Genome-wide association study of treatment response to venlafaxine XR in generalized anxiety disorder.
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SUBMITTER: Jung J
PROVIDER: S-EPMC5798606 | biostudies-literature | 2017 Aug
REPOSITORIES: biostudies-literature
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Genome-wide association study of treatment response to venlafaxine XR in generalized anxiety disorder.
Jung Jeesun J Tawa Elisabeth A EA Muench Christine C Rosen Allison D AD Rickels Karl K Lohoff Falk W FW
Psychiatry research 20170414
We conducted the first genome-wide association study (GWAS) in Generalized Anxiety Disorder (GAD) to identify potential predictors of venlafaxine XR treatment outcome. Ninety-eight European American patients participated in a venlafaxine XR clinical trial for GAD, with Hamilton Anxiety Scale (HAM-A) response/remission at 24 weeks as the primary outcome measure. All participants were genotyped with the Illumina PsychChip, and 266,820 common single nucleotide polymorphisms (SNPs) were analyzed. Al ...[more]
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Project description:Although generalized anxiety disorder (GAD) is heritable and aggregates in families, no genomic loci associated with GAD have been reported. We aimed to discover potential loci by conducting a genome-wide analysis of GAD symptoms in a large, population-based sample of Hispanic/Latino adults. Data came from 12,282 participants (aged 18-74) in the Hispanic Community Health Study/Study of Latinos. Using a shortened Spielberger Trait Anxiety measure, we analyzed the following: (i) a GAD symptoms score restricted to the three items tapping diagnostic features of GAD as defined by DSM-V; and (ii) a total trait anxiety score based on summing responses to all ten items. We first calculated the heritability due to common variants (h2SNP ) and then conducted a genome-wide association study (GWAS) of GAD symptoms. Replication was attempted in three independent Hispanic cohorts (Multi-Ethnic Study of Atherosclerosis, Women's Health Initiative, Army STARRS). The GAD symptoms score showed evidence of modest heritability (7.2%; P = 0.03), while the total trait anxiety score did not (4.97%; P = 0.20). One genotyped SNP (rs78602344) intronic to thrombospondin 2 (THBS2) was nominally associated (P = 5.28 × 10-8 ) in the primary analysis adjusting for psychiatric medication use and significantly associated with the GAD symptoms score in the analysis excluding medication users (P = 4.18 × 10-8 ). However, meta-analysis of the replication samples did not support this association. Although we identified a genome-wide significant locus in this sample, we were unable to replicate this finding. Evidence for heritability was also only detected for GAD symptoms, and not the trait anxiety measure, suggesting differential genetic influences within the domain of trait anxiety. © 2016 Wiley Periodicals, Inc.
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Project description:BackgroundLithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.MethodsHere, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.FindingsA single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).InterpretationThe response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.FundingDeutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.
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