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When building causal knowledge in behavioural genetics, the natural randomisation of genotypes at conception (approximately analogous to the artificial randomisation occurring in randomised controlled trials) facilitates the discovery of genetic causes. More importantly, the randomisation of genetic material within families also enables a better identification of (environmental) risk factors and aetiological pathways to diseases and behaviours.
The COVID-19 pandemic has affected all our lives, not only through the infection itself but also through the measures taken to control the spread of the virus (e.g. lockdown).
Here, we investigated how the COVID-19 pandemic and unprecedented lockdown affected the mental health of young adults in England and Wales.
We compared the mental health symptoms of up to 4773 twins in their mid-20s in 2018 prior to the COVID-19 pandemic (T1) and during four-wave longitudinal data collection during the pandemic in April, July and October 2020, and in March 2021 (T2–T5) using phenotypic and genetic longitudinal designs.
The average changes in mental health were small to medium and mainly occurred from T1 to T2 (average Cohen d = 0.14). Despite the expectation of catastrophic effects of the pandemic on mental health, we did not observe trends in worsening mental health during the pandemic (T3–T5). Young people with pre-existing mental health problems were disproportionately affected at the beginning of the pandemic, but their increased problems largely subsided as the pandemic persisted. Twin analyses indicated that the aetiology of individual differences in mental health symptoms did not change during the lockdown (average heritability 33%); the average genetic correlation between T1 and T2–T5 was 0.95, indicating that genetic effects before the pandemic were substantially correlated with genetic effects up to a year later.
We conclude that on average the mental health of young adults in England and Wales has been remarkably resilient to the effects of the pandemic and associated lockdown.
Retrospective self-reports of childhood trauma are associated with a greater risk of psychopathology in adulthood than prospective measures of trauma. Heritable reporter characteristics are anticipated to account for part of this association, whereby genetic predisposition to certain traits influences both the likelihood of self-reporting trauma and of developing psychopathology. However, previous research has not considered how gene–environment correlation influences these associations.
To investigate reporter characteristics associated with retrospective self-reports of childhood trauma and whether these associations are accounted for by gene–environment correlation.
In 3963 unrelated individuals from the Twins Early Development Study, we tested whether polygenic scores for 21 psychiatric, cognitive, anthropometric and personality traits were associated with retrospectively self-reported childhood emotional and physical abuse. To assess the presence of gene–environment correlation, we investigated whether these associations remained after controlling for composite scores of environmental adversity across development.
Retrospectively self-reported childhood trauma was associated with polygenic scores for autism spectrum disorder (ASD), body mass index (BMI), post-traumatic stress disorder (PTSD) and risky behaviours. When composite scores of environmental adversity were controlled for, only associations with the polygenic scores for ASD and PTSD remained significant.
Genetic predisposition to ASD and PTSD may increase liability to experiencing or interpreting events as traumatic. Associations between genetic predisposition for risky behaviour and BMI with self-reported childhood trauma may reflect gene–environment correlation. Studies of the association between retrospectively self-reported childhood trauma and later-life outcomes should consider that genetically influenced reporter characteristics may confound associations, both directly and through gene–environment correlation.
Low birth weight is associated with adult mental health, cognitive, and socioeconomic problems. However, the causal nature of these associations remains difficult to establish due to confounding. We aimed to estimate the contribution of birth weight to adult mental health, cognitive, and socioeconomic outcomes using two-sample Mendelian randomisation, an instrumental variable approach strengthening causal inference.
We used 48 independent single-nucleotide polymorphisms as genetic instruments for birth weight (N of the genome-wide association study, 264 498), and considered mental health (attention-deficit hyperactivity disorder [ADHD], autism spectrum disorders, bipolar disorder, major depressive disorders, obsessive-compulsive disorder, post-traumatic stress disorder [PTSD], schizophrenia, suicide attempt), cognitive (intelligence), and socioeconomic (educational attainment, income, social deprivation) outcomes. We performed a two-sample Mendelian randomisation using the random-effect Inverse Variance Weighing method as primary analysis, supplemented by a wide range of sensitivity analyses, including Egger regression, weighted median, and Pleiotropy Residual Sum and Outlier. Results were considered statistically significant after accounting for multiple testing using False Discovery Rate (q = 0.05).
After correction for multiple testing, we found evidence for a contribution of birth weight to ADHD (OR for 1 SD-unit decrease [~464 grams] in birth weight, 1.29; CI, 1.03–1.62), PTSD (OR = 1.69; CI = 1.06–2.71), and suicide attempt (OR = 1.39; CI = 1.05–1.84), as well as for intelligence (β= –0.07; CI= –0.13; –0.02), and socioeconomic outcomes, ie, educational attainment (β=−0.05; CI= –0.09; –0.01), income (β=−0.08; CI= –0.15; –0.02), and social deprivation (β=0.08; CI = 0.03; 0.13). However, no evidence was found for a contribution of birth weight to the other examined mental health outcomes. Results were consistent across main and sensitivity analyses.
