AUTHOR=Maadooliat Mehdi , Bansal Naveen K. , Upadhya Jiblal , Farazi Manzur R. , Li Xiang , He Max M. , Hebbring Scott J. , Ye Zhan , Schrodi Steven J. TITLE=The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem JOURNAL=Frontiers in Genetics VOLUME=7 YEAR=2016 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2016.00217 DOI=10.3389/fgene.2016.00217 ISSN=1664-8021 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.