Haplotype associations with quantitative traits in the presence of complex multilocus and heterogeneous effects.

Journal Article (Journal Article)

In genetic mapping of complex traits, scored haplotypes are likely to represent only a subset of all causal polymorphisms. At the extreme of this scenario, observed polymorphisms are not themselves functional, and only linked to causal ones via linkage disequilibrium (LD). We will demonstrate that due to such incomplete knowledge regarding the underlying genetic mechanism, the variance of a trait may become different between the scored haplotypes. Thus, unequal variances between haplotypes may be indicative of additional functional polymorphisms affecting the trait. Methods accounting for such haplotype-specific variance may also provide an increased power to detect complex associations. We suggest ways to estimate and test these haplotypic variance contrasts, and incorporate them into the haplotypic tests for association. We further extend this approach to data with unknown gametic phase via likelihood-based simultaneous estimation of haplotypic effects and their frequencies. We find our approach to provide additional power, especially under the following types of models: (a) where scored and unobserved variants are epistatically interacting with each other; and (b) under heterogeneity models, where multiple unobserved mutations are linked to non-functional observed polymorphisms via LD. An illustrative example of usefulness of the method is discussed, utilizing analysis of multilocus effects within the catechol-O-methyltransferase gene.

Full Text

Duke Authors

Cited Authors

  • Shibata, K; Diatchenko, L; Zaykin, DV

Published Date

  • January 2009

Published In

Volume / Issue

  • 33 / 1

Start / End Page

  • 63 - 78

PubMed ID

  • 18636529

Pubmed Central ID

  • PMC2700858

International Standard Serial Number (ISSN)

  • 0741-0395

Digital Object Identifier (DOI)

  • 10.1002/gepi.20358

Language

  • eng

Conference Location

  • United States