Low-coverage sequencing: Implications for design of complex trait association studies
- 1Department of Genetics, Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA;
- 2Istituto di Neurogenetica e Neurofarmacologia, CNR, Monserrato, 09042 Cagliari, Italy;
- 3Dipartimento di Scienze Biomediche, Università di Sassari, Sassari 07100, Italy;
- 4Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan 48109-2029, USA
Abstract
New sequencing technologies allow genomic variation to be surveyed in much greater detail than previously possible. While detailed analysis of a single individual typically requires deep sequencing, when many individuals are sequenced it is possible to combine shallow sequence data across individuals to generate accurate calls in shared stretches of chromosome. Here, we show that, as progressively larger numbers of individuals are sequenced, increasingly accurate genotype calls can be generated for a given sequence depth. We evaluate the implications of low-coverage sequencing for complex trait association studies. We systematically compare study designs based on genotyping of tagSNPs, sequencing of many individuals at depths ranging between 2× and 30×, and imputation of variants discovered by sequencing a subset of individuals into the remainder of the sample. We show that sequencing many individuals at low depth is an attractive strategy for studies of complex trait genetics. For example, for disease-associated variants with frequency >0.2%, sequencing 3000 individuals at 4× depth provides similar power to deep sequencing of >2000 individuals at 30× depth but requires only ∼20% of the sequencing effort. We also show low-coverage sequencing can be used to build a reference panel that can drive imputation into additional samples to increase power further. We provide guidance for investigators wishing to combine results from sequenced, genotyped, and imputed samples.
Footnotes
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↵5 Corresponding author.
E-mail goncalo{at}umich.edu; fax (734) 615 8322.
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[Supplemental material is available for this article. Software implementing the methods is available at http://genome.sph.umich.edu/wiki/Thunder.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.117259.110.
- Received October 30, 2010.
- Accepted March 9, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
