Anorexia nervosa (AN) occurs nine times more often in females than in males. Although environmental factors likely play a role, the reasons for this imbalanced sex ratio remain unresolved. AN ...displays high genetic correlations with anthropometric and metabolic traits. Given sex differences in body composition, we investigated the possible metabolic underpinnings of female propensity for AN. We conducted sex‐specific GWAS in a healthy and medication‐free subsample of the UK Biobank (n = 155,961), identifying 77 genome‐wide significant loci associated with body fat percentage (BF%) and 174 with fat‐free mass (FFM). Partitioned heritability analysis showed an enrichment for central nervous tissue‐associated genes for BF%, which was more prominent in females than males. Genetic correlations of BF% and FFM with the largest GWAS of AN by the Psychiatric Genomics Consortium were estimated to explore shared genomics. The genetic correlations of BF%male and BF%female with AN differed significantly from each other (p < .0001, δ = −0.17), suggesting that the female preponderance in AN may, in part, be explained by sex‐specific anthropometric and metabolic genetic factors increasing liability to AN.
Objective:Bipolar disorder is associated with high risk for suicidal behavior that often develops in adolescence and young adulthood. Elucidation of involved neural systems is critical for ...prevention. This study of adolescents and young adults with bipolar disorder with and without a history of suicide attempts combines structural, diffusion tensor, and functional MR imaging methods to investigate implicated abnormalities in the morphology and structural and functional connectivity within frontolimbic systems.Method:The study had 26 participants with bipolar disorder who had a prior suicide attempt (the attempter group) and 42 participants with bipolar disorder without a suicide attempt (the nonattempter group). Regional gray matter volume, white matter integrity, and functional connectivity during processing of emotional stimuli were compared between groups, and differences were explored for relationships between imaging modalities and associations with suicide-related symptoms and behaviors.Results:Compared with the nonattempter group, the attempter group showed significant reductions in gray matter volume in the orbitofrontal cortex, hippocampus, and cerebellum; white matter integrity in the uncinate fasciculus, ventral frontal, and right cerebellum regions; and amygdala functional connectivity to the left ventral and right rostral prefrontal cortex. In exploratory analyses, among attempters, there was a significant negative correlation between right rostral prefrontal connectivity and suicidal ideation and between left ventral prefrontal connectivity and attempt lethality.Conclusions:Adolescent and young adult suicide attempters with bipolar disorder demonstrate less gray matter volume and decreased structural and functional connectivity in a ventral frontolimbic neural system subserving emotion regulation. Among attempters, reductions in amygdala–prefrontal functional connectivity may be associated with severity of suicidal ideation and attempt lethality.
IMPORTANCE: Anxiety and stress-related disorders are among the most common mental disorders. Although family and twin studies indicate that both genetic and environmental factors play an important ...role underlying their etiology, the genetic underpinnings of anxiety and stress-related disorders are poorly understood. OBJECTIVES: To estimate the single-nucleotide polymorphism–based heritability of anxiety and stress-related disorders; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to evaluate the association of psychiatric comorbidities with genetic findings. DESIGN, SETTING, PARTICIPANTS: This genome-wide association study included individuals with various anxiety and stress-related diagnoses and controls derived from the population-based Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) study. Lifetime diagnoses of anxiety and stress-related disorders were obtained through the national Danish registers. Genes of interest were further evaluated in mice exposed to chronic social defeat. The study was conducted between June 2016 and November 2018. MAIN OUTCOMES AND MEASURES: Diagnoses of a relatively broad diagnostic spectrum of anxiety and stress-related disorders. RESULTS: The study sample included 12 655 individuals with various anxiety and stress-related diagnoses and 19 225 controls. Overall, 17 740 study participants (55.6%) were women. A total of 7308 participants (22.9%) were born between 1981-1985, 8840 (27.7%) between 1986-1990, 8157 (25.6%) between 1991-1995, 5918 (18.6%) between 1996-2000, and 1657 (5.2%) between 2001-2005. Standard association analysis revealed variants in PDE4B to be associated with anxiety and stress-related disorder (rs7528604; P = 5.39 × 10−11; odds ratio = 0.89; 95% CI, 0.86-0.92). A framework of sensitivity analyses adjusting for mental comorbidity supported this result showing consistent association of PDE4B variants with anxiety and stress-related disorder across analytical scenarios. In mouse models, alterations in Pde4b expression were observed in those mice displaying anxiety-like behavior after exposure to chronic stress in the prefrontal cortex (P = .002; t = −3.33) and the hippocampus (P = .001; t = −3.72). We also found a single-nucleotide polymorphism heritability of 28% (standard error = 0.027) and that the genetic signature of anxiety and stress-related overlapped with psychiatric traits, educational outcomes, obesity-related phenotypes, smoking, and reproductive success. CONCLUSIONS AND RELEVANCE: This study highlights anxiety and stress-related disorders as complex heritable phenotypes with intriguing genetic correlations not only with psychiatric traits, but also with educational outcomes and multiple obesity-related phenotypes. Furthermore, we highlight the candidate gene PDE4B as a robust risk locus pointing to the potential of PDE4B inhibitors in treatment of these disorders.
