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Genetic association between RGS1 and internalizing disorders.

ABSTRACT: Quantitative trait loci identified in animal models provide potential candidate susceptibility loci for human disorders. In this study, we investigated whether internalizing disorders (anxiety disorders, major depression, and neuroticism) were associated with a region on human chromosome 1 syntenic with a quantitative trait locus for rodent emotionality.We genotyped 31 single-nucleotide polymorphisms in genes located on chromosome 1q31.2 in a two-stage association study of 1128 individuals chosen for a high or a low genetic risk for internalizing disorders from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders.None of the individual single-nucleotide polymorphisms showed consistent association across stages. A four-marker haplotype in the regulator of G-protein signaling 1 gene (RGS1) was significantly associated with decreased internalizing risk in both stages, whereas another showed a nominal association with a higher risk.Our data suggest that markers in the RGS1 gene might be in linkage disequilibrium with a protective allele that reduces the risk of anxiety and depressive disorders.

SUBMITTER: Hettema JM

PROVIDER: S-EPMC3606916 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Genetic association between RGS1 and internalizing disorders.

Hettema John M JM An Seon-Sook SS van den Oord Edwin J C G EJ Neale Michael C MC Kendler Kenneth S KS Chen Xiangning X

Psychiatric genetics 20130401 2

<h4>Objective</h4>Quantitative trait loci identified in animal models provide potential candidate susceptibility loci for human disorders. In this study, we investigated whether internalizing disorders (anxiety disorders, major depression, and neuroticism) were associated with a region on human chromosome 1 syntenic with a quantitative trait locus for rodent emotionality.<h4>Methods</h4>We genotyped 31 single-nucleotide polymorphisms in genes located on chromosome 1q31.2 in a two-stage associati ...[more]

PMID: 23324853

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Project description:Much research has demonstrated that psychopathology can be described in terms of broad dimensions, representing liability for multiple psychiatric disorders. Broad spectra of psychopathology (e.g., internalizing and externalizing) are increasingly used as targets for research investigating the development, etiology, and course of psychopathology because they account for patterns of relatedness among disorders that were once presumed distinct. Thus, these spectra represent alluring targets due to their comprehensive and parsimonious nature. Nevertheless, little research has established the role of individual disorders over and above broad dimensions in the study of psychopathology. In the current study, we investigate whether there are unique etiological associations between individual internalizing disorders and personality traits after accounting for their etiological associations with a broad internalizing dimension. We used a community sample of twins (Npairs = 448) ages 4 to 19 to examine the etiological associations between internalizing psychopathology and Big Five personality dimensions. In terms of genetic covariation, a broad internalizing dimension was positively associated with neuroticism and negatively associated with extraversion, agreeableness, and conscientiousness. Moreover, internalizing accounted for most of the genetic variance shared between individual internalizing disorders and personality traits. Nevertheless, there were unique genetic associations between the following pairs of personality traits and disorders: neuroticism and social anxiety, extraversion and social anxiety, agreeableness and depression, and conscientiousness and compulsions. There was little evidence of environmental influences shared between internalizing and personality. In sum, a broad internalizing dimension adequately accounted for almost all of the etiologic covariation between internalizing disorders and personality, with several interesting exceptions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Project description:BackgroundElimination disorders are highly prevalent in childhood and often associated with clinically relevant comorbid psychological disorders. The aim of this study is to determine if, and to what extent, children with elimination disorders show higher internalizing and externalizing problems than their healthy peers.MethodsA multistep literature search was performed from database inception until May 1st, 2022. PRISMA/MOOSE-compliant systematic review (PROSPERO: CRD42022303555) were used to identify studies reporting on internalizing and/or externalizing symptoms in children with an elimination disorder and a healthy control (HC) group. First, a systematic review was provided. Second, where data allowed for it, a quantitative meta-analysis with random effects model was conducted to analyze the differences between the elimination disorder and the HC groups for internalizing and externalizing symptoms. Effect size was standardized mean difference. Meta-regression analyses were conducted to examine the effect of sex, age, and study quality. Funnel plots were used to detect a publication bias. Where found, the trim and fill method was used to correct it.Results36 articles were included, 32 of them reporting on enuresis (n = 3244; mean age = 9.4; SD = 3.4; 43.84% female) and 7 of them on encopresis (n = 214; mean age = 8.6; SD = 2.3; 36.24% female). Children with an elimination disorder presented significantly lower self-concept (ES:0.42; 95%CI [0.08; 9.76]; p = 0.017) and higher symptom scores for thought problems (ES:-0.26; 95%CI: -0.43;-0.09]; p = 0.003), externalizing symptoms (ES: -0.20; 95%CI [-0.37;-0.03]; p = 0.020), attention problems (ES:-0.37; 95%CI [-0.51;-0.22]; p = 0.0001), aggressive behavior (ES:-0.33; 95%CI [-0.62;-0.04]; p = 0.025) and social problems (ES:-0.39; 95%CI [-0.58;-0.21]; p = 0.0001). Significant publication biases were found across several of the studied domains. No significant effect of sex, age or quality of the study score was found.ConclusionsChildren with an elimination disorder may have significant internalizing and externalizing problems, as well as impaired self-concept. It is recommendable to screen for them in children with enuresis or encopresis and provide appropriate interventions.

