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A unified test of linkage analysis and rare-variant association for analysis of pedigree sequence data

Nature Biotechnology volume 32, pages 663–669 (2014)Cite this article

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Abstract

High-throughput sequencing of related individuals has become an important tool for studying human disease. However, owing to technical complexity and lack of available tools, most pedigree-based sequencing studies rely on an ad hoc combination of suboptimal analyses. Here we present pedigree-VAAST (pVAAST), a disease-gene identification tool designed for high-throughput sequence data in pedigrees. pVAAST uses a sequence-based model to perform variant and gene-based linkage analysis. Linkage information is then combined with functional prediction and rare variant case-control association information in a unified statistical framework. pVAAST outperformed linkage and rare-variant association tests in simulations and identified disease-causing genes from whole-genome sequence data in three human pedigrees with dominant, recessive and de novo inheritance patterns. The approach is robust to incomplete penetrance and locus heterogeneity and is applicable to a wide variety of genetic traits. pVAAST maintains high power across studies of monogenic, high-penetrance phenotypes in a single pedigree to highly polygenic, common phenotypes involving hundreds of pedigrees.

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Figure 1: A schematic illustration of pVAAST.
Figure 2: Rare Mendelian and common complex disease simulations.
Figure 3: pVAAST results on the enteropathy pedigree.
Figure 4: pVAAST identifies the dominant causal gene GATA4 in cardiac septal defect pedigree.
Figure 5: pVAAST identifies the recessive causal genes for Miller's syndrome (DHODH) and primary ciliary dyskinesia (DNAH5) with a two-generation pedigree.
Figure 6: The genome-wide ranking and lod score of GATA4 in challenging situations of pedigree studies.

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Acknowledgements

An allocation of computer time on the University of Texas MD Anderson Research Computing High Performance Computing (HPC) facility is gratefully acknowledged. This work was supported by US National Institutes of Health grants R01 GM104390 (M.Y., L.B.J., C.D.H. and H.H.), R01 DK091374 (S.L.G., C.D.H. and L.B.J.), R01 CA164138 (S.V.T. and C.D.H.), R44HG006579 (M.G.R. and M.Y.) and R01 GM59290 (L.B.J.) as well as the University of Luxembourg—Institute for Systems Biology Program. D.S. was supported by grants from the NHLBI (UO1 HL100406 and U01 HL098179) related to this project. H.C. was supported by NIH grants R01 MH094400 and R01 MH099134. H.H. was supported by the MD Anderson Cancer Center Odyssey Program. J.X. was supported by NIH grant R00HG005846.

Author information

Authors and Affiliations

  1. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Hao Hu,  Shankaracharya, Paul Scheet & Chad D Huff

  2. Institute for Systems Biology, Seattle, Washington, USA

    Jared C Roach, Gustavo Glusman, Robert Hubley, Hong Li & Leroy Hood

  3. Department of Psychiatry, University of Utah, Salt Lake City, Utah, USA

    Hilary Coon

  4. Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA

    Stephen L Guthery

  5. Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA

    Karl V Voelkerding

  6. ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah, USA

    Karl V Voelkerding, Rebecca L Margraf & Jacob D Durtschi

  7. Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

    Sean V Tavtigian

  8. Department of Human Genetics and USTAR Center for Genetic Discovery, University of Utah, Salt Lake City, Utah, USA

    Wilfred Wu, Barry Moore, Lynn B Jorde & Mark Yandell

  9. Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA

    Shuoguo Wang & Jinchuan Xing

  10. Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA

    Vidu Garg

  11. Center for Cardiovascular and Pulmonary Research, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA

    Vidu Garg

  12. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg

    David J Galas

  13. Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA

    David J Galas

  14. Gladstone Institute of Cardiovascular Disease and University of California, San Francisco, San Francisco, California, USA

    Deepak Srivastava

  15. Omicia, Inc., Oakland, California, USA

    Martin G Reese

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Contributions

C.D.H. conceived of the project. C.D.H. oversaw and coordinated the research. C.D.H. and H.H. designed the algorithms. H.H. and B.M. wrote the software. C.D.H., H.H. and P.S. contributed to the statistical development. C.D.H., H.H., J.C.R., M.Y., S.V.T., D.S., K.V.V., L.H., L.B.J., M.G.R. and S.L.G. designed the experiments. H.H., H.C., W.W., R.L.M., J.D.D., S.W., H.L., J.X., Shankaracharya, R.H., B.M., J.C. and G.G. performed the experiments. H.H., C.D.H., M.Y., S.V.T., S.L.G. and L.B.J. analyzed and interpreted the data. H.H. generated the figures. H.H., C.D.H., L.B.J., M.Y., S.L.G., P.S., and S.V.T. wrote the paper. S.L.G., D.S., V.G., D.J.G., L.H., H.L., R.H., K.V.V., R.L.M., J.D.D., G.G. participated in pedigree identification, recruitment and validation.

Corresponding authors

Correspondence to Mark Yandell or Chad D Huff.

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Competing interests

M.G.R. is a founder and officer of Omicia, Inc.

Supplementary information

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Supplementary Notes 1–4, Supplementary Figures 1–10 and Supplementary Table 1 (PDF 10164 kb)

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pVAAST source code (ZIP 97 kb)

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Hu, H., Roach, J., Coon, H. et al. A unified test of linkage analysis and rare-variant association for analysis of pedigree sequence data. Nat Biotechnol 32, 663–669 (2014). https://doi.org/10.1038/nbt.2895

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