Background Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm. Methods and findings Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10 −35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-PLOS MEDICINE

BackgroundAvailable evidence points towards lower birth weight as a risk factor for the development of attention deficit/hyperactivity disorder (ADHD) symptoms. We probed the causal nature of this putative effect of birth weight on ADHD symptoms using the twin differences design, which accounts for genetic and shared environmental confounds.MethodIn a large population‐based twin sample – 3,499 monozygotic (MZ) and 6,698 dizygotic (DZ) pairs – parents, teachers or twins rated the twins’ ADHD symptoms at nine assessment waves (2–16 years). We implemented the twin differences design, which completely accounts for shared environmental and genetic confounding in MZ twins. We tested whether: (a) the lighter‐born twins had elevated ADHD symptoms compared to the heavier‐born twins, by regressing within‐pair differences of ADHD symptoms on within‐pair differences of birth weight among MZ twins; (b) the effect of birth weight on ADHD was moderated by gender, gestational age and low birth weight; (c) this effect changed with age at ADHD assessment using adapted latent growth curve models; and (d) results differed for inattention and hyperactivity/impulsivity.ResultsBirth weight significantly predicted ADHD symptoms from early childhood to late adolescence. The lighter‐born twin had more ADHD symptoms than the heavier‐born cotwin among MZ twins across assessment waves and raters. No moderation effect was detected. The magnitude of the effect of birth weight decreased significantly across time for hyperactivity/impulsivity, but the decrease failed to reach significance for inattention. Estimates for inattention were significantly larger than for hyperactivity/impulsivity at each time point, implying stronger effect of birth weight on inattention symptoms.ConclusionsOur findings provide stringent evidence for environmental effect of lower birth weight on the causal pathway to elevated ADHD symptoms. Effect of birth weight persists across a 14‐year period from childhood into late adolescence, in particular for inattention symptoms.

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.

Objective: The disruption caused by the COVID-19 pandemic has been associated with poor mental health, including increases in eating disorders and self-harm symptoms. We investigated risk and protective factors for the new onset of these symptoms during the pandemic. Method: Data were from the COVID-19 Psychiatry and Neurological Genetics study and the Repeated Assessment of Mental health in Pandemics Study (n = 36,715).Exposures were socio-demographic characteristics, lifetime psychiatric disorder, and COVID-related variables, including SARS-CoV-2 infection/illness with COVID-19.We identified four subsamples of participants without pre-pandemic experience of our outcomes: binge eating (n = 24,211), low weight (n = 24,364), suicidal and/or

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Although health disparities among same-sex attracted compared to heterosexual individuals are typically explained by minority stress, there is limited evidence for a causal effect. This study investigated whether same-sex attraction was causally associated with psychological distress and risky sexual behavior using sociosexual behavior as a proxy. The sample comprised monozygotic and dizygotic twins and their non-twin siblings (n = 2036, 3780 and 2356, respectively) genotyped and assessed for same-sex attraction, psychological distress (anxiety and depressive symptoms), and risky sexual behavior. Causal influences were investigated with same-sex attraction as the predictor and psychological distress and risky sexual behavior as the outcomes in two separate Mendelian Randomization-Direction of Causation (MRDoC) models using OpenMx in R. The MRDoC model improves on the Mendelian Randomization and Direction of Causation twin models by allowing analyses of variables with similar genetic architectures, incorporating polygenic scores as instrumental variables and specifying pleiotropy and residual covariance. There were significant causal influences flowing from same-sex attraction to psychological distress and risky sexual behavior (standardized coefficients = 0.13 and 0.16; 95% CIs 0.03–0.23 and 0.08–0.25, respectively). Further analyses also demonstrated causal influences flowing from psychological distress and risky sexual behavior toward same-sex attraction. Causal influences from same-sex attraction to psychological distress and risky sexual behavior may reflect minority stress, which reinforces ongoing measures to minimize social disparities. Causal influences flowing in the opposite direction may reflect rejection sensitivity, stigma-inducing outcomes of risky sexual behavior, and recall bias; however, further research is required to specifically investigate these processes.

Objective: The disruption caused by the COVID-19 pandemic has been associated with poor mental health, including increases in eating disorder and self-harm symptoms. We investigated risk and protective factors for new onset of these symptoms during the pandemic. Method: Data were from the COVID-19 Psychiatry and Neurological Genetics study and the Repeated Assessment of Mental health in Pandemics Study (n = 45,058). Exposures were socio-demographic characteristics, lifetime psychiatric disorder, and COVID-related variables, including SARS-CoV-2 infection/illness with COVID-19. We identified four sub-samples of participants without pre-pandemic experience of our outcomes: binge eating (n = 18,172), low weight (n = 19,148), suicidal and/or self-harm ideation (n = 12,650), and self-harm (n = 20,266). Participants reported on our outcomes at frequent intervals (fortnightly to monthly). We fitted four logistic regression models to identify factors associated with new onset of our outcomes. Results: Within each subsample, new onset was reported by: 16.9% for binge eating, 8.9% for low weight, 26.6% for suicidal and/or self-harm ideation, and 3.3.% for self-harm. Shared risk factors included having a lifetime psychiatric disorder, not being in paid employment, and higher pandemic worry scores. Conversely, infection with SARS-CoV-2/illness with COVID-19 was linked to lower odds of all outcomes. Other factors were associated with one outcome, such as pandemic-related loneliness with suicidal and/or self-harm ideation. Discussion: Overall, we detected shared risk factors that may drive the comorbidity between eating disorders and self-harm. Subgroups of individuals with these risk factors may require more frequent monitoring during future pandemics.

Previous genetically informed studies have uncovered likely causal relationships between mental health problems and self-harm but resulting causal estimates may be biased due to unmediated pleiotropy. By fitting Mendelian Randomization - Direction of Causation (MR-DoC) models that explicitly model pleiotropy, we investigated the effect of four quantitatively measured mental health problems - major depressive disorder (MDD), schizophrenia, attention-deficit hyperactivity disorder (ADHD), and insomnia, on non-suicidal self-harm (NSSH) and suicidal self-harm (SSH), separately. We used data of 12,723 twins (56.6% females) in the Twins Early Development Study. Besides substantial pleiotropy, we found effects from child-rated depressive symptoms to both NSSH (β = 0.194, 95% CIs: 0.131, 0.257) and SSH (β = 0.210, 95% CIs: 0.125, 0.295). Similarly, effects flowed from parent-rated depressive symptoms to NSSH (β = 0.092, 95% CIs: 0.004, 0.181) and SSH (β = 0.165, 95% CIs: 0.051, 0.281). We did not find evidence of aetiological difference between NSSH and SSH.