Quantitative trait analysis in sequencing studies under trait-dependent sampling.

TitleQuantitative trait analysis in sequencing studies under trait-dependent sampling.
Publication TypeJournal Article
Year of Publication2013
AuthorsLin, Dan-Yu, Donglin Zeng, and Zheng-Zheng Tang
JournalProc Natl Acad Sci U S A
Volume110
Issue30
Pagination12247-52
Date Published2013 Jul 23
ISSN1091-6490
KeywordsExome, Humans, Quantitative Trait Loci, Sequence Analysis, DNA
Abstract

It is not economically feasible to sequence all study subjects in a large cohort. A cost-effective strategy is to sequence only the subjects with the extreme values of a quantitative trait. In the National Heart, Lung, and Blood Institute Exome Sequencing Project, subjects with the highest or lowest values of body mass index, LDL, or blood pressure were selected for whole-exome sequencing. Failure to account for such trait-dependent sampling can cause severe inflation of type I error and substantial loss of power in quantitative trait analysis, especially when combining results from multiple studies with different selection criteria. We present valid and efficient statistical methods for association analysis of sequencing data under trait-dependent sampling. We pay special attention to gene-based analysis of rare variants. Our methods can be used to perform quantitative trait analysis not only for the trait that is used to select subjects for sequencing but for any other traits that are measured. For a particular trait of interest, our approach properly combines the association results from all studies with measurements of that trait. This meta-analysis is substantially more powerful than the analysis of any single study. By contrast, meta-analysis of standard linear regression results (ignoring trait-dependent sampling) can be less powerful than the analysis of a single study. The advantages of the proposed methods are demonstrated through simulation studies and the National Heart, Lung, and Blood Institute Exome Sequencing Project data. The methods are applicable to other types of genetic association studies and nongenetic studies.

DOI10.1073/pnas.1221713110
Alternate JournalProc Natl Acad Sci U S A
Original PublicationQuantitative trait analysis in sequencing studies under trait-dependent sampling.
PubMed ID23847208
PubMed Central IDPMC3725118
Grant ListR01 CA082659 / CA / NCI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
R37 GM047845 / GM / NIGMS NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
P30 CA016086 / CA / NCI NIH HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
P01 CA142538 / CA / NCI NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
Project: