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Extremely low-coverage sequencing and imputation increases power for genome-wide association studies


Genome-wide association studies (GWAS) have proven to be a powerful method to identify common genetic variants contributing to susceptibility to common diseases. Here, we show that extremely low-coverage sequencing (0.1–0.5×) captures almost as much of the common (>5%) and low-frequency (1–5%) variation across the genome as SNP arrays. As an empirical demonstration, we show that genome-wide SNP genotypes can be inferred at a mean r2 of 0.71 using off-target data (0.24× average coverage) in a whole-exome study of 909 samples. Using both simulated and real exome-sequencing data sets, we show that association statistics obtained using extremely low-coverage sequencing data attain similar P values at known associated variants as data from genotyping arrays, without an excess of false positives. Within the context of reductions in sample preparation and sequencing costs, funds invested in extremely low-coverage sequencing can yield several times the effective sample size of GWAS based on SNP array data and a commensurate increase in statistical power.

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Figure 1: Genotype imputation accuracy as function of coverage in 1000 Genomes Project simulations.
Figure 2: Observed versus expected association −log10 P values at 103,977 SNPs across the genome in simulated null data sets over 909 samples of the combined data set.
Figure 3: Genotype imputation accuracy in IHCS whole-exome data as a function of coverage (solid lines).
Figure 4: Coverage and corresponding number of samples for a fixed budget of $300,000.


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We would like to acknowledge the ARRA Autism Sequencing Consortium (AASC) principal investigators for use of the autism data sets, including E. Boerwinkle, J.D. Buxbaum, E.H. Cook Jr., M.J. Daly (communicating principal investigator), B. Devlin, R. Gibbs, K. Roeder, A. Sabo, G.D. Schellenberg and J.S. Sutcliffe. We thank T. Lehner, A. Felsenfeld and P. Bender for their support and contribution to the AASC project and to the generation of AUT sequencing data. This research was supported by US National Institutes of Health (NIH) grants (R01 HG006399 to B.P., N.P., D.R. and A.L.P. and R01 MH084676 to S.S.). The IHCS acknowledges generous support from the Mark and Lisa Schwartz Foundation and the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation. The IHCS was also supported in part by NIH grants (P-30-AI060354 to the Harvard University Center for AIDS Research, AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, Al32782, AI27661, AI25859, AI28568, AI30914, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853, AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI68634, AI069502, AI069419, AI068636 and RR024975 to the AIDS Clinical Trials Group and AI077505 to D.W.H.). Data generation for the NIMH controls was directly supported by NIH grants (R01MH089208, R01 MH089025, R01 MH089004 and R01 MH089482). SCZ data generation was supported by an NIMH grant (5RC2MH089905; P.S. and S.M.P.) and by the Sylvan Herman Foundation and the Stanley Medical Research Institute (a gift to the Stanley Center for Psychiatric Research).

Author information




B.P., N.R., N.P., A.L.P. and D.R. conceived and designed the study. B.P. conducted the analyses. L.L., S.S., N.R., P.J.M., N.Z. and H.L. provided bioinformatics and statistical support. P.I.W.d.B., N.G., K.G., B.M.N., M.J.D., P.S., P.F.S., S.B., J.L.M., C.M.H., P.L., P.M., S.M.P. and D.W.H. recruited and provided samples and data for these analyses. B.P., A.L.P. and D.R. wrote the paper. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Bogdan Pasaniuc or David Reich or Alkes L Price.

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The authors declare no competing financial interests.

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Supplementary Tables 1–6, Supplementary Figures 1–8 and Supplementary Note (PDF 1490 kb)

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Pasaniuc, B., Rohland, N., McLaren, P. et al. Extremely low-coverage sequencing and imputation increases power for genome-wide association studies. Nat Genet 44, 631–635 (2012).

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