A genomic background based method for association analysis in related individuals

Abstract

Background: Feasibility of genotyping of hundreds and thousands of single nucleotide polymorphisms (SNPs) in thousands of study subjects have triggered the need for fast, powerful, and reliable methods for genome-wide association analysis. Here we consider a situation when study participants are genetically related (e.g. due to systematic sampling of families or because a study was performed in a genetically isolated population). Of the available methods that account for relatedness, the Measured Genotype (MG) approach is considered the 'gold standard'. However, MG is not efficient with respect to time taken for the analysis of genome-wide data. In this context we proposed a fast two-step method called Genome-wide Association using Mixed Model and Regression (GRAMMAR) for the analysis of pedigree-based quantitative traits. This method certainly overcomes the drawback of time limitation of the measured genotype (MG) approach, but pays in power. One of the major drawbacks of both MG and GRAMMAR, is that they crucially depend on the availability of complete and correct pedigree data, which is rarely available.

Methodology: In this study we first explore type 1 error and relative power of MG, GRAMMAR, and Genomic Control (GC) approaches for genetic association analysis. Secondly, we propose an extension to GRAMMAR i.e. GRAMMAR-GC. Finally, we propose application of GRAMMAR-GC using the kinship matrix estimated through genomic marker data, instead of (possibly missing and/or incorrect) genealogy.

Conclusion: Through simulations we show that MG approach maintains high power across a range of heritabilities and possible pedigree structures, and always outperforms other contemporary methods. We also show that the power of our proposed GRAMMAR-GC approaches to that of the 'gold standard' MG for all models and pedigrees studied. We show that this method is both feasible and powerful and has correct type 1 error in the context of genome-wide association analysis in related individuals.

Figure 1. Power of MG (red line), GRAMMAR (green line), PedGR-GC (blue dashed line), and GC (pink dashed line) to detect association under different heritability models and pedigree structures.

The three rows show the power under different heritability models (from 30% to 80%) and the three columns show power achieved in different pedigrees namely nuclear pedigrees (NP), Erasmus Rucphen Family (ERF), and idealized pig population (IPP). The y-axis of each panel shows power while the x-axis shows the proportion of variance explained by the QTL under study. The red (for MG), green (for GRAMMAR), blue (for PedGR-GC), and pink (for GC) circles show the empirical power estimates. The power estimates are based on α = 0.01. The empirical power estimates are based on 1000 simulations for NP, and IPP, and 100 simulations for ERF.

Figure 2. Type 1 error (A) and power (B) to achieve 5% genome-wide significance at the truly associated SNP in a study of 695 ERF people genotyped for 5524 autosomal SNPs.