Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 80, Issue 1, Pages 126-139Publisher
UNIV CHICAGO PRESS
DOI: 10.1086/510686
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Funding
- NHLBI NIH HHS [U01 HL086528, U01-HL086528-01] Funding Source: Medline
- NIA NIH HHS [P30 AG019610, P30 AG19610] Funding Source: Medline
- NIMH NIH HHS [R01 MH057899] Funding Source: Medline
- NINDS NIH HHS [U24 NS043571, 1U24NS043571] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [U01HL086528] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH057899] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [U24NS043571] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P30AG019610] Funding Source: NIH RePORTER
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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.
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