Project description:ObjectiveTo evaluate the influence of extensive genetic and psychosocial confounding on the association between early childhood infection and five major psychiatric disorders METHODS: A case-cohort study including participants from the Danish iPSYCH2012 sample, a case-cohort sample where all cases born between May 1, 1981, and December 31, 2005, diagnosed with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar affective disorder (BIP), Major Depressive Disorder (MDD) or schizophrenia (SCZ), were identified and pooled with a representative sample (subcohort) of the Danish population. We used Cox proportional hazards regression customized to the case-cohort setup to calculate hazard ratios of outcome with 95% confidence intervals (CIs), following exposure to early childhood infection before the age of 5 years for ADHD and ASD, and before the age of 10 years for BIP, MDD, and SCZ. To evaluate psychosocial confounding we included sex, calendar period, sibling infections, urbanicity, parental socio-economic status, parental mental health information, and polygenic risk scores for all five disorders, as covariates. To estimate how liability for psychiatric disorders measured through the PRS influenced the risk of early childhood infection, we calculated odds ratios (ORs) with 95% CIs, using logistic regression RESULTS: Early childhood infection was associated with ADHD, ASD, MDD, and SCZ with number of childhood infections increasing the hazard. The HR was still significant in the model with full adjustments after 1 infection for ADHD (HR 1.29, 95% CI: 1.19-1.41), ASD (HR 1.28, 95% CI: 1.18-1.40), MDD (HR 1.23, 95% CI: 1.14-1.33), and SCZ (HR 1.21, 95% CI: 1.07-1.36), but not for BIP (HR1.17, 95% CI: 0.96-1.42). Probands exposed to sibling infections, but not own infection had an absolute risk of ADHD, BIP, MDD, and SCZ that closely approached the absolute risk for individuals exposed to own infections. We found evidence of gene-environment correlation with higher PRS of MDD and to some extent SCZ increasing the risk of infections and higher PRS of BIP associated with significantly decreased risk CONCLUSION: Early childhood infection is significantly associated with ADHD, ASD, MDD, and SCZ and not explained by genetic or psychosocial confounding. Although we found evidence of gene-environment correlation, it had minor impact on the results.

Project description:ImportancePeople with major psychiatric disorders (MPDs) have a 10- to 20-year shorter life span than the rest of the population, and this difference is mainly due to comorbid cardiovascular diseases. Genome-wide association studies have identified common variants involved in schizophrenia (SCZ), bipolar disorder (BIP), and major depression (MD) and body mass index (BMI), a key cardiometabolic risk factor. However, genetic variants jointly influencing MPD and BMI remain largely unknown.ObjectiveTo assess the extent of the overlap between the genetic architectures of MPDs and BMI and identify genetic loci shared between them.Design, setting, and participantsUsing a conditional false discovery rate statistical framework, independent genome-wide association study data on individuals with SCZ (n = 82 315), BIP (n = 51 710), MD (n = 480 359), and BMI (n = 795 640) were analyzed. The UK Biobank cohort (n = 29 740) was excluded from the MD data set to avoid sample overlap. Data were collected from August 2017 to May 2018, and analysis began July 2018.Main outcomes and measuresThe primary outcomes were a list of genetic loci shared between BMI and MPDs and their functional pathways.ResultsGenome-wide association study data from 1 380 284 participants were analyzed, and the genetic correlation between BMI and MPDs varied (SCZ: r for genetic = -0.11, P = 2.1 × 10-10; BIP: r for genetic = -0.06, P = .0103; MD: r for genetic = 0.12, P = 6.7 × 10-10). Overall, 63, 17, and 32 loci shared between BMI and SCZ, BIP, and MD, respectively, were analyzed at conjunctional false discovery rate less than 0.01. Of the shared loci, 34% (73 of 213) in SCZ, 52% (36 of 69) in BIP, and 57% (56 of 99) in MD had risk alleles associated with higher BMI (conjunctional false discovery rate <0.05), while the rest had opposite directions of associations. Functional analyses indicated that the overlapping loci are involved in several pathways including neurodevelopment, neurotransmitter signaling, and intracellular processes, and the loci with concordant and opposite association directions pointed mostly to different pathways.Conclusions and relevanceIn this genome-wide association study, extensive polygenic overlap between BMI and SCZ, BIP, and MD were found, and 111 shared genetic loci were identified, implicating novel functional mechanisms. There was mixture of association directions in SCZ and BMI, albeit with a preponderance of discordant ones.

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Genetic association between RGS1 and internalizing disorders.

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Genetic association between RGS1 and internalizing disorders.

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