Anxiety disorders are among the most common psychiatric disorders worldwide. They often onset early in life, with symptoms and consequences that can persist for decades. This makes anxiety disorders ...some of the most debilitating and costly disorders of our time. Although much is known about the synaptic and circuit mechanisms of fear and anxiety, research on the underlying genetics has lagged behind that of other psychiatric disorders. However, alongside the formation of the Psychiatric Genomic Consortium Anxiety workgroup, progress is rapidly advancing, offering opportunities for future research.Here we review current knowledge about the genetics of anxiety across the lifespan from genetically informative designs (i.e. twin studies and molecular genetics). We include studies of specific anxiety disorders (e.g. panic disorder, generalised anxiety disorder) as well as those using dimensional measures of trait anxiety. We particularly address findings from large-scale genome-wide association studies and show how such discoveries may provide opportunities for translation into improved or new therapeutics for affected individuals. Finally, we describe how discoveries in anxiety genetics open the door to numerous new research possibilities, such as the investigation of specific gene-environment interactions and the disentangling of causal associations with related traits and disorders.We discuss how the field of anxiety genetics is expected to move forward. In addition to the obvious need for larger sample sizes in genome-wide studies, we highlight the need for studies among young people, focusing on specific underlying dimensional traits or components of anxiety.
The Genetic Links to Anxiety and Depression (GLAD) Study is a large cohort of individuals with lifetime anxiety and/or depression, designed to facilitate re-contact of participants for mental health ...research. At the start of the pandemic, participants from three cohorts, including the GLAD Study, were invited to join the COVID-19 Psychiatry and Neurological Genetics (COPING) study to monitor mental and neurological health. However, previous research suggests that participation in longitudinal studies follows a systematic, rather than random, process, which can ultimately bias results. Therefore, this study assessed participation biases following the re-contact of GLAD Study participants.
In April 2020, all current GLAD Study participants (N = 36,770) were invited to the COPING study. Using logistic regression, we investigated whether sociodemographic, mental, and physical health characteristics were associated with participation in the COPING baseline survey (aim one). Subsequently, we used a zero-inflated negative binomial regression to examine whether these factors were also related to participation in the COPING follow-up surveys (aim two).
For aim one, older age, female gender identity, non-binary or self-defined gender identities, having one or more physical health disorders, and providing a saliva kit for the GLAD Study were associated with an increased odds of completing the COPING baseline survey. In contrast, lower educational attainment, Asian or Asian British ethnic identity, Black or Black British ethnic identity, higher alcohol consumption at the GLAD sign-up survey, and current or ex-smoking were associated with a reduced odds. For aim two, older age, female gender, and saliva kit provision were associated with greater COPING follow-up survey completion. Lower educational attainment, higher alcohol consumption at the GLAD Study sign-up, ex-smoking, and self-reported attention deficit hyperactivity disorder had negative relationships.
Participation biases surrounding sociodemographic and physical health characteristics were particularly evident when re-contacting the GLAD Study volunteers. Factors associated with participation may vary depending on study design. Researchers should examine the barriers and mechanisms underlying participation bias in order to combat these issues and address recruitment biases in future studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and Aims
The use of cannabis has previously been linked to both depression and self‐harm; however, the role of genetics in this relationship is unclear. This study aimed to estimate the ...phenotypic and genetic associations between cannabis use and depression and self‐harm.
Design
Cross‐sectional data collected through UK Biobank were used to test the phenotypic association between cannabis use, depression and self‐harm. UK Biobank genetic data were then combined with consortia genome‐wide association study summary statistics to further test the genetic relationships between these traits using LD score regression, polygenic risk scoring and Mendelian randomization methods.
Setting
United Kingdom, with additional international consortia data.
Participants
A total of 126 291 British adults aged between 40 and 70 years, recruited into UK Biobank.
Measurements
Phenotypic outcomes were life‐time history of cannabis use (including initial and continued cannabis use), depression (including single‐episode and recurrent depression) and self‐harm. Genome‐wide genetic data were used and assessment centre, batch and the first six principal components were included as key covariates when handling genetic data.
