many large naevi but with non-red colour hair may benefit further from clinical MC1R genotyping.

Are rumination and neuroticism genetically or environmentally distinct risk factors for psychopathology?

Neuroticism, a dispositional trait of heightened negative emotionality, is a vulnerability factor for psychopathology. Given neuroticism's strong association with rumination, a repetitive thought pattern that intensifies and prolongs emotions, some question whether these constructs capture the same or unique information about vulnerability for psychopathology. The present study examined whether neuroticism is genetically and environmentally distinct from two clinically relevant ruminative subtypes-anger and depressive rumination-and whether genetic and environmental influences specific to rumination versus shared with neuroticism overlap with internalizing and externalizing psychopathology. These analyses were conducted on 439 same-sex twin pairs in the Colorado Longitudinal Twin study. Rumination and neuroticism latent variables were created from multiple rumination questionnaires administered at age 23 and shortened Eysenck Personality Questionnaires administered at ages 17 and 21, respectively. Lifetime psychopathology symptoms, assessed by two structured clinical interviews, were used to create ordinal composite variables. Multivariate Cholesky decompositions indicated that neuroticism, anger rumination, and depressive rumination have common genetic and nonshared environmental influences but are differentiated by nonshared environmental influences specific to each ruminative subtype. Genetic influences common to rumination and neuroticism explained considerable variance in internalizing psychopathology, suggesting possible genetic mediation or common genetic causes. Genetic and environmental influences on externalizing psychopathology did not substantially overlap with those on neuroticism and rumination. These findings suggest that rumination and neuroticism share most genetic influences yet are influenced by distinct environmental influences. Furthermore, our results indicate that a comprehensive understanding of transdiagnostic risk factors must include an examination of both genetic and environmental influences. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Rumination and executive functions: Understanding cognitive vulnerability for psychopathology

IntroductionBoth rumination, a pattern of repetitive, self-focused thought in response to distress, and deficits in executive functions (EFs), a set of cognitive abilities that facilitate higher-order thinking, have transdiagnostic associations with psychopathology. Although empirical studies suggest associations between EFs and rumination, this literature has not examined subtypes of rumination and different components of EFs. It also has not examined whether rumination and EFs explain overlapping variance in psychopathology, which is relevant to theoretical models suggesting that rumination might mediate the EF–psychopathology association. MethodsWe used structural equation modeling to examine the association between latent factors for two types of rumination (anger and depressive) and three components of EF (a Common EF factor, and factors specific to updating working memory and shifting mental sets) and whether they independently relate to internalizing and externalizing psychopathology in a population sample of 764 young adults (mean age 23 years) from the Colorado Longitudinal Twin Study. ResultsDepressive and Anger Rumination showed small correlations with a Common EF factor (rs = –.09 to –.11). Anger Rumination and Common EF ability were associated with independent variance in externalizing psychopathology, whereas Depressive Rumination, but not Common EF, was associated with internalizing psychopathology. LimitationsExamination of cross-sectional relations in a population sample led to low symptom endorsement for psychopathology and necessitated examination of lifetime, rather than past-year, psychopathology. ConclusionsInconsistent with mediation hypotheses, Common EF abilities and rumination are correlated yet largely independent constructs that both predict psychopathology.

Twenty-Five and Up (25Up) Study: A New Wave of the Brisbane Longitudinal Twin Study.

The aim of the 25 and Up (25Up) study was to assess a wide range of psychological and behavioral risk factors behind mental illness in a large cohort of Australian twins and their non-twin siblings. Participants had already been studied longitudinally from the age of 12 and most recently in the 19Up study (mean age = 26.1 years, SD = 4.1, range = 20-39). This subsequent wave follows up these twins several years later in life (mean age = 29.7 years, SD=2.2, range= 22-44). The resulting data set enables additional detailed investigations of genetic pathways underlying psychiatric illnesses in the Brisbane Longitudinal Twin Study (BLTS). Data were collected between 2016 and 2018 from 2540 twins and their non-twin siblings (59% female, including 341 monozygotic complete twin-pairs, 415 dizygotic complete pairs and 1028 non-twin siblings and singletons). Participants were from South-East Queensland, Australia, and the sample was of predominantly European ancestry. The 25Up study collected information on 20 different mental disorders, including depression, anxiety, substance use, psychosis, bipolar and attention-deficit hyper-activity disorder, as well as general demographic information such as occupation, education level, number of children, self-perceived IQ and household environment. In this article, we describe the prevalence, comorbidities and age of onset for all 20 examined disorders. The 25Up study also assessed general and physical health, including physical activity, sleep patterns, eating behaviors, baldness, acne, migraines and allergies, as well as psychosocial items such as suicidality, perceived stress, loneliness, aggression, sleep-wake cycle, sexual identity and preferences, technology and internet use, traumatic life events, gambling and cyberbullying. In addition, 25Up assessed female health traits such as morning sickness, breastfeeding and endometriosis. Furthermore, given that the 25Up study is an extension of previous BLTS studies, 86% of participants have already been genotyped. This rich resource will enable the assessment of epidemiological risk factors, as well as the heritability and genetic correlations of mental conditions.

Genetic and environmental influences on attention-deficit/hyperactivity disorder symptoms in Chinese adolescents: a longitudinal twin study.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. However, no study has examined genetic and environmental influences in the longitudinal developmental course of ADHD symptoms in a non-Western population. This study investigated changes of genetic and environmental influences and their contributions to the stability and change of ADHD symptoms of hyperactivity/impulsivity and inattention in Chinese adolescent twins. A prospective sample of 602 twin pairs (48% male) self-reported both DSM-IV ADHD symptom subscales three times at the approximate age of 12, 13, and 15years. Longitudinal multivariate genetic analyses through structural equation modelling examined genetic and environmental contributions to the developmental course of ADHD symptoms. From early (time 1 and 2) to middle adolescence (time 3), both symptoms showed modest and non-significant genetic influences that became substantial and significant, whereas shared environmental influences were substantial and significant and became modest and non-significant. The same genetic factors influenced ADHD symptoms throughout adolescence, while shared and non-shared environmental influences largely came from new emerging factors. In early adolescence, genetic factor contributed to the stability of inattention, whereas shared environmental factor contributed to the stability of hyperactivity/impulsivity. Genetic influences of ADHD tended to be smaller, whereas shared environmental influences tended to be larger in Chinese than in Western populations. Genetic factors played a large role in the stability of ADHD throughout adolescence, while shared and non-shared environment primarily contributed to its change. Findings highlight the importance of shared family, neighbourhood, and community experiences on child psychopathology in a collectivistic culture such as the Chinese society.