Guidelines for Large-Scale Sequence-Based Complex Trait Association Studies: Lessons Learned from the NHLBI Exome Sequencing Project. Am J Hum Genet 2016 Oct 06;99(4):791-801
Date
09/27/2016Pubmed ID
27666372Pubmed Central ID
PMC5065683DOI
10.1016/j.ajhg.2016.08.012Scopus ID
2-s2.0-84991577085 (requires institutional sign-in at Scopus site) 73 CitationsAbstract
Massively parallel whole-genome sequencing (WGS) data have ushered in a new era in human genetics. These data are now being used to understand the role of rare variants in complex traits and to advance the goals of precision medicine. The technological and computing advances that have enabled us to generate WGS data on thousands of individuals have also outpaced our ability to perform analyses in scientifically and statistically rigorous and thoughtful ways. The past several years have witnessed the application of whole-exome sequencing (WES) to complex traits and diseases. From our analysis of NHLBI Exome Sequencing Project (ESP) data, not only have a number of important disease and complex trait association findings emerged, but our collective experience offers some valuable lessons for WGS initiatives. These include caveats associated with generating automated pipelines for quality control and analysis of rare variants; the importance of studying minority populations; sample size requirements and efficient study designs for identifying rare-variant associations; and the significance of incidental findings in population-based genetic research. With the ESP as an example, we offer guidance and a framework on how to conduct a large-scale association study in the era of WGS.
Author List
Auer PL, Reiner AP, Wang G, Kang HM, Abecasis GR, Altshuler D, Bamshad MJ, Nickerson DA, Tracy RP, Rich SS, NHLBI GO Exome Sequencing Project, Leal SMAuthor
Paul L. Auer PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ExomeFemale
Genetic Association Studies
Genetic Variation
Genome, Human
Guidelines as Topic
Humans
Male
National Heart, Lung, and Blood Institute (U.S.)
Quality Control
Reproducibility of Results
Sequence Analysis, DNA
United States