Findings
In UK Biobank, cannabis use is associated with an increased likelihood of depression odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.59–1.70 and self‐harm (OR = 2.85, 95% CI = 2.69–3.01). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Using consortia genome‐wide summary statistics, significant genetic correlations are seen between cannabis use and depression rg = 0.289, standard error (SE) = 0.036. Polygenic risk scores for cannabis use and depression explain a small but significant proportion of variance in cannabis use, depression and self‐harm within a UK Biobank target sample. However, two‐sample Mendelian randomization analyses were not significant.
Conclusions
Cannabis use appeared to be both phenotypically and genetically associated with depression and self‐harm. Limitations in statistical power mean that conclusions could not be made on the direction of causality between these traits.
Background
Anxiety and depressive disorders can be classified under a bidimensional model, where depression and generalized anxiety disorder are represented by distress and the other anxiety ...disorders, by fear. The phenotypic structure of this model has been validated, but twin studies only show partial evidence for genetic and environmental distinctions between distress and fear. Moreover, the effects of genetic variants are mostly shared between anxiety and depression, but the genome‐wide genetic distinction between distress and fear remains unexplored. This study aimed to examine the degree of common genetic variation overlap between distress and fear, and their associations with the psychosocial risk factors of loneliness and social isolation.
Methods
We used genome‐wide data from 157,366 individuals in the UK Biobank who answered a mental health questionnaire.
Results
Genetic correlations indicated that depression and generalized anxiety had a substantial genetic overlap, and that they were genetically partially distinct from fear disorders. Associations with loneliness, but not social isolation, showed that loneliness was more strongly associated with both distress disorders than with fear.
Conclusions
Our findings shed light on genetic and environmental mechanisms that are common and unique to distress and fear and contribute to current knowledge on individuals’ susceptibility to anxiety and depression.
Fear conditioning paradigms use various measures to assess learned fear, including autonomic arousal responses like skin conductance, and self-reports of both associative (US-expectancies) and ...evaluative (affective ratings) learning. The present study uses a dimensional approach to examine associations among fear indices directly.
Seventy-three participants completed a differential fear conditioning experiment, during which a neutral stimulus (CS+) was paired with an electric shock (US), while another stimulus (CS-) was never paired with the shock (partially instructed fear acquisition). Ten minutes later, both stimuli were presented without any shocks (fear extinction). Skin conductance responses and US-expectancy ratings were recorded during each phase, while self-reported negative affect was assessed for each CS at the end of extinction.
Results showed a positive association among US-expectancy ratings and skin conductance responses during acquisition and early extinction. US-expectancy ratings during overall extinction were positively associated with post-extinction negative affect.
The lack of affective ratings post-acquisition may have obscured associations between associative and evaluative learning indices.
Results provide evidence for the expected correspondence among different indices of associative fear learning. Findings emphasize the need for incorporating both associative and evaluative learning measures in fear conditioning paradigms.
•Fear conditioning studies use physiological and self-report measures to assess fear.•We examined the association among these indices using a dimensional approach.•Autonomic arousal was associated with US-expectancy ratings.•US-expectancy ratings during extinction predicted post-extinction negative affect.•Results support the need for both associative and evaluative indices of learned fear.
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.
Twin studies have shown that emotional problems (anxiety and depression) in childhood and adolescence are moderately heritable (~20-50%). In contrast, DNA-based 'SNP heritability' estimates are ...generally <15% and non-significant. One notable feature of emotional problems is that they can be somewhat transient, but the moderate stability seen across time and across raters is predominantly influenced by stable genetic influences. This suggests that by capturing what is in common across time and across raters, we might be more likely to tap into any underlying genetic vulnerability. We therefore hypothesised that a phenotype capturing the pervasive stability of emotional problems would show higher heritability. We fitted single-factor latent trait models using 12 emotional problems measures across ages 7, 12 and 16, rated by parents, teachers and children themselves in the Twins Early Development Study sample. Twin and SNP heritability estimates for stable emotional problems (N = 6110 pairs and 6110 unrelated individuals, respectively) were compared to those for individual measures. Twin heritability increased from 45% on average for individual measures to 76% (se = 0.023) by focusing on stable trait variance. SNP heritability rose from 5% on average (n.s.) to 14% (se = 0.049; p = 0.002). Heritability was also higher for stable within-rater composites. Polygenic scores for both adult anxiety and depression significantly explained variance in stable emotional problems (0.4%; p = 0.0001). The variance explained was more than in most individual measures. Stable emotional problems also showed significant genetic correlation with adult depression and anxiety (average = 52%). These results demonstrate the value of examining stable emotional problems in gene-finding and prediction studies.
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