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Hum Hered. 2018;83(1):30-39. doi: 10.1159/000486854. Epub 2018 May 16.

Using Gene Genealogies to Localize Rare Variants Associated with Complex Traits in Diploid Populations.



Many methods can detect trait association with causal variants in candidate genomic regions; however, a comparison of their ability to localize causal variants is lacking. We extend a previous study of the detection abilities of these methods to a comparison of their localization abilities.


Through coalescent simulation, we compare several popular association methods. Cases and controls are sampled from a diploid population to mimic human studies. As benchmarks for comparison, we include two methods that cluster phenotypes on the true genealogical trees: a naive Mantel test considered previously in haploid populations and an extension that takes into account whether case haplotypes carry a causal variant. We first work through a simulated dataset to illustrate the methods. We then perform a simulation study to score the localization and detection properties.


In our simulations, the association signal was localized least precisely by the naive Mantel test and most precisely by its extension. Most other approaches had intermediate performance similar to the single-variant Fisher exact test.


Our results confirm earlier findings in haploid populations about potential gains in performance from genealogy-based approaches. They also highlight differences between haploid and diploid populations when localizing and detecting causal variants.


Association methods; Complex traits; Detection; Diploid population; Gene genealogy; Localization; Rare variants

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