Frontiers Media S.A.
Frontiers in Genetics
Original Item ID
DOI: 10.3389/fgene.2016.00217, PMID: 28018425
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Maadooliat, Mehdi; Bansal, Naveen K.; Upadhya, Jibal; Farazi, Manzur R.; Li, Xiang; He, Max M.; Hebbring, Scott J.; Ye, Zhan; and Schrodi, Steven J., "The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem" (2016). Mathematics, Statistics and Computer Science Faculty Research and Publications. 454.