These findings support that birthweight could be an important element on the causal pathway to mental health, cognitive and socioeconomic outcomes. Early interventions targeting birth weight may therefore have a positive impact on promoting mental health and improving socioeconomic outcomes.
This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 793396
Low birth weight is associated with adult mental health, cognitive and socioeconomic problems. However, the causal nature of these associations remains difficult to establish owing to confounding.
To estimate the contribution of birth weight to adult mental health, cognitive and socioeconomic outcomes using two-sample Mendelian randomisation, an instrumental variable approach strengthening causal inference.
We used 48 independent single-nucleotide polymorphisms as genetic instruments for birth weight (genome-wide association studies’ total sample: n = 264 498) and considered mental health (attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, major depressive disorder, obsessive–compulsive disorder, post-traumatic stress disorder (PTSD), schizophrenia, suicide attempt), cognitive (intelligence) and socioeconomic (educational attainment, income, social deprivation) outcomes.
We found evidence for a contribution of birth weight to ADHD (OR for 1 s.d. unit decrease (~464 g) in birth weight, 1.29; 95% CI 1.03–1.62), PTSD (OR = 1.69; 95% CI 1.06–2.71) and suicide attempt (OR = 1.39; 95% CI 1.05–1.84), as well as for intelligence (β = −0.07; 95% CI −0.13 to −0.02) and socioeconomic outcomes, i.e. educational attainment (β = −0.05; 95% CI −0.09 to −0.01), income (β = −0.08; 95% CI −0.15 to −0.02) and social deprivation (β = 0.08; 95% CI 0.03–0.13). However, no evidence was found for a contribution of birth weight to the other examined mental health outcomes. Results were consistent across a wide range of sensitivity analyses.
These findings support the hypothesis that birth weight could be an important element on the causal pathway to mental health, cognitive and socioeconomic outcomes.
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.
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.
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.
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.
The rise of social media use in young people has sparked concern about the impact of cyber-victimisation on mental health. Although cyber-victimisation is associated with mental health problems, it is not known whether such associations reflect genetic and environmental confounding.
We used the co-twin control design to test the direct association between cyber-victimisation and multiple domains of mental health in young people. Participants were 7708 twins drawn from the Twins Early Development Study, a UK-based population cohort followed from birth to age 22.
Monozygotic twins exposed to greater levels of cyber-victimisation had more symptoms of internalising, externalising and psychotic disorders than their less victimised co-twins at age 22, even after accounting for face-to-face peer victimisation and prior mental health. However, effect sizes from the most stringent monozygotic co-twin control analyses were decreased by two thirds from associations at the individual level [pooled β across all mental health problems = 0.06 (95% CI 0.03–0.10) v. 0.17 (95% CI 0.15–0.19) in individual-level analyses].
Cyber-victimisation has a small direct association with multiple mental health problems in young people. However, a large part of the association between cyber-victimisation and mental health is due to pre-existing genetic and environmental vulnerabilities and co-occurring face-to-face victimisation. Therefore, preventative interventions should target cyber-victimisation in conjunction with pre-existing mental health vulnerabilities and other forms of victimisation.
Childhood maltreatment is robustly associated with increased risk of poor mental health outcome and changes in brain function. The authors investigated whether childhood experience of abuse (e.g. physical, emotional and sexual abuse) and neglect (physical and emotional deprivation) was differentially associated with neural reactivity to threat.
Participants were drawn from an existing study and allocated to one of four groups based on self-report of childhood maltreatment experience: individuals with childhood abuse experiences (n = 70); individuals with childhood neglect experiences (n = 87); individuals with combined experience of childhood abuse and neglect (n = 50); and non-maltreated individuals (n = 207) propensity score matched (PSM) on gender, age, IQ, psychopathology and SES. Neural reactivity to facial cues signalling threat was compared across groups, allowing the differential effects associated with particular forms of maltreatment experience to be isolated.
Brain imaging analyses indicated that while childhood abuse was associated with heightened localised threat reactivity in ventral amygdala, experiences of neglect were associated with heightened reactivity in a distributed cortical fronto-parietal network supporting complex social and cognitive processing as well as in the dorsal amygdala. Unexpectedly, combined experiences of abuse and neglect were associated with hypo-activation in several higher-order cortical regions as well as the amygdala.
Different forms of childhood maltreatment exert differential effects in neural threat reactivity: while the effects of abuse are more focal, the effects of neglect and combined experiences of abuse are more distributed. These findings are relevant for understanding the range of psychiatric outcomes following childhood maltreatment and have implications for intervention.
The phenotypic and aetiological architecture of depression symptomatology has been mostly studied in Western samples. In this study, we conducted a genetically informed factor analysis to elucidate both the phenotypic and aetiological architectures of self-reported depression among a Japanese adult twin sample.
Depressive symptoms assessed by Zung's Self-rating Depression Scale were self-rated by 425 twin pairs (301 monozygotic and 124 dizygotic twin pairs) in a community sample in Japan.
