Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies

Am J Hum Genet. 2007 Jan;80(1):126-39. doi: 10.1086/510686. Epub 2006 Dec 6.

Abstract

We report the development and validation of experimental methods, study designs, and analysis software for pooling-based genomewide association (GWA) studies that use high-throughput single-nucleotide-polymorphism (SNP) genotyping microarrays. We first describe a theoretical framework for establishing the effectiveness of pooling genomic DNA as a low-cost alternative to individually genotyping thousands of samples on high-density SNP microarrays. Next, we describe software called "GenePool," which directly analyzes SNP microarray probe intensity data and ranks SNPs by increased likelihood of being genetically associated with a trait or disorder. Finally, we apply these methods to experimental case-control data and demonstrate successful identification of published genetic susceptibility loci for a rare monogenic disease (sudden infant death with dysgenesis of the testes syndrome), a rare complex disease (progressive supranuclear palsy), and a common complex disease (Alzheimer disease) across multiple SNP genotyping platforms. On the basis of these theoretical calculations and their experimental validation, our results suggest that pooling-based GWA studies are a logical first step for determining whether major genetic associations exist in diseases with high heritability.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Case-Control Studies
  • Computer Simulation
  • Genetic Markers
  • Genome, Human*
  • Genotype
  • Gonadal Dysgenesis / genetics
  • Humans
  • Male
  • Models, Genetic*
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide / genetics*
  • Research Design
  • Software*
  • Supranuclear Palsy, Progressive / genetics
  • Syndrome
  • Testis / abnormalities

Substances

  • Genetic Markers