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Association of repeatedly measured intermediate risk factors for complex diseases with high dimensional SNP data.

ABSTRACT: BACKGROUND:The causes of complex diseases are difficult to grasp since many different factors play a role in their onset. To find a common genetic background, many of the existing studies divide their population into controls and cases; a classification that is likely to cause heterogeneity within the two groups. Rather than dividing the study population into cases and controls, it is better to identify the phenotype of a complex disease by a set of intermediate risk factors. But these risk factors often vary over time and are therefore repeatedly measured. RESULTS:We introduce a method to associate multiple repeatedly measured intermediate risk factors with a high dimensional set of single nucleotide polymorphisms (SNPs). Via a two-step approach, we summarized the time courses of each individual and, secondly apply these to penalized nonlinear canonical correlation analysis to obtain sparse results. CONCLUSIONS:Application of this method to two datasets which study the genetic background of cardiovascular diseases, show that compared to progression over time, mainly the constant levels in time are associated with sets of SNPs.

SUBMITTER: Waaijenborg S

PROVIDER: S-EPMC2828454 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Association of repeatedly measured intermediate risk factors for complex diseases with high dimensional SNP data.

Waaijenborg Sandra S Zwinderman Aeilko H AH

Algorithms for molecular biology : AMB 20100211

<h4>Background</h4>The causes of complex diseases are difficult to grasp since many different factors play a role in their onset. To find a common genetic background, many of the existing studies divide their population into controls and cases; a classification that is likely to cause heterogeneity within the two groups. Rather than dividing the study population into cases and controls, it is better to identify the phenotype of a complex disease by a set of intermediate risk factors. But these r ...[more]

PMID: 20205905

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Project description:Genetic researchers often collect disease related quantitative traits in addition to disease status because they are interested in understanding the pathophysiology of disease processes. In genome-wide association (GWA) studies, these quantitative phenotypes may be relevant to disease development and serve as intermediate phenotypes or they could be behavioral or other risk factors that predict disease risk. Statistical tests combining both disease status and quantitative risk factors should be more powerful than case-control studies, as the former incorporates more information about the disease. In this paper, we proposed a modified inverse-variance weighted meta-analysis method to combine disease status and quantitative intermediate phenotype information. The simulation results showed that when an intermediate phenotype was available, the inverse-variance weighted method had more power than did a case-control study of complex diseases, especially in identifying susceptibility loci having minor effects. We further applied this modified meta-analysis to a study of imputed lung cancer genotypes with smoking data in 1154 cases and 1137 matched controls. The most significant SNPs came from the CHRNA3-CHRNA5-CHRNB4 region on chromosome 15q24-25.1, which has been replicated in many other studies. Our results confirm that this CHRNA region is associated with both lung cancer development and smoking behavior. We also detected three significant SNPs--rs1800469, rs1982072, and rs2241714--in the promoter region of the TGFB1 gene on chromosome 19 (p?=?1.46×10(-5), 1.18×10(-5), and 6.57×10(-6), respectively). The SNP rs1800469 is reported to be associated with chronic obstructive pulmonary disease and lung cancer in cigarette smokers. The present study is the first GWA study to replicate this result. Signals in the 3q26 region were also identified in the meta-analysis. We demonstrate the intermediate phenotype can potentially enhance the power of complex disease association analysis and the modified meta-analysis method is robust to incorporate intermediate phenotype or other quantitative risk factor in the analysis.

Project description:BackgroundHuman genome sequencing has enabled the association of phenotypes with genetic loci, but our ability to effectively translate this data to the clinic has not kept pace. Over the past 60 years, pharmaceutical companies have successfully demonstrated the safety and efficacy of over 1,200 novel therapeutic drugs via costly clinical studies. While this process must continue, better use can be made of the existing valuable data. In silico tools such as candidate gene prediction systems allow rapid identification of disease genes by identifying the most probable candidate genes linked to genetic markers of the disease or phenotype under investigation. Integration of drug-target data with candidate gene prediction systems can identify novel phenotypes which may benefit from current therapeutics. Such a drug repositioning tool can save valuable time and money spent on preclinical studies and phase I clinical trials.MethodsWe previously used Gentrepid (http://www.gentrepid.org) as a platform to predict 1,497 candidate genes for the seven complex diseases considered in the Wellcome Trust Case-Control Consortium genome-wide association study; namely Type 2 Diabetes, Bipolar Disorder, Crohn's Disease, Hypertension, Type 1 Diabetes, Coronary Artery Disease and Rheumatoid Arthritis. Here, we adopted a simple approach to integrate drug data from three publicly available drug databases: the Therapeutic Target Database, the Pharmacogenomics Knowledgebase and DrugBank; with candidate gene predictions from Gentrepid at the systems level.ResultsUsing the publicly available drug databases as sources of drug-target association data, we identified a total of 428 candidate genes as novel therapeutic targets for the seven phenotypes of interest, and 2,130 drugs feasible for repositioning against the predicted novel targets.ConclusionsBy integrating genetic, bioinformatic and drug data, we have demonstrated that currently available drugs may be repositioned as novel therapeutics for the seven diseases studied here, quickly taking advantage of prior work in pharmaceutics to translate ground-breaking results in genetics to clinical treatments.

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Association of repeatedly measured intermediate risk factors for complex diseases with high dimensional SNP data.

Publications

Association of repeatedly measured intermediate risk factors for complex diseases with high dimensional SNP data.

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