title: Allelic-based gene-gene interaction associated with quantitative traits.
abstract: Recent studies have shown that quantitative phenotypes may be influenced not only by multiple single nucleotide polymorphisms (SNPs) within a gene but also by the interaction between SNPs at unlinked genes. We propose a new statistical approach that can detect gene-gene interactions at the allelic level which contribute to the phenotypic variation in a quantitative trait. By testing for the association of allelic combinations at multiple unlinked loci with a quantitative trait, we can detect the SNP allelic interaction whether or not it can be detected as a main effect. Our proposed method assigns a score to unrelated subjects according to their allelic combination inferred from observed genotypes at two or more unlinked SNPs, and then tests for the association of the allelic score with a quantitative trait. To investigate the statistical properties of the proposed method, we performed a simulation study to estimate type I error rates and power and demonstrated that this allelic approach achieves greater power than the more commonly used genotypic approach to test for gene-gene interaction. As an example, the proposed method was applied to data obtained as part of a candidate gene study of sodium retention by the kidney. We found that this method detects an interaction between the calcium-sensing receptor gene (CaSR), the chloride channel gene (CLCNKB) and the Na, K, 2Cl cotransporter gene (CLC12A1) that contributes to variation in diastolic blood pressure.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, Indiana, USA. jeejung@iupui.edu
authors.forename: Jeesun
authors.initials: J
authors.lastname: Jung
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.forename: Deukwoo
authors.initials: D
authors.lastname: Kwon
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Koller
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
mesh_terms: D000483:Alleles; D001794:Blood Pressure / Q000235:genetics; D018118:Chloride Channels / Q000235:genetics; D004812:Epidemiologic Methods; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008957:Models, Genetic; D015233:Models, Statistical; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics
chemical_list: C095550:CASR protein, human; C412733:CLCNKB protein, human; D018118:Chloride Channels; D044169:Receptors, Calcium-Sensing; D028021:Sodium-Potassium-Chloride Symporters; D012964:Sodium