Investigating the genetic and environmental aetiologies of non-suicidal and suicidal self-harm: a twin study

BACKGROUND: Self-harm is a major health concern, not only as a signal of distress but also as a strong predictor of later suicide. Self-harm can be further refined into suicidal self-harm (SSH, i.e. suicide attempt) and non-suicidal self-harm (NSSH). Understanding the aetiologies of NSSH and SSH can help inform suicide prevention strategies. Using a twin design, we investigated the phenotypic and aetiological relationships between NSSH and SSH, and their aetiological overlap with mental health problems. METHODS: We analysed data from the Twins Early Development Study using structural equation modelling. At age 21 years, 9063 twins (62.4% female) answered questions related to self-harm. At age 16 years, 19 self- or parent-reported mental health measures were administered, including measures of internalising and externalising problems, psychotic-like experiences and substance abuse. RESULTS: Prevalences for NSSH and SSH were 21.9% and 10.5%, respectively. Additive genetic factors explained half of the variance in NSSH (55%) and SSH (50%), with the rest explained by non-shared environmental factors. Phenotypically, NSSH and SSH were strongly correlated (r = 0.87) with their correlation explained by genetic (57%) and non-shared environmental (43%) factors. We found no evidence that NSSH and SSH differed in their phenotypic and aetiological relationships with mental health measures. CONCLUSION: Our findings suggest no aetiological difference between NSSH and SSH. NSSH and SSH should be regarded as two different ends of a continuum, rather than as two distinct categories

Protecting against researcher bias in secondary data analysis: challenges and potential solutions

Analysis of secondary data sources (such as cohort studies, survey data, and administrative records) has the potential to provide answers to science and society’s most pressing questions. However, researcher biases can lead to questionable research practices in secondary data analysis, which can distort the evidence base. While pre-registration can help to protect against researcher biases, it presents challenges for secondary data analysis. In this article, we describe these challenges and propose novel solutions and alternative approaches. Proposed solutions include approaches to (1) address bias linked to prior knowledge of the data, (2) enable pre-registration of non-hypothesis-driven research, (3) help ensure that pre-registered analyses will be appropriate for the data, and (4) address difficulties arising from reduced analytic flexibility in pre-registration. For each solution, we provide guidance on implementation for researchers and data guardians. The adoption of these practices can help to protect against researcher bias in secondary data analysis, to improve the robustness of research based on existing data

Childhood trajectories of inattention, hyperactivity and oppositional behaviors and prediction of substance abuse/dependence: a 15-year longitudinal population-based study.

Numerous prospective studies have shown that children diagnosed with attention deficit/hyperactivity disorder (ADHD) are at higher risk of long-term substance abuse/dependence. However, there are three important limits to these studies: (a) most did not differentiate the role of hyperactivity and inattention; (b) most did not control for associated behavioral problems; and (c) most did not consider females. Our aim was to clarify the unique and interactive contributions of childhood inattention and hyperactivity symptoms to early adulthood substance abuse/dependence. Behavioral problems of 1803 participants (814 males) in a population-based longitudinal study were assessed yearly between 6 and 12 years by mothers and teachers. The prevalence of substance abuse/dependence at age 21 years was 30.7% for nicotine, 13.4% for alcohol, 9.1% for cannabis and 2.0% for cocaine. The significant predictors of nicotine dependence were inattention (odds ratio (OR): 2.25; 95% confidence interval (CI): 1.63-3.11) and opposition (OR: 1.65; 95%: 1.20-2.28). Only opposition contributed to the prediction of cannabis dependence (OR: 2.33; 95% CI: 1.40-3.87) and cocaine dependence (OR: 2.97; 95% CI: 1.06-8.57). The best behavioral predictor of alcohol abuse/dependence (opposition) was only marginally significant (OR: 1.38; 95% CI: 0.98-1.95). Frequent oppositional behaviors during elementary school were clearly the most pervasive predictors of substance abuse/dependence in early adulthood. The association of childhood ADHD with substance abuse/dependence is largely attributable to its association with opposition problems during childhood. However, inattention remained an important predictor of nicotine dependence, in line with genetic and molecular commonalities between the two phenotypes suggested in the literature

The developmental course of inattention symptoms predicts academic achievement due to shared genetic aetiology: a longitudinal twin study

Symptoms of attention-deficit hyperactivity disorder, in particular inattention symptoms, are associated with academic achievement. However, whether and why the developmental course of inattention symptoms (i.e. systematic decreases or increases of symptoms with age) predicts academic achievement remains unclear. A total of 5634 twin pairs born in the UK were included in the current study. We used latent growth curve modelling to estimate the baseline level and the developmental course of inattention symptoms (assessed at ages 8, 11, 14 and 16 years) and test whether they predicted the General Certificate of Secondary Education scores (GCSE, at age 16 years). We then implemented multivariate twin modelling to determine the role of genetic and environmental factors in explaining the relationship between inattention symptoms and GCSE scores. Increasing inattention symptoms across childhood and adolescence predicted poorer GCSE scores independently of the baseline level of inattention. Genetic factors explained most of this relationship, i.e. genetic factors contributing to individual differences in the developmental course of inattention also influenced GCSE scores. In conclusion, our study demonstrates that genetic factors underlying the developmental course of inattention symptoms across childhood and adolescence also influence academic achievement. This may result from indirect mechanism, whereby genetic factors explain systematic changes in inattention levels with age, which in turn impact academic achievement. The shared genetic aetiology may also suggest common neurobiological processes underlying both the developmental course of inattention symptoms and academic achievement

Systematic Review and Meta-analysis of Genetically Informed Research: Associations between Parent Anxiety and Offspring Internalizing Problems

OBJECTIVE: Parent anxiety is associated with offspring internalizing problems (emotional problems related to anxiety and depression). This may reflect causal processes, whereby exposure to parent anxiety directly influences offspring internalizing (and/or vice versa). However, parent-offspring associations could also be attributable to their genetic relatedness. We present a systematic review and meta-analysis to investigate whether exposure to parent anxiety is associated with offspring internalizing after controlling for genetic relatedness. METHOD: A literature search in five databases identified 429 records. Publications were retained if they used a quasi-experimental design in a general population sample to control for participant relatedness in associations between parent anxiety and offspring internalizing outcomes. Publications were excluded if they involved an experimental exposure or intervention. Studies of pre- and post-natal anxiety exposure were meta-analysed separately. Pearson's correlation coefficient estimates (r) were pooled using multilevel random effects models. RESULTS: Eight publications were retained. Data were drawn from four population cohorts, each unique to a quasi-experimental design: adoption, sibling-comparison, children-of-twins or in-vitro-fertilisation. Cohorts were located in northern Europe or America. Families were predominantly of European ancestry. Three publications (Nfamilies>11,700; offspring aged 0.5-10 years) showed no association between prenatal anxiety exposure and offspring internalizing outcomes after accounting for participant relatedness (r=.04, CI -.07,.14). Six publications (Nfamilies>12,700; offspring aged 0.75-22 years) showed a small but significant association between concurrent symptoms in parents and offspring, after accounting for participant relatedness (r=.13, CI .04,.21). CONCLUSION: Initial literature, derived from homogenous populations, suggests that prenatal anxiety exposure does not cause offspring internalizing outcomes. However, postnatal anxiety exposure may be causally associated with concurrent offspring internalizing, via non-genetic pathways. Longitudinal stability, child-to-parent effects, and the role of moderators and methodological biases require attention

Adolescent cannabis use, change in neurocognitive function, and high-school graduation: A longitudinal study from early adolescence to young adulthood

The main objective of this prospective longitudinal study was to investigate bidirectional associations between adolescent cannabis use (CU) and neurocognitive performance in a community sample of 294 young men from ages 13 to 20 years. The results showed that in early adolescence, and prior to initiation to CU, poor short-term and working memory, but high verbal IQ, were associated with earlier age of onset of CU. In turn, age of CU onset and CU frequency across adolescence were associated with (a) specific neurocognitive decline in verbal IQ and executive function tasks tapping trial and error learning and reward processing by early adulthood and (b) lower rates of high-school graduation. The association between CU onset and change in neurocognitive function, however, was found to be accounted for by CU frequency. Whereas the link between CU frequency across adolescence and change in verbal IQ was explained (mediated) by high school graduation, the link between CU frequency and tasks tapping trial and error learning were independent from high school graduation, concurrent cannabis and other substance use, adolescent alcohol use, and externalizing behaviors. Findings support prevention efforts aimed at delaying onset and reducing frequency of CU

Nernst and Seebeck Coefficients of the Cuprate SuperconductorYBa2_2Cu3_3O6.67_{6.67}: A Study of Fermi Surface Reconstruction

