Lessons from dwarf8 on the strengths and weaknesses of structured association mapping

Authors: LARSON, SARA - Cornell University; Lipka, Alexander; Buckler, Edward - Ed

Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/2/2012
Publication Date: 2/21/2013
Publication URL: http://DOI: 10.1371/journal.pgen.1003246.
Citation: Larson, S., Lipka, A.E., Buckler IV, E.S. 2013. Lessons from dwarf8 on the strengths and weaknesses of structured association mapping. PLoS Genetics. 9(2):e1003246.

Interpretive Summary: Eleven years ago, association mapping was a cutting-edge tool used to identify regions of a genome associated with phenotypic variation. One of the first association studies performed in plants was reported in Thornsberry, et al. in 2001. Since then, researchers continued to develop new and improved genotyping, phenotyping, and statistical methods to examine the relationship between genotype and phenotype. Reanalysis of the old data for the d8 locus and flowering time, as well as new and improved data sets, gives us a unique opportunity to examine the strengths and weaknesses of association studies. These new analyses reveal that the results reported in 2001 significantly overestimated the association between genotype and phenotype, in particular the estimated effect size. The key issues with the Thornsberry et al. (2001) study were lack of control for population structure and relatedness between individuals, as well as a potential confounding between the phenotype and the population structure examined. The new analysis demonstrates a marginal association between d8 and flowering time, and a minimal effect (if any).

Technical Abstract: The strengths of association mapping lie in its resolution and allelic richness, but spurious associations arising from historical relationships and selection patterns need to be accounted for in statistical analyses. Here we reanalyze one of the first generation structured association mapping studies of the Dwarf8 (d8) locus with flowering time in maize using the full range of new mapping populations, statistical approaches, and haplotype maps. Because this trait was highly correlated with population structure, we found that basic structured association methods overestimate phenotypic effects in the region, while mixed model approaches perform substantially better. Combined with analysis of the maize nested association mapping population (a multi-family crossing design), it is concluded that most, if not all, of the QTL effects at the general location of the d8 locus are from rare extended haplotypes that include other linked QTLs and that d8 is unlikely to be involved in controlling flowering time in maize. Previous independent studies have shown evidence for selection at the d8 locus. Based on the evidence of population bottleneck, selection patterns, and haplotype structure observed in the region, we suggest that multiple traits may be strongly correlated with population structure and that selection on these traits has influenced segregation patterns in the region. Overall, this study provides insight into how modern association and linkage mapping, combined with haplotype analysis, can produce results that are more robust.