85 research outputs found

    Integrative analysis of genomic and exposomic influences on youth mental health

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    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

    CryoEM structural exploration of catalytically active enzyme pyruvate carboxylase

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    Pyruvate carboxylase (PC) is a tetrameric enzyme that contains two active sites per subunit that catalyze two consecutive reactions. A mobile domain with an attached prosthetic biotin links both reactions, an initial biotin carboxylation and the subsequent carboxyl transfer to pyruvate substrate to produce oxaloacetate. Reaction sites are at long distance, and there are several co-factors that play as allosteric regulators. Here, using cryoEM we explore the structure of active PC tetramers focusing on active sites and on the conformational space of the oligomers. The results capture the mobile domain at both active sites and expose catalytic steps of both reactions at high resolution, allowing the identification of substrates and products. The analysis of catalytically active PC tetramers reveals the role of certain motions during enzyme functioning, and the structural changes in the presence of additional cofactors expose the mechanism for allosteric regulation.This study was supported by grants from the HFSP (RGP0062), and from the Spanish Ministerio de Ciencia e Innovacion (PGC2018-098996-B-100) to M.V., and grants from the NIGMS (R35GM118093) and the NIAID (R01AI116669) to L.T

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

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    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

    The clinical characterization of the adult patient with an anxiety or related disorder aimed at personalization of management

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    The clinical construct of “anxiety neurosis” was broad and poorly defined, so that the delineation of specific anxiety disorders in the DSM‐III was an important advance. However, anxiety and related disorders are not only frequently comorbid, but each is also quite heterogeneous; thus diagnostic manuals provide only a first step towards formulating a management plan, and the development of additional decision support tools for the treatment of anxiety conditions is needed. This paper aims to describe systematically important domains that are relevant to the personalization of management of anxiety and related disorders in adults. For each domain, we summarize the available research evidence and review the relevant assessment instruments, paying special attention to their suitability for use in routine clinical practice. We emphasize areas where the available evidence allows the clinician to personalize the management of anxiety conditions, and we point out key unmet needs. Overall, the evidence suggests that we are becoming able to move from simply recommending that anxiety and related disorders be treated with selective serotonin reuptake inhibitors, cognitive‐behavioral therapy, or their combination, to a more complex approach which emphasizes that the clinician has a broadening array of management modalities available, and that the treatment of anxiety and related disorders can already be personalized in a number of important respects

    Exposure to early childhood maltreatment and its effect over time on social cognition

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    Social cognitive deficits can have many negative consequences, spanning social withdrawal to psychopathology. Prior work has shown that child maltreatment may associate with poorer social cognitive skills in later life. However, no studies have examined this association from early childhood into adolescence. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 4,438), we examined the association between maltreatment (caregiver physical or emotional abuse; sexual or physical abuse), assessed repeatedly (every 1-3 years) from birth to age 9, and social cognitive skills at ages 7.5, 10.5, and 14 years. We evaluated the role of both the developmental timing (defined by age at exposure) and accumulation of maltreatment (defined as the number of occasions exposed) using a least angle regression variable selection procedure, followed by structural equation modeling. Among females, accumulation of maltreatment explained the most variation in social cognitive skills. For males, no significant associations were found. These findings underscore the importance of early intervention to minimize the accumulation of maltreatment and showcase the importance of prospective studies to understand the development of social cognition over time

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

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    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

    Genomeâ wide analyses of psychological resilience in U.S. Army soldiers

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    Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genomeâ wide association studies (GWASs) of selfâ assessed (by questionnaire) and outcomeâ based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Selfâ assessed resilience (Nâ =â 11,492) was found to have significant commonâ variant heritability (h2 =â 0.162, seâ =â 0.050, pâ =â 5.37â Ã â 10â 4), and to be significantly negatively genetically correlated with neuroticism (rgâ =â â 0.388, pâ =â .0092). GWAS results from the EUR soldiers revealed a genomeâ wide significant locus on an intergenic region on Chr 4 upstream from doublecortinâ like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 [pâ =â 5.65â Ã â 10â 9] is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelchâ like family member 36 (KLHL36) was detected at geneâ wise genomeâ wide significance [pâ =â 1.89â Ã â 10â 6]. A polygenic risk score derived from the selfâ assessed resilience GWAS was not significantly associated with outcomeâ based resilience. In very preliminary results, genomeâ wide significant association with outcomeâ based resilience was found for one locus (top SNP: rs12580015 [pâ =â 2.37â Ã â 10â 8]) on Chr 12 downstream from solute carrier family 15 member 5 (SLC15A5) in subjects (Nâ = 581) exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stressâ related psychopathology and point to new avenues for therapeutic intervention.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149528/1/ajmgb32730.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149528/2/ajmgb32730_am.pd

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

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    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