An exploratory factor analysis extracted three symptom domains representing cognitive, affective and somatic symptomatology. A confirmatory factor analysis demonstrated that a bi-factor solution fitted better than the alternative solutions, implying that depression may be defined as a combination of a single general construct and three factors specific to each of the three symptom domains. A multivariate genetic analysis with the bi-factor solution showed that the general factor was substantially heritable (47%), and that only the affective symptom domain was significantly heritable (29%) among the three specific factors, their remaining variance being explained by non-shared environmental influences.
Depression symptomatology appears to be adequately captured by a substantially heritable general factor. The heritability of this factor (47%) in a Japanese adult sample is in line with commonly reported heritability estimates for depression. The three specific factors – cognitive, affective and somatic – are mostly explained by non-shared environmental factors, which include measurement error. The extent to which these specific factors are uniquely associated with correlates of depression when the general factor is accounted for should be investigated in future studies.
Evidence regarding the association between cannabis use and depression remain conflicting, especially as studies have not typically adopted a longitudinal design with a follow-up period that was long enough to adequately cover the risk period for onset of depression.
Males from the Cambridge Study in Delinquent Development (CSDD) (N = 285) were assessed seven times from age 8 to 48 years to prospectively investigate the association between cannabis use and risk of major depressive disorder (MDD). A combination of multiple analyses (logistic regression, Cox regression, fixed-effects analysis) was employed to explore the strength and direction of effect within different developmental stages.
Multiple regression analyses revealed that early-onset cannabis use (before age 18) but not late-onset cannabis use (after age 27) was associated with a higher risk and shorter time until a subsequent MDD diagnosis. This effect was present in high-frequency [(odds ratio (OR) 8.83, 95% confidence interval (CI) 1.29–70.79]; [hazard ratio (HR) 8.69, 95% CI 2.07–36.52)] and low-frequency early-onset users (OR 2.41, 95% CI 1.22–4.76; HR 2.09, 95% CI 1.16–3.74). Effect of increased frequency of cannabis use on increased risk of subsequent MDD was observed only for use during adolescence (age 14–18) but not at later life stages, while controlling for observed and non-unobserved time-invariant factors. Conversely, MDD in adulthood (age 18–32) was linked to a reduction in subsequent cannabis use (age 32–48).
The present findings provide evidence implicating frequent cannabis use during adolescence as a risk factor for later life depression. Future studies should further examine causality of effects in larger samples.
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.
While maltreatment is known to impact social and emotional functioning, threat processing, and neural structure, the potentially dimorphic influence of sex on these outcomes remains relatively understudied. We investigated sex differences across these domains in a large community sample of children aged 10 to 14 years (n = 122) comprising 62 children with verified maltreatment experience and 60 well-matched nonmaltreated peers. The maltreated group relative to the nonmaltreated comparison group exhibited poorer social and emotional functioning (more peer problems and heightened emotional reactivity). Cognitively, they displayed a pattern of attentional avoidance of threat in a visual dot-probe task. Similar patterns were observed in males and females in these domains. Reduced gray matter volume was found to characterize the maltreated group in the medial orbitofrontal cortex, bilateral middle temporal lobes, and bilateral supramarginal gyrus; sex differences were observed only in the supramarginal gyrus. In addition, a disordinal interaction between maltreatment exposure and sex was found in the postcentral gyrus. Finally, attentional avoidance to threat mediated the relationship between maltreatment and emotional reactivity, and medial orbitofrontal cortex gray matter volume mediated the relationship between maltreatment and peer functioning. Similar mediation patterns were observed across sexes. This study highlights the utility of combining multiple levels of analysis when studying the “latent vulnerability” engendered by childhood maltreatment and yields tentative findings regarding a neural basis of sex differences in long-term outcomes for maltreated children.
The impact of longitudinal psychiatric comorbidity, parenting and social characteristics on attention-deficit hyperactivity disorder (ADHD) medication use is still poorly understood.
To assess the baseline and longitudinal influences of behavioural and environmental factors on ADHD medication use.
Survival regressions with time-dependent covariates were used to model data from a population-based longitudinal birth cohort. The sample (n = 1920) was assessed from age 5 months to 10 years. Measures of children's psychiatric symptoms, parenting practices and social characteristics available at baseline and during follow-up were used to identify individual and family-level features associated with subsequent use of ADHD medication.
Use of ADHD medication ranged from 0.2 to 8.6% between ages 3.5 to 10 years. Hyperactivity–inattention was the strongest predictor of medication use (hazard ratio (HR) = 2.75, 95% CI 2.35–3.22). Among all social variables examined, low maternal education increased the likelihood of medication use (HR = 2.09, 95% CI 1.38–3.18) whereas immigrant status lowered this likelihood (HR = 0.40, 95% CI 0.17–0.92).
Beyond ADHD symptoms, the likelihood of receiving ADHD medication is predicted by social variables and not by psychiatric comorbidity or by parenting. This emphasises the need to improve global interventions by offering the same therapeutic opportunities (including medication) as those received by the rest of the population to some subgroups (i.e. immigrants) and by diminishing possible unnecessary prescriptions.
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