Haplotype block partitioning as a tool for dimensionality reduction in SNP association studies View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2008-12

AUTHORS

Cristian Pattaro, Ingo Ruczinski, Danièle M Fallin, Giovanni Parmigiani

ABSTRACT

BACKGROUND: Identification of disease-related genes in association studies is challenged by the large number of SNPs typed. To address the dilution of power caused by high dimensionality, and to generate results that are biologically interpretable, it is critical to take into consideration spatial correlation of SNPs along the genome. With the goal of identifying true genetic associations, partitioning the genome according to spatial correlation can be a powerful and meaningful way to address this dimensionality problem. RESULTS: We developed and validated an MCMC Algorithm To Identify blocks of Linkage DisEquilibrium (MATILDE) for clustering contiguous SNPs, and a statistical testing framework to detect association using partitions as units of analysis. We compared its ability to detect true SNP associations to that of the most commonly used algorithm for block partitioning, as implemented in the Haploview and HapBlock software. Simulations were based on artificially assigning phenotypes to individuals with SNPs corresponding to region 14q11 of the HapMap database. When block partitioning is performed using MATILDE, the ability to correctly identify a disease SNP is higher, especially for small effects, than it is with the alternatives considered. Advantages can be both in terms of true positive findings and limiting the number of false discoveries. Finer partitions provided by LD-based methods or by marker-by-marker analysis are efficient only for detecting big effects, or in presence of large sample sizes. The probabilistic approach we propose offers several additional advantages, including: a) adapting the estimation of blocks to the population, technology, and sample size of the study; b) probabilistic assessment of uncertainty about block boundaries and about whether any two SNPs are in the same block; c) user selection of the probability threshold for assigning SNPs to the same block. CONCLUSION: We demonstrate that, in realistic scenarios, our adaptive, study-specific block partitioning approach is as or more efficient than currently available LD-based approaches in guiding the search for disease loci. More... »

PAGES

405

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1471-2164-9-405

DOI

http://dx.doi.org/10.1186/1471-2164-9-405

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1049132422

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18759977


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