title: Simultaneous estimation of the locations and effects of multiple disease loci in case-control studies.
abstract: The genetic basis of complex diseases often involves multiple causative loci. Under such a disease etiology, assuming one disease locus in linkage disequilibrium mapping is likely to induce bias and lead to efficiency loss in disease locus estimation. An approach is needed for simultaneously localizing multiple functional loci within the same region. However, due to the increasing number of parameters accompanying disease loci, these estimates can be computationally infeasible. To circumvent this problem, we propose to estimate the main and two-adjacent-locus joint effects and a nuisance parameter at the disease loci separately through a linear approximation. Estimates of the genetic effects are entered into a generalized estimating equation to estimate disease loci, and the procedure is conducted iteratively until convergence. The proposed method provides estimates and confidence intervals (CIs) for the disease loci, the genetic main effects, and the joint effects of two adjacent disease loci, with the CIs for the disease loci providing useful regions for further fine-mapping. We apply the proposed approach to a data example of case-control studies. Results of the simulations and data example suggest that the developed method performs well in terms of bias, variance, and coverage probability under scenarios with up to three disease loci.
authors.affiliation: Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli 35053, Taiwan, ROC.
authors.forename: Li-Chu
authors.initials: LC
authors.lastname: Chien
authors.affiliation: Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli 35053, Taiwan, ROC; Institute of Statistics, National Chiao Tung University Hsinchu 30010, Taiwan, ROC; Biostatistics Center, China Medical University, Taichung 40402, Taiwan, ROC yfchiu@nhri.org.tw.
authors.forename: Yen-Feng
authors.initials: YF
authors.lastname: Chiu
authors.affiliation: Institution of Public Health and Department of Public Health, National Yang Ming University, Taipei 11221, Taiwan.
authors.forename: Kung-Yee
authors.initials: KY
authors.lastname: Liang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei 10051, Taiwan.
authors.forename: Lee-Ming
authors.initials: LM
authors.lastname: Chuang
mesh_terms: D016022:Case-Control Studies; D003627:Data Interpretation, Statistical; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008957:Models, Genetic; D058729:Peripheral Arterial Disease / Q000235:genetics
keywords: Association analysis; Case–control design; Generalized estimating equations; Linkage disequilibrium; Multi-locus