title: A knowledge-based method for association studies on complex diseases.
abstract: Complex disorders are a class of diseases whose phenotypic variance is caused by the interplay of multiple genetic and environmental factors. Analyzing the complexity underlying the genetic architecture of such traits may help develop more efficient diagnostic tests and therapeutic protocols. Despite the continuous advances in revealing the genetic basis of many of complex diseases using genome-wide association studies (GWAS), a major proportion of their genetic variance has remained unexplained, in part because GWAS are unable to reliably detect small individual risk contributions and to capture the underlying genetic heterogeneity. In this paper we describe a hypothesis-based method to analyze the association between multiple genetic factors and a complex phenotype. Starting from sets of markers selected based on preexisting biomedical knowledge, our method generates multi-marker models relevant to the biological process underlying a complex trait for which genotype data is available. We tested the applicability of our method using the WTCCC case-control dataset. Analyzing a number of biological pathways, the method was able to identify several immune system related multi-SNP models significantly associated with Rheumatoid Arthritis (RA) and Crohn's disease (CD). RA-associated multi-SNP models were also replicated in an independent case-control dataset. The method we present provides a framework for capturing joint contributions of genetic factors to complex traits. In contrast to hypothesis-free approaches, its results can be given a direct biological interpretation. The replicated multi-SNP models generated by our analysis may serve as a predictor to estimate the risk of RA development in individuals of Caucasian ancestry.
authors.affiliation: Department of Molecular Genetics and Microbiology and UF Genetics Institute, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Alireza
authors.initials: A
authors.lastname: Nazarian
authors.forename: Heike
authors.initials: H
authors.lastname: Sichtig
authors.forename: Alberto
authors.initials: A
authors.lastname: Riva
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics*; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D051188:Knowledge Bases; D016015:Logistic Models; D008957:Models, Genetic; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics