title: The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem.
abstract: Several important and fundamental aspects of disease genetics models have yet to be described. One such property is the relationship of disease association statistics at a marker site closely linked to a disease causing site. A complete description of this two-locus system is of particular importance to experimental efforts to fine map association signals for complex diseases. Here, we present a simple relationship between disease association statistics and the decline of linkage disequilibrium from a causal site. Specifically, the ratio of Chi-square disease association statistics at a marker site and causal site is equivalent to the standard measure of pairwise linkage disequilibrium,r2. A complete derivation of this relationship from a general disease model is shown. Quite interestingly, this relationship holds across all modes of inheritance. Extensive Monte Carlo simulations using a disease genetics model applied to chromosomes subjected to a standard model of recombination are employed to better understand the variation around this fine mapping theorem due to sampling effects. We also use this relationship to provide a framework for estimating properties of a non-interrogated causal site using data at closely linked markers. Lastly, we apply this way of examining association data from high-density genotyping in a large, publicly-available data set investigating extreme BMI. We anticipate that understanding the patterns of disease association decay with declining linkage disequilibrium from a causal site will enable more powerful fine mapping methods and provide new avenues for identifying causal sites/genes from fine-mapping studies.
authors.affiliation: Department of Mathematics, Statistics and Computer Science, Marquette UniversityMilwaukee, WI, USA; Center for Human Genetics, Marshfield Clinic Research FoundationMarshfield, WI, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Maadooliat
authors.affiliation: Department of Mathematics, Statistics and Computer Science, Marquette University Milwaukee, WI, USA.
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Bansal
authors.affiliation: Department of Mathematics, Statistics and Computer Science, Marquette University Milwaukee, WI, USA.
authors.forename: Jiblal
authors.initials: J
authors.lastname: Upadhya
authors.affiliation: Department of Mathematics, Statistics and Computer Science, Marquette University Milwaukee, WI, USA.
authors.forename: Manzur R
authors.initials: MR
authors.lastname: Farazi
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation Marshfield, WI, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research FoundationMarshfield, WI, USA; Biomedical Informatics Research Center, Marshfield Clinic Research FoundationMarshfield, WI, USA; Computation and Informatics in Biology and Medicine, University of Wisconsin-MadisonMadison, WI, USA.
authors.forename: Max M
authors.initials: MM
authors.lastname: He
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research FoundationMarshfield, WI, USA; Computation and Informatics in Biology and Medicine, University of Wisconsin-MadisonMadison, WI, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hebbring
authors.affiliation: Biomedical Informatics Research Center, Marshfield Clinic Research Foundation Marshfield, WI, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Center for Human Genetics, Marshfield Clinic Research FoundationMarshfield, WI, USA; Computation and Informatics in Biology and Medicine, University of Wisconsin-MadisonMadison, WI, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schrodi
keywords: disease association; disease genetics; fine-mapping; linkage disequilibrium; mode of inheritance; statistical genetics/genomics; theoretical genetics; two-site model