Originally published as Genetics Published Articles Ahead of Print on September 15, 2004.

Genetics, Vol. 169, 441-453, January 2005, Copyright © 2005
doi:10.1534/genetics.104.030080

Tree Scanning

A Method for Using Haplotype Trees in Phenotype/Genotype Association Studies

Alan R. Templeton^*,1, Taylor Maxwell^*, David Posada^,2, Jari H. Stengård, Eric Boerwinkle and Charles F. Sing^**

^* Department of Biology, Washington University, St. Louis, Missouri 63130-4899
Variagenics, Cambridge, Massachusetts 02139
Department of Epidemiology and Health Promotion, KTL-National Public Health Institute, Helsinki, Finland, FIN-00300
Human Genetics Center, University of Texas Health Science Center, Houston, Texas 77225-0334
^** Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109

¹ Corresponding author: Department of Biology, Campus Box 1137, Washington University, St. Louis, MO 63130-4899.
E-mail: temple_a{at}biology.wustl.edu

We use evolutionary trees of haplotypes to study phenotypic associations by exhaustively examining all possible biallelic partitions of the tree, a technique we call tree scanning. If the first scan detects significant associations, additional rounds of tree scanning are used to partition the tree into three or more allelic classes. Two worked examples are presented. The first is a reanalysis of associations between haplotypes at the Alcohol Dehydrogenase locus in Drosophila melanogaster that was previously analyzed using a nested clade analysis, a more complicated technique for using haplotype trees to detect phenotypic associations. Tree scanning and the nested clade analysis yield the same inferences when permutation testing is used with both approaches. The second example is an analysis of associations between variation in various lipid traits and genetic variation at the Apolipoprotein E (APOE) gene in three human populations. Tree scanning successfully identified phenotypic associations expected from previous analyses. Tree scanning for the most part detected more associations and provided a better biological interpretative framework than single SNP analyses. We also show how prior information can be incorporated into the tree scan by starting with the traditional three electrophoretic alleles at APOE. Tree scanning detected genetically determined phenotypic heterogeneity within all three electrophoretic allelic classes. Overall, tree scanning is a simple, powerful, and flexible method for using haplotype trees to detect phenotype/genotype associations at candidate loci.

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