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Generalised Anxiety Disorder--A Twin Study of Genetic Architecture, Genome-Wide Association and Differential Gene Expression.

ABSTRACT: Generalised Anxiety Disorder (GAD) is a common anxiety-related diagnosis, affecting approximately 5% of the adult population. One characteristic of GAD is a high degree of anxiety sensitivity (AS), a personality trait which describes the fear of arousal-related sensations. Here we present a genome-wide association study of AS using a cohort of 730 MZ and DZ female twins. The GWAS showed a significant association for a variant within the RBFOX1 gene. A heritability analysis of the same cohort also confirmed a significant genetic component with h2 of 0.42. Additionally, a subset of the cohort (25 MZ twins discordant for AS) was studied for evidence of differential expression using RNA-seq data. Significant differential expression of two exons with the ITM2B gene within the discordant MZ subset was observed, a finding that was replicated in an independent cohort. While previous research has shown that anxiety has a high comorbidity with a variety of psychiatric and neurodegenerative disorders, our analysis suggests a novel etiology specific to AS.

SUBMITTER: Davies MN

PROVIDER: S-EPMC4537268 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Generalised Anxiety Disorder--A Twin Study of Genetic Architecture, Genome-Wide Association and Differential Gene Expression.

Davies Matthew N MN Verdi Serena S Burri Andrea A Trzaskowski Maciej M Lee Minyoung M Hettema John M JM Jansen Rick R Boomsma Dorret I DI Spector Tim D TD

PloS one 20150814 8

Generalised Anxiety Disorder (GAD) is a common anxiety-related diagnosis, affecting approximately 5% of the adult population. One characteristic of GAD is a high degree of anxiety sensitivity (AS), a personality trait which describes the fear of arousal-related sensations. Here we present a genome-wide association study of AS using a cohort of 730 MZ and DZ female twins. The GWAS showed a significant association for a variant within the RBFOX1 gene. A heritability analysis of the same cohort als ...[more]

PMID: 26274327

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Project description:ObjectiveStudies have shown that area-level deprivation measured by factors, such as non-home ownership, non-car ownership and household overcrowding, can increase the risk for mental disorders over and above individual-level circumstances, such as education and social class. Whether area-level deprivation is associated with generalised anxiety disorder (GAD) independent of personal circumstances, and whether this association is different between British women and men is unknown.DesignLarge, population study.SettingUK population-based cohort.Participants30?445 people from the general population aged 40?years and older and living in England consented to participate at study baseline, and of these, 21?921 participants completed a structured health and lifestyle questionnaire used to capture GAD. Area deprivation was measured in 1991 using Census data, and GAD was assessed in 1996-2000. 10?275 women and 8219 men had complete data on all covariates.Main outcome measurePast-year GAD defined according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV).ResultsIn this study, 2.5% (261/10?275) of women and 1.8% (145/8219) of men had GAD. Women living in the most deprived areas were over 60% more likely to develop anxiety than those living in areas that were not deprived (OR=1.63, 95% CI 1.21 to 2.21; p=0.001), but this association between deprivation and GAD was not apparent in men (OR=1.13, 95% CI 0.72 to 1.77; p=0.598).ConclusionsThe absolute numbers of people living in deprived conditions are large worldwide. This, combined with a growing mental health burden, means that the findings obtained in this study remain highly relevant. The WHO has emphasised the need to reduce social and health inequalities. Our findings provide a strong evidence base to this call, showing that the environment needs to be taken into account when developing mental health policy; gender is important when it comes to assessing the influence of the environment on our mental health.

Project description:The husk is a leafy outer tissue that encloses a maize ear. Previously, we identified the optimum husk structure by measuring the husk length, husk layer number, husk thickness and husk width. Husk tightness (HTI) is a combined trait based on the above four husk measurements. Unveiling the genetic basis of HTI will aid in guiding the genetic improvement of maize for mechanical harvesting and for protecting the ear from pest damage and pathogen infection. Here, we used a maize associate population of 508 inbred lines with tropical, subtropical and temperate backgrounds to analyze the genetic architecture of HTI. Evaluating the phenotypic diversity in three different environments showed that HTI exhibited broad natural variations and a moderate heritability level of 0.41. A diversity analysis indicated that the inbred lines having a temperate background were more loosely related than those having a tropical or subtropical background. HTI showed significant negative correlations with husk thickness and width, which indicates that thicker and wider husks wrapped the ear tighter than thinner and slimmer husks. Combining husk traits with ?1.25 million single nucleotide polymorphisms in a genome-wide association study revealed 27 variants that were significantly associated with HTI above the threshold of P < 7.26 × 10-6. We found 27 candidate genes for HTI that may participate in (1) husk senescence involving lipid peroxidation (GRMZM2G017616) and programmed cell death (GRMZM2G168898 and GRMZM2G035045); (2) husk morphogenesis involving cell division (GRMZM5G869246) and cell wall architecture (GRMZM2G319798); and (3) cell signal transduction involving protein phosphorylation (GRMZM2G149277 and GRMZM2G004207) and the ABSISIC ACID INSENSITIVE3/VIVIPAROUS1 transcription factor (GRMZM2G088427). These results provide useful information for understanding the genetic basis of husk development. Further studies of identified candidate genes will help elucidate the molecular pathways that regulate HTI in maize.

Project description:ObjectiveInflammation has been implicated in the aetiology of mental illness. We conducted the first systematic review and meta-analysis of the association between peripheral markers of inflammation and generalised anxiety disorder (GAD).DesignSystematic review and meta-analysis of studies measuring peripheral cytokine levels in people with GAD compared with controls.Data sourcesMEDLINE (1950-), EMBASE (1947-), PsycINFO (1872-) and Web of Science (1945-) databases up until January 2018.Eligibility criteriaPrimary, quantitative research studies of people with a diagnosis of GAD assessed using a standardised clinical interview that measured peripheral inflammatory markers.Data extraction and synthesisTwo independent reviewers extracted data and assessed study quality. Meta-analysis using a random-effects model was conducted for individual cytokines where data from three or more studies were available.Results14 of 1718 identified studies met the inclusion criteria, comprising 1188 patients with GAD and 10 623 controls. In total 16 cytokines were evaluated. Significantly raised levels of C reactive protein (CRP), interferon-γ and tumour necrosis factor-α were reported in patients with GAD compared with controls in two or more studies. Ten further proinflammatory cytokines were reported to be significantly raised in GAD in at least one study. However, 5 of 14 studies found no difference in the levels of at least one cytokine. Only CRP studies reported sufficient data for meta-analysis. CRP was significantly higher in people with GAD compared with controls, with a small effect size (Cohen's d=0.38, 0.06-0.69), comparable with that reported in schizophrenia. However, heterogeneity was high (I2=75%), in keeping with meta-analyses of inflammation in other psychiatric conditions and reflecting differences in participant medication use, comorbid depression and cytokine sampling methodology.ConclusionThere is preliminary evidence to suggest an inflammatory response in GAD, but it remains unclear whether inflammatory cytokines play a role in the aetiology. GAD remains a poorly studied area of neuroinflammation compared with other mental disorders, and further longitudinal studies are required.

Dataset Information

Generalised Anxiety Disorder--A Twin Study of Genetic Architecture, Genome-Wide Association and Differential Gene Expression.

Publications

Generalised Anxiety Disorder--A Twin Study of Genetic Architecture, Genome-Wide Association and Differential Gene Expression.

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