Determinants of QTL Mapping Power in the Realized Collaborative Cross

Abstract

The Collaborative Cross (CC) is a mouse genetic reference population whose range of applications includes quantitative trait loci (QTL) mapping. The design of a CC QTL mapping study involves multiple decisions, including which and how many strains to use, and how many replicates per strain to phenotype, all viewed within the context of hypothesized QTL architecture. Until now, these decisions have been informed largely by early power analyses that were based on simulated, hypothetical CC genomes. Now that more than 50 CC strains are available and more than 70 CC genomes have been observed, it is possible to characterize power based on realized CC genomes. We report power analyses from extensive simulations and examine several key considerations: 1) the number of strains and biological replicates, 2) the QTL effect size, 3) the presence of population structure, and 4) the distribution of functionally distinct alleles among the founder strains at the QTL. We also provide general power estimates to aide in the design of future experiments. All analyses were conducted with our R package, SPARCC (Simulated Power Analysis in the Realized Collaborative Cross), developed for performing either large scale power analyses or those tailored to particular CC experiments.

Designing a QTL Mapping Study for Implementation in the Realized Collaborative Cross Genetic Reference Population

“…Table 1, which gives power of the realized CC reference population as a function of the three factors mentioned above for the simplest case, where all genetic variation in the target trait among the CC strains is due to segregation of a single diallelic QTL, with frequency of 0.5 in the eight founder strains of the CC resource (i.e., positive allele present in four of the parental strains and negative allele in the remaining four). Power for more complex scenarios (multiple alleles, unbalanced allele distribution, presence of multiple QTL and/or polygenic background genetic variation) is considered in greater detail in Keele, Crouse, Kelada, & Valdar (2019).…”

“…Again, the total number of animals in the experiment goes from 90 to 150. Power aside, there are other advantages in increasing replicates rather than strains (see Keele et al, 2019 for further details).…”

“…Protocol describes step-by-step for example of target effect 0.2, 30 strains. Table 1 of Keele et al (2019). Locate column 1 (1 obs) row 0.2 corresponding to 1 obs, columns headed n = 30.…”

“…Herein, we present general guidelines for design of QTL mapping experiments using the CC resource-along with full step-by-step protocols and methods that were implemented in our lab for the phenotypic and genotypic characterization of the different CC lines-for mapping the genes underlying host response to infectious and chronic diseases. C 2019 by John Wiley & Sons, Inc.Basic Protocol 1: CC lines for whole body mass index (BMI) Basic Protocol 2: A detailed assessment of the power to detect effect sizes based on the number of lines used, and the number of replicates per line Basic Protocol 3: Obtaining power for QTL with given target effect by interpolating in Table 1 of Keele et al (2019) Keywords: Collaborative Cross mouse model r complex traits r experimental design for QTL mapping r genetic reference population r quantitative trait loci r statistical power…”

“…Basic Protocol 1: CC lines for whole body mass index (BMI) Basic Protocol 2: A detailed assessment of the power to detect effect sizes based on the number of lines used, and the number of replicates per line Basic Protocol 3: Obtaining power for QTL with given target effect by interpolating in Table 1 of Keele et al (2019) Keywords: Collaborative Cross mouse model r complex traits r experimental design for QTL mapping r genetic reference population r quantitative trait loci r statistical power…”