Testing Pleiotropy vs. Separate QTL in Multiparental Populations

Abstract

The high mapping resolution of multiparental populations, combined with technology to measure tens of thousands of phenotypes, presents a need for quantitative methods to enhance understanding of the genetic architecture of complex traits. When multiple traits map to a common genomic region, knowledge of the number of distinct loci provides important insight into the underlying mechanism and can assist planning for subsequent experiments. We extend the method of Jiang and Zeng (1995), for testing pleiotropy with a pair of traits, to the case of more than two alleles. We also incorporate polygenic random effects to account for population structure. We use a parametric bootstrap to determine statistical significance. We apply our methods to a behavioral genetics data set from Diversity Outbred mice. Our methods have been incorporated into the R package qtl2pleio.

Keywords: MPP; Multiparent Advanced Generation Inter-Cross (MAGIC); Quantitative trait locus; linear mixed effects models; multiparental populations; multivariate analysis; pleiotropy; systems genetics.

Figure 1

Pleiotropy vs. separate QTL power curves for each of four sets of parameter settings. Factors that differ among the four curves are allele effects difference and allele partitioning. Red denotes high allele effects difference, while black is the low allele effects difference. Solid line denotes the even allele partitioning (ABCD:EFGH), while dashed line denotes the uneven allele partitioning (F:ABCDEGH).

Figure 2

Chromosome 8 univariate LOD scores for percent time in light and hot plate latency reveal broad, overlapping peaks between 53 cM and 64 cM. The peak for percent time in light spans the region from approximately 53 cM to 60 cM, with a maximum near 55 cM. The peak for hot plate latency begins near 56 cM and ends about 64 cM.

Figure 3

Chromosome 8 founder allele effects for percent time in light and hot plate latency demonstrate distinct allele patterns between 53cM and 64 cM.

Figure 4

Profile LOD curves for the pleiotropy vs. separate QTL hypothesis test for “percent time in light” and “hot plate latency”. Gray trace denotes pleiotropy LOD values. Likelihood ratio test statistic value corresponds to the height of the blue and gold traces at their maxima.