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Nat Biotechnol. 2014 Jul;32(7):663-9. doi: 10.1038/nbt.2895. Epub 2014 May 18.

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

Author information

1
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
2
Institute for Systems Biology, Seattle, Washington, USA.
3
Department of Psychiatry, University of Utah, Salt Lake City, Utah, USA.
4
Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.
5
1] Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA. [2] ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah, USA.
6
ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah, USA.
7
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
8
Department of Human Genetics and USTAR Center for Genetic Discovery, University of Utah, Salt Lake City, Utah, USA.
9
Department of Genetics, Rutgers, the State University of New Jersey, Piscataway, New Jersey, USA.
10
1] Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA. [2] Center for Cardiovascular and Pulmonary Research, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
11
1] Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg. [2] Pacific Northwest Diabetes Research Institute, Seattle, Washington, USA.
12
Gladstone Institute of Cardiovascular Disease and University of California, San Francisco, San Francisco, California, USA.
13
Omicia, Inc., Oakland, California, USA.

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.

PMID:
24837662
PMCID:
PMC4157619
DOI:
10.1038/nbt.2895
[Indexed for MEDLINE]
Free PMC Article

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