The Seebeck and Nernst coefficients $S$ and $\nu$ of the cuprate superconductor YBa$_2$Cu$_3$O$_y$ (YBCO) were measured in a single crystal with doping $p = 0.12$ in magnetic fields up to H = 28 T. Down to T=9 K, $\nu$ becomes independent of field by $H \simeq 30$ T, showing that superconducting fluctuations have become negligible. In this field-induced normal state, $S/T$ and $\nu/T$ are both large and negative in the $T \to 0$ limit, with the magnitude and sign of $S/T$ consistent with the small electron-like Fermi surface pocket detected previously by quantum oscillations and the Hall effect. The change of sign in $S(T)$ at $T \simeq 50$ K is remarkably similar to that observed in La$_{2-x}$Ba$_x$CuO$_4$, La$_{2-x-y}$Nd$_y$Sr$_x$CuO$_4$ and La$_{2-x-y}$Eu$_y$Sr$_x$CuO$_4$, where it is clearly associated with the onset of stripe order. We propose that a similar density-wave mechanism causes the Fermi surface reconstruction in YBCO.Comment: Final version accepted for publication in Phys. Rev. Lett. New title, shorter abstract, minor revision of text and added reference

The p factor: genetic analyses support a general dimension of psychopathology in childhood and adolescence

Background: Diverse behaviour problems in childhood correlate phenotypically, suggesting a general dimension of psychopathology that has been called the p factor. The shared genetic architecture between childhood psychopathology traits also supports a genetic p. This study systematically investigates the manifestation of this common dimension across self‐, parent‐ and teacher‐rated measures in childhood and adolescence. / Methods: The sample included 7,026 twin pairs from the Twins Early Development Study (TEDS). First, we employed multivariate twin models to estimate common genetic and environmental influences on p based on diverse measures of behaviour problems rated by children, parents and teachers at ages 7, 9, 12 and 16 (depressive traits, emotional problems, peer problems, autism traits, hyperactivity, antisocial behaviour, conduct problems and psychopathic tendencies). Second, to assess the stability of genetic and environmental influences on p across time, we conducted longitudinal twin modelling of the first phenotypic principal components of childhood psychopathological measures across each of the four ages. Third, we created a genetic p factor in 7,026 unrelated genotyped individuals based on eight polygenic scores for psychiatric disorders to estimate how a general polygenic predisposition to mostly adult psychiatric disorders relates to childhood p. / Results: Behaviour problems were consistently correlated phenotypically and genetically across ages and raters. The p factor is substantially heritable (50%–60%) and manifests consistently across diverse ages and raters. However, residual variation in the common factor models indicates unique contributions as well. Genetic correlations of p components across childhood and adolescence suggest stability over time (49%–78%). A polygenic general psychopathology factor derived from studies of psychiatric disorders consistently predicted a general phenotypic p factor across development (0.3%–0.9%). / Conclusions: Diverse forms of psychopathology generally load on a common p factor, which is highly heritable. There are substantial genetic influences on the stability of p across childhood. Our analyses indicate genetic overlap between general risk for psychiatric disorders in adulthood and p in childhood, even as young as age 7. The p factor has far‐reaching implications for genomic research and, eventually, for diagnosis and treatment of behaviour problems.

Combining multivariate genomic approaches to elucidate the comorbidity between autism spectrum disorder and attention deficit hyperactivity disorder

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two highly heritable neurodevelopmental disorders. Several lines of evidence point towards the presence of shared genetic factors underlying ASD and ADHD. We conducted genomic analyses of common risk variants (i.e. single nucleotide polymorphisms, SNPs) shared by ASD and ADHD, and those specific to each disorder. METHODS: With the summary data from two GWAS, one on ASD (N = 46,350) and another on ADHD (N = 55,374) individuals, we used genomic structural equation modelling and colocalization analysis to identify SNPs shared by ASD and ADHD and SNPs specific to each disorder. Functional genomic analyses were then conducted on shared and specific common genetic variants. Finally, we performed a bidirectional Mendelian randomization analysis to test whether the shared genetic risk between ASD and ADHD was interpretable in terms of reciprocal relationships between ASD and ADHD. RESULTS: We found that 37.5% of the SNPs associated with ASD (at p < 1e-6) colocalized with ADHD SNPs and that 19.6% of the SNPs associated with ADHD colocalized with ASD SNPs. We identified genes mapped to SNPs that are specific to ASD or ADHD and that are shared by ASD and ADHD, including two novel genes INSM1 and PAX1. Our bidirectional Mendelian randomization analyses indicated that the risk of ASD was associated with an increased risk of ADHD and vice versa. CONCLUSIONS: Using multivariate genomic analyses, the present study uncovers shared and specific genetic variants associated with ASD and ADHD. Further functional investigation of genes mapped to those shared variants may help identify pathophysiological pathways and new targets for treatment