Joint discovery of haplotype blocks and complex trait associations from SNP sequences

TL;DR

This paper introduces a hierarchical statistical model that jointly infers haplotype blocks and their associations with complex traits from SNP sequences, effectively handling missing data and allele ambiguity without requiring pedigree information.

Contribution

It presents a novel data-driven method that simultaneously estimates haplotype block structure, transitions, and trait associations, improving robustness and accuracy over existing approaches.

Findings

Achieved 80% detection rate for Crohn's disease from SNP data.

Effectively modeled haplotype variability without pedigree data.

Handled allele ambiguity and missing data in a unified framework.

Abstract

Haplotypes, the global patterns of DNA sequence variation, have important implications for identifying complex traits. Recently, blocks of limited haplotype diversity have been discovered in human chromosomes, intensifying the research on modelling the block structure as well as the transitions or co-occurrence of the alleles in these blocks as a way to compress the variability and infer the associations more robustly. The haplotype block structure analysis is typically complicated by the fact that the phase information for each SNP is missing, i.e., the observed allele pairs are not given in a consistent order across the sequence. The techniques for circumventing this require additional information, such as family data, or a more complex sequencing procedure. In this paper we present a hierarchical statistical model and the associated learning and inference algorithms that simultaneously deal with the allele ambiguity per locus, missing data, block estimation, and the complex trait association. While the blo structure may differ from the structures inferred by other methods, which use the pedigree information or previously known alleles, the parameters we estimate, including the learned block structure and the estimated block transitions per locus, define a good model of variability in the set. The method is completely datadriven and can detect Chron's disease from the SNP data taken from the human chromosome 5q31 with the detection rate of 80% and a small error variance.