Identification of the genetic basis for complex disorders by use of pooling-based genomewide single-nucleotide-polymorphism association studies.
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.
Pearson
John V
JV
Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
Huentelman
Matthew J
MJ
Halperin
Rebecca F
RF
Tembe
Waibhav D
WD
Melquist
Stacey
S
Homer
Nils
N
Brun
Marcel
M
Szelinger
Szabolcs
S
Coon
Keith D
KD
Zismann
Victoria L
VL
Webster
Jennifer A
JA
Beach
Thomas
T
Sando
Sigrid B
SB
Aasly
Jan O
JO
Heun
Reinhard
R
Jessen
Frank
F
Kolsch
Heike
H
Tsolaki
Magdalini
M
Daniilidou
Makrina
M
Reiman
Eric M
EM
Papassotiropoulos
Andreas
A
Hutton
Michael L
ML
Stephan
Dietrich A
DA
Craig
David W
DW
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
D005819:Genetic Markers