Integrative analysis of genomic and exposomic influences on youth mental health

Background: Understanding complex influences on mental health problems in young people is needed to inform early prevention strategies. Both genetic and environmental factors are known to influence youth mental health, but a more comprehensive picture of their interplay, including wide-ranging environmental exposures – that is, the exposome – is needed. We perform an integrative analysis of genomic and exposomic data in relation to internalizing and externalizing symptoms in a cohort of 4,314 unrelated youth from the Adolescent Brain and Cognitive Development (ABCD) Study. / Methods: Using novel GREML-based approaches, we model the variance in internalizing and externalizing symptoms explained by additive and interactive influences from the genome (G) and modeled exposome (E) consisting of up to 133 variables at the family, peer, school, neighborhood, life event, and broader environmental levels, including genome-by-exposome (G × E) and exposome-by-exposome (E × E) effects. / Results: A best-fitting integrative model with G, E, and G × E components explained 35% and 63% of variance in youth internalizing and externalizing symptoms, respectively. Youth in the top quintile of model-predicted risk accounted for the majority of individuals with clinically elevated symptoms at follow-up (60% for internalizing; 72% for externalizing). Of note, different domains of environmental exposures were most impactful for internalizing (life events) and externalizing (contextual including family, school, and peer-level factors) symptoms. In addition, variance explained by G × E contributions was substantially larger for externalizing (33%) than internalizing (13%) symptoms. / Conclusions: Advanced statistical genetic methods in a longitudinal cohort of youth can be leveraged to address fundamental questions about the role of ‘nature and nurture’ in developmental psychopathology

Individual and combined associations between cardiorespiratory fitness and grip strength with common mental disorders: a prospective cohort study in the UK Biobank

Background: Depression and anxiety are common mental disorders that increase physical health risks and are leading causes of global disability. Several forms of physical fitness could be modifiable risk factors for common mental disorders in the population. We examined associations between individual and combined markers of cardiorespiratory fitness and grip strength with the incidence of common mental disorders. Methods: A 7-year prospective cohort study in 152,978 UK Biobank participants. An exercise test and dynamometer were used to measure cardiorespiratory and grip strength, respectively. We used Patient Health Questionnaire-9 and Generalised Anxiety Disorder-7 scales to estimate the incidence of common mental disorders at follow-up. Results: Fully adjusted, longitudinal models indicated a dose-response relationship. Low and medium cardiorespiratory fitness was associated with 1.485 (95% CIs, 1.301 to 1.694, p <  0.001) and 1.141 (95% CIs, 1.005 to 1.297, p = 0.041) higher odds of depression or anxiety, compared to high cardiorespiratory fitness. Low and medium grip strength was associated with 1.381 (95% CIs, 1.315 to 1.452, p <  0.001) and 1.116 (95% CIs, 1.063 to 1.172, p <  0.001) higher odds of common mental disorder compared to high grip strength. Individuals in the lowest group for both cardiorespiratory fitness and grip strength had 1.981 (95% CIs, 1.553 to 2.527, p <  0.001) higher odds of depression, 1.599 (95% CIs, 1.148 to 2.118, p = 0.004) higher odds of anxiety, and 1.814 (95% CIs, 1.461 to 2.252, p <  0.001) higher odds of either common mental disorder, compared to high for both types of fitness. Conclusions: Objective cardiorespiratory and muscular fitness markers represent modifiable risk factors for common mental disorders. Public health strategies to reduce common mental disorders could include combinations of aerobic and resistance activities

Longitudinal cohort study of depression, post-traumatic stress, and alcohol use in South African women who attend alcohol serving venues

CITATION; Abler, L.A. et al. 2014. Longitudinal cohort study of depression, post-traumatic stress, and alcohol use in South African women who attend alcohol serving venues. BMC Psychiatry, 14(1):224, doi:10.1186/s12888-014-0224-9.The original publication is available at http://www.biomedcentral.com/1471-244X/14/224Background: In South Africa, alcohol use poses a public health burden. Hazardous alcohol use often co-occurs with psychological distress (e.g., depression and post-traumatic stress). However, the majority of the research establishing the relationship between alcohol use and psychological distress has been cross-sectional, so the nature of co-occurring changes in psychological distress and alcohol use over time is not well characterized. The objective of this study is to examine the longitudinal relationship between psychological distress and alcohol use among South African women who attend alcohol serving venues. Methods Four waves of data were collected over the course of a year from 560 women in a Cape Town township who attended drinking venues. At each assessment wave, participants reported depressive symptoms, post-traumatic stress symptoms, and alcohol use. Multilevel growth models were used to: 1) assess the patterns of alcohol use; 2) examine how depressive symptoms uniquely, post-traumatic stress symptoms uniquely, and depressive and post-traumatic stress symptoms together were associated with alcohol use; and 3) characterize the within person and between person associations of depressive symptoms and post-traumatic stress symptoms with alcohol use. Results Women reported high levels of alcohol use throughout the study period, which declined slightly over time. Post-traumatic stress symptoms were highly correlated with depressive symptoms. Modeled separately, both within person and between person depressive and post-traumatic stress symptoms were uniquely associated with alcohol use. When modeled together, significant between person effects indicated that women who typically have more post-traumatic stress symptoms, when controlling for depressive symptoms, are at risk for increased alcohol use; however, women with more depressive symptoms, controlling for post-traumatic stress symptoms, do not have differential risk for alcohol use. Significant within person effects indicated an interaction between depressive and post-traumatic stress symptoms; women reported more alcohol use than usual at times when they had higher post-traumatic stress symptoms, and this increase in alcohol use was further exacerbated for women who also had higher depressive symptoms than usual. Conclusions These findings suggest that interventions targeting post-traumatic stress, especially when post-traumatic stress is comorbid with depression, may reduce alcohol use among South African women who drink.Publishers' Versio

Assessment of bidirectional relationships between physical activity and depression among adults a 2-sample Mendelian randomization study

IMPORTANCE Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity. OBJECTIVE To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference. DESIGN, SETTING, AND PARTICIPANTS This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes-self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)-and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018. MAIN OUTCOMES AND MEASURES MDD and physical activity. RESULTS GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [OR], 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P =.006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = −0.08 in mean acceleration per MDD vs control status; 95% CI, −0.47 to 0.32; P =.70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P =.48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, −0.008 to 0.05; P =.15). CONCLUSIONS AND RELEVANCE Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed-but not self-reported-physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression

International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Meta-analyses of genome-wide association studies for postpartum depression

Objective: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. Method: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)–based heritability (), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. Results: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. Conclusions: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone)