|HAMBLIN, MARTHA - Cornell University|
Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/6/2010
Publication Date: 11/22/2010
Citation: Lorenz, A.J., Hamblin, M.T., Jannink, J. 2010. Performance of single nucleotide polymorphisms versus haplotypes for genome-wide association analysis in barley. PLoS Genetics. 5(II):e14079.
Interpretive Summary: Genome-wide mapping of genes underlying complex traits is usually performed by testing single markers for associations with phenotypes. There is some evidence that grouping sets of adjacent DNA markers into haplotype blocks may increase power, by generating new alleles with different relationships to the unobserved causal loci (QTL). However, previous findings are conflicting, suggesting that any advantages of haplotypes may depend on characteristics of the study. We investigated the utility of haplotypes for gene discovery in barley, thereby offering the first look at this issue in a crop species. Through simulations using marker data collected as part of the Barley Coordinated Agricultural Project, we showed that the relative performance of single markers and haplotypes varies according to mutational and recombinational history of causal variants and the marker variants surrounding them. Analysis of real heading date data revealed associations between haplotypes and heading date that were not found using single markers. However, due to a number of technical issues, haplotype methods suffer a loss of power that sometimes offsets their advantages. We conclude that both single markers and haplotype markers should be used for genome-wide association analysis to take advantage of the full information content of the genotype data.
Technical Abstract: Genome-wide association studies (GWAS) may benefit from using haplotype information for making marker-phenotype associations. Several rationales for grouping single nucleotide polymorphisms (SNPs) into haplotype blocks exist, but any advantage may depend on the genetic architecture of traits, patterns of linkage disequilibrium in the population, and marker density. The objective of this study was to explore the utility of haplotypes for GWAS in barley (Hordeum vulgare) to offer a first detailed look at this issue in crops. We used genotype and phenotype data from the Barley Coordinated Agricultural Project and constructed haplotypes using three different methods. When QTL were simulated using single SNPs dropped from the marker dataset, a single SNP analysis performed at least as well in terms of power and false discovery rate as any of the haplotype analyses. However, the haplotype analyses performed better 1) when QTL were simulated as polymorphisms that arose subsequent to marker variants, and 2) in analysis of empirical heading date data. These results demonstrate that the information content of haplotypes is dependent on the particular mutational and recombinational history of the QTL and nearby markers. Analysis of the empirical data also confirmed our intuition that the distribution of QTL alleles in nature is often unlike the distribution of marker variants, and hence utilizing haplotype information could capture associations that would elude single SNPs. We recommend routine use of both single SNP and haplotype markers for GWAS to take advantage of the full information content of the genotype data.