A Method to Assess Linkage Disequilibrium between CNVs and SNPs Inside Copy Number Variable Regions

Hemant K Tiwari,Nathan E Wineinger,Nicholas M Pajewski

doi:10.3389/fgene.2011.00017

Hemant K Tiwari, Nathan E Wineinger + Show 1 more

Open Access

https://doi.org/10.3389/fgene.2011.00017

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Abstract

Since the discovery of the ubiquitous contribution of copy number variation to genetic variability, researchers have commonly used metrics such as r2 to quantify linkage disequilibrium (LD) between copy number variants (CNVs) and single nucleotide polymorphisms (SNPs). However, these reports have been restricted to SNPs outside copy number variable regions (CNVR) as current methods have not been adapted to account for SNPs displaying variable copy number. We show that traditional LD metrics inappropriately quantify SNP/CNV covariance when SNPs lie within CNVR. We derive a new method for measuring LD that solves this issue, and defaults to traditional metrics otherwise. Finally, we present a procedure to estimate CNV–SNP allele frequencies from unphased CNV–SNP genotypes. Our method allows researchers to include all SNPs in SNP/CNV LD measurements, regardless of copy number.

Highlights

Examination of linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) has played a key role in our understanding of worldwide patterns of genetic variation, including determining the extent of haplotype diversity (Conrad et al, 2006), detecting regions of positive selection (Sabeti et al, 2007), and guiding the design of most current genotyping arrays through the selection of appropriate haplotype tagging SNPs
Genome-wide copy number variants (CNVs) surveys such as that performed by the Wellcome Trust Case Control Consortium (WTCCC) have concluded that common CNVs were adequately tagged by SNPs; and unlikely to substantially contribute to the genetic basis of common human diseases (Conrad et al, 2010; Wellcome Trust Case Control Consortium et al, 2010)
We find that traditional LD metrics are sufficient for exterior SNPs; these same metrics inappropriately quantify covariance for interior SNPs

Summary

Introduction

Examination of linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) has played a key role in our understanding of worldwide patterns of genetic variation, including determining the extent of haplotype diversity (Conrad et al, 2006), detecting regions of positive selection (Sabeti et al, 2007), and guiding the design of most current genotyping arrays through the selection of appropriate haplotype tagging SNPs. With the current understanding that copy number variation (CNV) significantly contributes to genetic variation (Redon et al, 2006), research has turned to the role for CNV in disease risk (Gonzalez et al, 2005; Aitman et al, 2006; McCarroll and Altshuler, 2007; Sebat et al, 2007), as a partial explanation for the so-called missing heritability (Manolio et al, 2009; Eichler et al, 2010). We explicitly derive the covariance between SNPs and CNVs under a range of scenarios where SNPs either fall inside (interior) or outside (exterior) of a CNVR. We find that traditional LD metrics are sufficient for exterior SNPs; these same metrics inappropriately quantify covariance for interior SNPs

Methods

Results

Conclusion