title: Two-stage designs to identify the effects of SNP combinations on complex diseases.
abstract: The genetic basis of complex diseases is expected to be highly heterogeneous, with many disease genes, where each gene by itself has only a small effect. Based on the nonlinear contributions of disease genes across the genome to complex diseases, we introduce the concept of single nucleotide polymorphism (SNP) synergistic blocks. A two-stage approach is applied to detect the genetic association of synergistic blocks with a disease. In the first stage, synergistic blocks associated with a complex disease are identified by clustering SNP patterns and choosing blocks within a cluster that minimize a diversity criterion. In the second stage, a logistic regression model is given for a synergistic block. Using simulated case-control data, we demonstrate that our method has reasonable power to identify gene-gene interactions. To further evaluate the performance of our method, we apply our method to 17 loci of four candidate genes for paranoid schizophrenia in a Chinese population. Five synergistic blocks are found to be associated with schizophrenia, three of which are negatively associated (odds ratio, OR < 0.3, P < 0.05), while the others are positively associated (OR > 2.0, P < 0.05). The mathematical models of these five synergistic blocks are presented. The results suggest that there may be interactive effects for schizophrenia among variants of the genes neuregulin 1 (NRG1, 8p22-p11), G72 (13q34), the regulator of G-protein signaling-4 (RGS4, 1q21-q22) and frizzled 3 (FZD3, 8p21). Using synergistic blocks, we can reduce the dimensionality in a multi-locus association analysis, and evaluate the sizes of interactive effects among multiple disease genes on complex phenotypes.
authors.affiliation: Key Laboratory of Systems and Control, Institute of Systems Science, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100080, China.|Department of Biostatistics, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Guolian
authors.initials: G
authors.lastname: Kang
authors.affiliation: Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing, 100083, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Yue
authors.affiliation: Key Laboratory of Systems and Control, Institute of Systems Science, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, 100080, China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Statistics and Probability, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Huebner
authors.affiliation: Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing, 100083, China.
authors.forename: Handi
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing, 100083, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing, 100083, China.
authors.forename: Tianlan
authors.initials: T
authors.lastname: Lu
authors.affiliation: Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing, 100083, China.
authors.forename: Yansu
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Department of Statistics and Probability, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Zuo
authors.affiliation: Key Laboratory for Mental Health, Ministry of Health, Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing, 100083, China. daizhang@hsc.pku.edu.cn.
authors.forename: Dai
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000465:Algorithms; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods / Q000706:statistics & numerical data; D003198:Computer Simulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D020412:Multifactorial Inheritance / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics