Abstract
Disease gene discovery in humans has a long history, predating even the identification of DNA as the genetic molecule and the determination of the number of human chromosomes. Study design, laboratory methods, and analytic approaches differ by trait type (Mendelian or complex) and hypothesis being tested (rare disease‐rare variant, Mendelian positional cloning; common disease‐common variant [genome‐wide association studies]; common disease‐rare variant [whole‐exome sequencing or whole‐genome sequencing and individual variant or set‐based association]). This chapter describes these approaches. It discusses the steps in a complex trait gene identification study, providing an overview of each component and a guide to the chapter(s) providing more detail on these points. In addition to the confounding factors involved in single‐gene disorders, such as genetic heterogeneity and phenocopies, gene–gene and gene–environment interactions must be considered when a complex trait is dissected.