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Exome sequencing and the genetic basis of complex traits

Nature Genetics volume 44, pages 623–630 (2012)Cite this article

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Exome sequencing–based studies are emerging as a popular approach to test for association of rare coding variants with complex phenotypes. The promise of exome sequencing is grounded in theoretical population genetics and in the empirical successes of candidate gene sequencing studies. We discuss here several aspects of exome sequencing studies that we view as particularly important. We analyze exome sequencing data from 438 individuals and use this as a basis to review processing and quality control of raw sequence data, evaluate the statistical properties of exome sequencing studies, discuss rare variant burden tests to detect association to phenotypes and show the importance of accounting for population stratification in the analysis of rare variants. We conclude that enthusiasm for exome sequencing studies to identify the genetic basis of complex traits should be combined with caution stemming from the observation that on the order of over 10,000 samples may be required to reach sufficient statistical power.

Next-generation sequencing1,2,3,4,5 coupled with efficient DNA capture6,7,8 enables the use of exome sequencing as a new approach to study the genetic basis of human phenotypes. A number of genes underlying Mendelian diseases have been mapped using this approach6,9,10,11,12,13,14,15. Exome sequencing has also been applied to tumors16,17,18,19,20, where sample purity, read mapping and chromosomal rearrangements are critical and form a very distinctive set of issues. Here, we restrict our focus to complex traits. In complex trait genetics, exome sequencing studies can be used to identify rare coding variants that are not detected by microarray-based genome-wide association studies (GWAS). The promise of exome sequencing studies of complex traits has its basis in the success of candidate gene studies21,22,23,24,25,26 and has firm roots in population genetic theory27,28,29,30,31,32,33,34,35.

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Figure 1: Discovery of novel variants for increasing numbers of samples.
Figure 2: Association analysis.
Figure 3: Extrapolation of gene burden results.

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Acknowledgements

The authors are grateful to S. Pollack for assistance with EIGENSOFT. This work was made possible, in part, by the US National Institutes of Health (NIH; grant 5R01 MH084676) and, in part, by the International HIV Controllers Study, supported by the Collaboration for AIDS Vaccine Discovery of the Bill and Melinda Gates Foundation (to P.I.W.d.B.), and the AIDS Clinical Trials Group, supported by the NIH (grants 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, RR024975 and AI077505). Sequencing of the SCZ control individuals was funded by the NIH (grant RC2MH089905), the Herman Foundation and the Stanley Medical Research Institute. N.O.S. was supported, in part, by an NIH Training Grant (T32-HL07604-25; Division of Cardiovascular Medicine, Brigham and Women's Hospital). B.M.N. was supported by a National Institute of Mental Health (NIMH) grant (1R01MH089208-01). R.D. is supported by a Canadian Institutes of Health Research Banting Postdoctoral Fellowship. The views expressed in this paper do not necessarily represent the views of the NIMH, NIH, Department of Health and Human Services (HHS) or the US government.

Author information

Author notes

  1. Adam Kiezun, Kiran Garimella, Ron Do and Nathan O Stitziel: These authors contributed equally to this work.

  2. Alkes L Price, Paul I W de Bakker, Shaun M Purcell and Shamil R Sunyaev: These authors jointly directed this work.

Authors and Affiliations

  1. Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Adam Kiezun, Paul J McLaren, Paul I W de Bakker & Shamil R Sunyaev

  2. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Adam Kiezun, Kiran Garimella, Ron Do, Nathan O Stitziel, Benjamin M Neale, Paul J McLaren, Namrata Gupta, Jennifer L Moran, Alkes L Price, Paul I W de Bakker & Shamil R Sunyaev

  3. The Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA

    Ron Do & Benjamin M Neale

  4. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Nathan O Stitziel

  5. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA

    Benjamin M Neale & Shaun M Purcell

  6. Department of Psychiatry, Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York, USA

    Pamela Sklar

  7. Institute for Genomics and Multi-scale Biology, Mount Sinai School of Medicine, New York, New York, USA

    Pamela Sklar

  8. Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    Patrick F Sullivan

  9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Christina M Hultman, Paul Lichtenstein & Patrik Magnusson

  10. Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health, Bethesda, Maryland, USA

    Thomas Lehner

  11. Division of Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland, USA

    Yin Yao Shugart

  12. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA

    Alkes L Price

  13. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

    Alkes L Price

  14. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    Paul I W de Bakker

  15. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

    Paul I W de Bakker

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  1. Adam Kiezun
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Correspondence to Shamil R Sunyaev.

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Kiezun, A., Garimella, K., Do, R. et al. Exome sequencing and the genetic basis of complex traits. Nat Genet 44, 623–630 (2012). https://doi.org/10.1038/ng.2303

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