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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.

Abstract

BACKGROUND AND AIMS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

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

PMID:
29763929
DOI:
10.1159/000486854
[Indexed for MEDLINE]

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