title: Sibship analysis of associations between SNP haplotypes and a continuous trait with application to mammographic density.
abstract: Haplotype-based association studies have been proposed as a powerful comprehensive approach to identify causal genetic variation underlying complex diseases. Data comparisons within families offer the additional advantage of dealing naturally with complex sources of noise, confounding and population stratification. Two problems encountered when investigating associations between haplotypes and a continuous trait using data from sibships are (i) the need to define within-sibship comparisons for sibships of size greater than two and (ii) the difficulty of resolving the joint distribution of haplotype pairs within sibships in the absence of parental genotypes. We therefore propose first a method of orthogonal transformation of both outcomes and exposures that allow the decomposition of between- and within-sibship regression effects when sibship size is greater than two. We conducted a simulation study, which confirmed analysis using all members of a sibship is statistically more powerful than methods based on cross-sectional analysis or using subsets of sib-pairs. Second, we propose a simple permutation approach to avoid errors of inference due to the within-sibship correlation of any errors in haplotype assignment. These methods were applied to investigate the association between mammographic density (MD), a continuously distributed and heritable risk factor for breast cancer, and single nucleotide polymorphisms (SNPs) and haplotypes from the VDR gene using data from a study of 430 twins and sisters. We found evidence of association between MD and a 4-SNP VDR haplotype. In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software.
authors.affiliation: Centre for Molecular, Environmental, Genetic, and Analytic (MEGA) Epidemiology, University of Melbourne, Melbourne, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Stone
authors.forename: L C
authors.initials: LC
authors.lastname: Gurrin
authors.forename: V M
authors.initials: VM
authors.lastname: Hayes
authors.forename: M C
authors.initials: MC
authors.lastname: Southey
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.forename: G B
authors.initials: GB
authors.lastname: Byrnes
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D003198:Computer Simulation; D004200:Diseases in Twins; D005192:Family Health; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008327:Mammography / Q000379:methods*; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics; D012044:Regression Analysis; D017422:Sequence Analysis, DNA; D035781:Siblings
chemical_list: D018167:Receptors, Calcitriol