A Tool for Selecting SNPS for Association Studies Based on Observed Linkage Disequilibrium Patterns

Abstract

The design of genetic association studies using single-nucleotide polymorphisms (SNPs) requires the selection of subsets of the variants providing high statistical power at a reasonable cost. SNPs must be selected to maximize the probability that a causative mutation is in linkage disequilibrium (LD) with at least one marker genotyped in the study. The HapMap project performed a genome-wide survey of genetic variation with about a million SNPs typed in four populations, providing a rich resource to inform the design of association studies. A number of strategies have been proposed for the selection of SNPs based on observed LD, including construction of metric LD maps and the selection of haplotype tagging SNPs. Power calculations are important at the study design stage to ensure successful results. Integrating these methods and annotations can be challenging: the algorithms required to implement these methods are complex to deploy, and all the necessary data and annotations are deposited in disparate databases. Here, we present the SNPbrowser™ Software, a freely available tool to assist in the LD-based selection of markers for association studies. This stand-alone application provides fast query capabilities and swift visualization of SNPs, gene annotations, power, haplotype blocks, and LD map coordinates. Wizards implement several common SNP selection workflows including the selection of optimal subsets of SNPs (e.g. tagging SNPs). Selected SNPs are screened for their conversion potential to either TaqMan® SNP Genotyping Assays or the SNPlex™ Genotyping System, two commercially available genotyping platforms, expediting the setup of genetic studies with an increased probability of success.

Clinical and genetic risk factors of self-reported penicillin allergy

“…The first 2 of these SNPs are located in another gene (KIF3A) but are in the same linkage disequilibrium block as IL4 (LDU 5 0.5; SNPbrowser 3.5.2). 32 Penicillin allergy was marginally associated with a LACTB SNP, rs2729835 (P 5 .058), but not with the SNPs related to IL4R or IL10. Because there was only 1 case with a variant allele, the data for SNP rs34536322 are less reliable.…”

Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects

“…The tag SNP selection is based on the HapMap database (release 20, January 24, 2006) with two methods: pair-wise r 2 (r 2 C 0.8) and haplotype R 2 (R 2 C 0.8) (De La Vega et al 2006). In addition to tag SNPs, we chose other SNPs in the promoter, including 3 0 UTR, and exons region that indicate potential functional importance.…”

Sequence variants in the PLEKHH2 region are associated with diabetic nephropathy in the GoKinD study population

“…1. We selected additional SNPs that tagged the entire PLEKHH2 region spanning approximately 190 kb using the tagging approach of Carlson et al (Carlson et al 2004), implemented in the SNPbrowser Software version 3.5 (Applied Biosystems, Foster City, CA, USA) and by measured linkage disequilibrium (LD) values for CEPH European individuals based on pairwise r 2 (¸0.8) from the HapMap database (http://www.hapmap.org) (The International HapMap Consortium 2005;De La Vega et al 2006). All AVymetrix array SNP genotype conWrmation and follow-up genotyping was done by 5Јnuclease assay (TaqMan assaysApplied Biosystems, Foster City, CA, USA) as 5 l reactions in 384-well plates on an Applied Biosystems 7900HT Real-Time PCR System, as per manufacturer's instructions.…”

“…SNP assays were selected based on pair-wise linkage disequilibrium of the PLEKHH2 gene as measured in CEPH European reference samples from the International Haplotype Map project and from LD maps from Applied Biosystem's SNPbrowser program available from their website, www.appliedbiosystems.com (The International HapMap Consortium 2005;De La Vega et al 2006).…”