Lessons from Dwarf8 on the Strengths and Weaknesses of Structured Association Mapping

Sara J Larsson,Alexander E Lipka,Edward S Buckler,Jonathan K Pritchard

doi:10.1371/journal.pgen.1003246

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.

Highlights

Association mapping, which was developed as a necessity for large-scale human studies, is commonly used in conjunction with family mapping in plant and animal genetic studies
It was concluded that association mapping offers higher resolution than linkage mapping due to quicker linkage disequilibrium (LD) decay, that structured association mapping is crucial for controlling false positives arising from population structure, and that Dwarf8 (d8) (RefGen_v2 position: Chr. 1; 266,094,769–266,097,836 bp) is associated with flowering time
The 6 bp indel is more significantly associated with flowering time in the smaller population (92 lines) than it is in the 282 association panel analyzed with mixed linear model (MLM) (K model) without controlling for population structure, but controlling for familial relatedness

Summary

Introduction

Association mapping, which was developed as a necessity for large-scale human studies, is commonly used in conjunction with family (linkage) mapping in plant and animal genetic studies. It was concluded that association mapping offers higher resolution than linkage mapping due to quicker linkage disequilibrium (LD) decay, that structured association mapping is crucial for controlling false positives arising from population structure, and that Dwarf (d8) (RefGen_v2 position: Chr. 1; 266,094,769–266,097,836 bp) is associated with flowering time This initial study has been cited extensively, and has been the basis of several reanalyses of d8. The application of association mapping to animal and plant studies has been very successful, culminating in many important findings [2,3,4,5,6,7,8,9,10] In this light, the Thornsberry et al (2001) study has attracted a lot of interest to the area and led to more studies and the development of techniques to control for population structure and familial relatedness. Linkage mapping is a valuable complementary approach in these situations, and in maize, large-scale connected mapping populations issued from diverse founders have been developed [11,12] in order to conduct joint linkage-association analyses [10,13,14]

Objectives

Methods

Results

Discussion

Conclusion