title: Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies.
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.
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Halperin
authors.forename: Waibhav D
authors.initials: WD
authors.lastname: Tembe
authors.forename: Stacey
authors.initials: S
authors.lastname: Melquist
authors.forename: Nils
authors.initials: N
authors.lastname: Homer
authors.forename: Marcel
authors.initials: M
authors.lastname: Brun
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szelinger
authors.forename: Keith D
authors.initials: KD
authors.lastname: Coon
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Zismann
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Webster
authors.forename: Thomas
authors.initials: T
authors.lastname: Beach
authors.forename: Sigrid B
authors.initials: SB
authors.lastname: Sando
authors.forename: Jan O
authors.initials: JO
authors.lastname: Aasly
authors.forename: Reinhard
authors.initials: R
authors.lastname: Heun
authors.forename: Frank
authors.initials: F
authors.lastname: Jessen
authors.forename: Heike
authors.initials: H
authors.lastname: Kolsch
authors.forename: Magdalini
authors.initials: M
authors.lastname: Tsolaki
authors.forename: Makrina
authors.initials: M
authors.lastname: Daniilidou
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Andreas
authors.initials: A
authors.lastname: Papassotiropoulos
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hutton
authors.forename: Dietrich A
authors.initials: DA
authors.lastname: Stephan
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D016022:Case-Control Studies; D003198:Computer Simulation; D005819:Genetic Markers; D015894:Genome, Human; D005838:Genotype; D006059:Gonadal Dysgenesis / Q000235:genetics; D006801:Humans; D008297:Male; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012107:Research Design; D012984:Software; D013494:Supranuclear Palsy, Progressive / Q000235:genetics; D013577:Syndrome; D013737:Testis / Q000002:abnormalities
chemical_list: D005819:Genetic Markers