Can Exome Sequencing Help Us Understand Complex Traits?

Exome sequencing, sequencing the parts of the genome that codes for proteins, has been the go to approach identifying gene variant that may be causing simple mendelian traits and for personal genomic studies. However, the use of exome sequencing data for understanding complex traits is yet to be unexplored. (Well, this is true in general as well).

In this week’s Nature Genetics, Kiezun et. al., a team of scientists from Harvard and Netherland, ask a number of interesting questions on the use of Exome sequencing and the genetic basis of complex traits .

Exome sequencing and the genetic basis of complex traits

Adam Kiezun, Kiran Garimella, Ron Do, Nathan O Stitziel, Benjamin M Neale, Paul J McLaren, Namrata Gupta, Pamela Sklar, Patrick F Sullivan, Jennifer L Moran, Christina M Hultman, Paul Lichtenstein, Patrik Magnusson, Thomas Lehner, Yin Yao Shugart, Alkes L Price, Paul I W de Bakker, Shaun M Purcell & Shamil R Sunyaev

Nature Genetics 44, 623–630 (2012) doi:10.1038/ng.2303, Published online 29 May 2012

Exome sequencing–based studies are emerging as a popular approach to test for association of rare coding variants with complex phenotypes. The promise of exome sequencing is grounded in theoretical population genetics and in the empirical successes of candidate gene sequencing studies. We discuss here several aspects of exome sequencing studies that we view as particularly important. We analyze exome sequencing data from 438 individuals and use this as a basis to review processing and quality control of raw sequence data, evaluate the statistical properties of exome sequencing studies, discuss rare variant burden tests to detect association to phenotypes and show the importance of accounting for population stratification in the analysis of rare variants. We conclude that enthusiasm for exome sequencing studies to identify the genetic basis of complex traits should be combined with caution stemming from the observation that on the order of over 10,000 samples may be required to reach sufficient statistical power.