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Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes.

ABSTRACT: Catechol-O-methyltransferase (COMT) has been investigated for its possible role in a wide range of psychiatric phenotypes. In particular, several studies support association of this gene with panic disorder and other anxiety-related traits.We examined the COMT gene for association with genetic risk across a range of anxiety spectrum phenotypes. We used multivariate structural equation modeling to select twin pairs scoring at the extremes of a latent genetic risk factor shared by neuroticism, several anxiety disorders, and major depression from a large population-based twin sample. With one member from each of these pairs, the resulting sample of 589 cases and 539 control subjects were entered into a two-stage association study in which genetic markers were screened in stage 1, the positive results of which were tested for replication in stage 2.The functional val158met polymorphism (rs4680) plus nine other single nucleotide polymorphism markers selected to capture the major allelic variation across the COMT locus were analyzed for differences between cases and control subjects. Although the val (G) allele of rs4680 showed marginally significant association in our combined stage 1 plus stage 2 sample, a high-risk haplotype of this allele with the A allele of rs165599 was significantly over-represented in cases (p = 1.97e-5, odds ratio = 1.95). This haplotype also predicted individual differences in neuroticism and risk for several anxiety disorders and major depression. Consistent with prior studies, our findings are female-specific.Variations in the COMT gene contribute to genetic risk shared across a range of anxiety-related phenotypes.

SUBMITTER: Hettema JM

PROVIDER: S-EPMC2597663 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes.

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

Biological psychiatry 20080423 4

<h4>Background</h4>Catechol-O-methyltransferase (COMT) has been investigated for its possible role in a wide range of psychiatric phenotypes. In particular, several studies support association of this gene with panic disorder and other anxiety-related traits.<h4>Methods</h4>We examined the COMT gene for association with genetic risk across a range of anxiety spectrum phenotypes. We used multivariate structural equation modeling to select twin pairs scoring at the extremes of a latent genetic ris ...[more]

PMID: 18436194

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Project description:While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb); http://cpag.oit.duke.edu ) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs with severe COVID-19 demonstrated colocalization of the GWAS signal of the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN), pointing to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches.

Dataset Information

Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes.

Publications

Catechol-O-methyltransferase contributes to genetic susceptibility shared among anxiety spectrum phenotypes.

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