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Beyond genome-wide significance: integrative approaches to the interpretation and extension of GWAS findings for alcohol use disorder.

ABSTRACT: Alcohol use disorder (AUD) is a heritable complex behavior. Due to the highly polygenic nature of AUD, identifying genetic variants that comprise this heritable variation has proved to be challenging. With the exception of functional variants in alcohol metabolizing genes (e.g. ADH1B and ALDH2), few other candidate loci have been confidently linked to AUD. Genome-wide association studies (GWAS) of AUD and other alcohol-related phenotypes have either produced few hits with genome-wide significance or have failed to replicate on further study. These issues reinforce the complex nature of the genetic underpinnings for AUD and suggest that both GWAS studies with larger samples and additional analysis approaches that better harness the nominally significant loci in existing GWAS are needed. Here, we review approaches of interest in the post-GWAS era, including in silico functional analyses; functional partitioning of single nucleotide polymorphism heritability; aggregation of signal into genes and gene networks; and validation of identified loci, genes and gene networks in postmortem brain tissue and across species. These integrative approaches hold promise to illuminate our understanding of the biological basis of AUD; however, we recognize that the main challenge continues to be the extremely polygenic nature of AUD, which necessitates large samples to identify multiple loci associated with AUD liability.

SUBMITTER: Salvatore JE

PROVIDER: S-EPMC6037617 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Beyond genome-wide significance: integrative approaches to the interpretation and extension of GWAS findings for alcohol use disorder.

Salvatore Jessica E JE Han Shizhong S Farris Sean P SP Mignogna Kristin M KM Miles Michael F MF Agrawal Arpana A

Addiction biology 20180109 2

Alcohol use disorder (AUD) is a heritable complex behavior. Due to the highly polygenic nature of AUD, identifying genetic variants that comprise this heritable variation has proved to be challenging. With the exception of functional variants in alcohol metabolizing genes (e.g. ADH1B and ALDH2), few other candidate loci have been confidently linked to AUD. Genome-wide association studies (GWAS) of AUD and other alcohol-related phenotypes have either produced few hits with genome-wide significanc ...[more]

PMID: 29316088

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Project description:Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes-notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space. We solve the model for the phenotypic distribution and allelic dynamics at steady state and derive robust, closed-form solutions for summary statistics of the genetic architecture. Our results provide a simple interpretation for missing heritability and why it varies among traits. They predict that the distribution of variances contributed by loci identified in GWASs is well approximated by a simple functional form that depends on a single parameter: the expected contribution to genetic variance of a strongly selected site affecting the trait. We test this prediction against the results of GWASs for height and body mass index (BMI) and find that it fits the data well, allowing us to make inferences about the degree of pleiotropy and mutational target size for these traits. Our findings help to explain why the GWAS for height explains more of the heritable variance than the similarly sized GWAS for BMI and to predict the increase in explained heritability with study sample size. Considering the demographic history of European populations, in which these GWASs were performed, we further find that most of the associations they identified likely involve mutations that arose shortly before or during the Out-of-Africa bottleneck at sites with selection coefficients around s = 10-3.

Project description:Purpose of Review Neurodegenerative diseases, neuropsychiatric disorders, and related traits have highly complex etiologies but are also highly heritable and identifying the causal genes and biological pathways underlying these traits may advance the development of treatments and preventive strategies. While many genome-wide association studies (GWAS) have successfully identified variants contributing to polygenic neurodegenerative and neuropsychiatric phenotypes including Alzheimer’s disease (AD), schizophrenia (SCZ), and bipolar disorder (BPD) amongst others, interpreting the biological roles of significantly-associated variants in the genetic architecture of these traits remains a significant challenge. Here we review several ‘omics’ approaches which attempt to bridge the gap from associated genetic variants to phenotype by helping define the functional roles of GWAS loci in the development of neuropsychiatric disorders and traits. Recent Findings Several common ‘omics’ approaches have been applied to examine neuropsychiatric traits, such as nearest-gene mapping, trans-ethnic fine mapping, annotation enrichment analysis, transcriptomic analysis, and pathway analysis, and each of these approaches has strengths and limitations in providing insight into biological mechanisms. One popular emerging method is the examination of tissue-specific genetically-regulated gene expression (GReX), which aggregates the genetic variants’ effects at the gene-level. Furthermore, proteomic, metabolomic, and microbiomic studies and phenome-wide association studies will further enhance our understanding of neuropsychiatric traits. Summary GWAS has been applied to neuropsychiatric traits for a decade, but our understanding about the biological function of identified variants remains limited. Today, technological advancements have created analytical approaches for integrating transcriptomics, metabolomics, proteomics, pharmacology and toxicology as tools for understanding the functional roles of genetics variants. These data, as well as the broader clinical information provided by electronic health records, can provide additional insight and complement genomic analyses.

Project description:BackgroundSelf-efficacy has been proposed as a key predictor of alcohol treatment outcomes and a potential mechanism of success in achieving abstinence or drinking reductions following alcohol treatment. Integrative data analysis, where data from multiple studies are combined for analyses, can be used to synthesize analyses across multiple alcohol treatment trials by creating a commensurate measure and controlling for differential item functioning (DIF) to determine whether alcohol treatments improve self-efficacy.MethodThe current study used moderated nonlinear factor analysis (MNLFA) to examine the effect of treatment on self-efficacy across four different treatment studies (N = 3720; 72.5% male, 68.4% non-Hispanic white). Self-efficacy was measured using the Alcohol Abstinence Self-Efficacy Scale (AASE) in the COMBINE Study (n = 1383) and Project MATCH (n = 1726), and the Drug Taking Confidence Questionnaire (DTCQ) in two studies of Telephone Continuing Care (TEL Study 1: n = 303; TEL Study 2: n = 212). DIF was examined across time, study, treatment condition, marital status, age, and sex.ResultsWe identified 12 items from the AASE and DTCQ to create a commensurate measure of self-efficacy using MNLFA. All active treatments, including cognitive-behavioral treatment, a combined behavioral intervention, medication management, motivation enhancement treatment, telephone continuing care, twelve-step facilitation, and relapse prevention, were associated with significant increases in self-efficacy from baseline to posttreatment that were maintained for up to a year. Importantly, treatment as usual in community settings, which consisted of weekly group therapy that included addiction counseling and twelve-step recovery support, was not associated with significant increases in self-efficacy.ConclusionsAlcohol self-efficacy increases following treatment and numerous evidence-based treatments are associated with significant increases in self-efficacy, which are maintained over time. Community treatment that focuses solely on addiction counseling and twelve-step support may not promote increases in self-efficacy.

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Beyond genome-wide significance: integrative approaches to the interpretation and extension of GWAS findings for alcohol use disorder.

Publications

Beyond genome-wide significance: integrative approaches to the interpretation and extension of GWAS findings for alcohol use disorder.

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