Identification of the Genetic Basis for Complex Disorders by Use of Pooling-Based Genomewide Single-Nucleotide–Polymorphism Association Studies

• Published in: American journal of human genetics Vol. 80; no. 1; pp. 126 - 139
• Main Authors: Pearson, John V., Huentelman, Matthew J., Halperin, Rebecca F., Tembe, Waibhav D., Melquist, Stacey, Homer, Nils, Brun, Marcel, Szelinger, Szabolcs, Coon, Keith D., Zismann, Victoria L., Webster, Jennifer A., Beach, Thomas, Sando, Sigrid B., Aasly, Jan O., Heun, Reinhard, Jessen, Frank, Kölsch, Heike, Tsolaki, Magdalini, Daniilidou, Makrina, Reiman, Eric M., Papassotiropoulos, Andreas, Hutton, Michael L., Stephan, Dietrich A., Craig, David W.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.01.2007; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Alzheimer Disease - genetics; Biological and medical sciences; Case-Control Studies; Computer Simulation; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Markers; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genomics; Genotype; Genotype & phenotype; Gonadal Dysgenesis - genetics; Humans; Male; Medical genetics; Medical sciences; Models, Genetic; Molecular and cellular biology; Oligonucleotide Array Sequence Analysis; Polymorphism; Polymorphism, Single Nucleotide - genetics; Research Design; Software; Supranuclear Palsy, Progressive - genetics; Syndrome; Testis - abnormalities; Human; Association; Use; Genetics; Genetic identification; Single nucleotide polymorphism; Genome; Complexes
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/510686

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.