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

TitleA unified test of linkage analysis and rare-variant association for analysis of pedigree sequence data.
Publication TypeJournal Article
Year of Publication2014
AuthorsHu H, Roach JC, Coon H, Guthery SL, Voelkerding KV, Margraf RL, Durtschi JD, Tavtigian SV, Wu W, Scheet P, Wang S, Xing J, Glusman G, Hubley R, Li H, Garg V, Moore B, Hood L, Galas DJ, Srivastava D, Reese MG, Jorde LB, Yandell M, Huff CD
JournalNat Biotechnol
Volume32
Issue7
Pagination663-9
Date Published2014 Jul
ISSN1546-1696
KeywordsBase Sequence, Chromosome Mapping, DNA, DNA Mutational Analysis, Genetic Linkage, Genetic Markers, Genetic Variation, High-Throughput Nucleotide Sequencing, Molecular Sequence Data, Pedigree
Abstract<p>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.</p>
DOI10.1038/nbt.2895
Alternate JournalNat. Biotechnol.
PubMed ID24837662
PubMed Central IDPMC4157619
Grant ListU01 HL098179 / HL / NHLBI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
R01 MH099134 / MH / NIMH NIH HHS / United States
R01 CA164138 / CA / NCI NIH HHS / United States
U01 HL100406 / HL / NHLBI NIH HHS / United States
R01 DK091374 / DK / NIDDK NIH HHS / United States
R00 HG005846 / HG / NHGRI NIH HHS / United States
R01 GM104390 / GM / NIGMS NIH HHS / United States
R01 GM59290 / GM / NIGMS NIH HHS / United States
R44 HG006579 / HG / NHGRI NIH HHS / United States
R01 GM059290 / GM / NIGMS NIH HHS / United States
R01 MH094400 / MH / NIMH NIH HHS / United States
R44HG006579 / HG / NHGRI NIH HHS / United States
R01 HL109758 / HL / NHLBI NIH HHS / United States
R00HG005846 / HG / NHGRI NIH HHS / United States