Nonparametric Disequilibrium Mapping of Functional Sites Using Haplotypes of Multiple Tightly Linked Single-Nucleotide Polymorphism Markers

Nonparametric Disequilibrium Mapping of Functional Sites Using Haplotypes of Multiple Tightly Linked Single-Nucleotide Polymorphism Markers

Rong Cheng^a, Jennie Z. Ma^a,b, Fred A. Wright^c, Shili Lin^d, Xin Gao^c, Daolong Wang^c, Robert C. Elston^e, and Ming D. Li^a
^a Department of Psychiatry, The University of Texas Health Science Center, San Antonio, Texas 78229,
^b Center for Biostatistics and Epidemiology, The University of Texas Health Science Center, San Antonio, Texas 78229,
^c Division of Human Cancer Genetics, Ohio State University, Columbus, Ohio 43210
^d Department of Statistics, Ohio State University, Columbus, Ohio 43210
^e Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44109

Corresponding author: Ming D. Li, Mail Code 7792, 7703 Floyd Curl Dr., San Antonio, TX 78229., lim2{at}uthscsa.edu (E-mail)

Communicating editor: Z-B. ZENG

As the speed and efficiency of genotyping single-nucleotidepolymorphisms (SNPs) increase, using the SNP map, it becomespossible to evaluate the extent to which a common haplotypecontributes to the risk of disease. In this study we proposea new procedure for mapping functional sites or regions of acandidate gene of interest using multiple linked SNPs. Basedon a case-parent trio family design, we use expectation-maximization(EM) algorithm-derived haplotype frequency estimates of multipletightly linked SNPs from both unambiguous and ambiguous familiesto construct a contingency statistic S for linkage disequilibrium(LD) analysis. In the procedure, a moving-window scan for functionalSNP sites or regions can cover an unlimited number of loci exceptfor the limitation of computer storage. Within a window, allpossible widths of haplotypes are utilized to find the maximumstatistic S* for each site (or locus). Furthermore, this methodcan be applied to regional or genome-wide scanning for determininglinkage disequilibrium using SNPs. The sensitivity of the proposedprocedure was examined on the simulated data set from the GeneticAnalysis Workshop (GAW) 12. Compared with the conventional andgeneralized TDT methods, our procedure is more flexible andpowerful.

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