Ethical challenges in genotype-driven research recruitment: Box 1.

Many genetic and genomic studies are conducted using a phenotype-driven approach: Cases and controls are identified based on the presence or absence of a particular condition and analyses are undertaken to identify gene variants associated with that condition. The inverse—a genotype-driven approach—is receiving increasing attention as another powerful research tool. In this setting, investigators use existing study populations for which genotype or complete sequence data are available to identify cases and controls based on the presence or absence of a particular gene variant. Participants are then recontacted for recruitment into follow-up studies involving in-depth phenotyping to understand the relationship between observable traits and the gene variant of interest. One driver for this framework is the genetics community's increasing focus on rarer gene variants that exert a large effect on risk for common diseases. Enabling such a “bottom-up” approach to identifying and recruiting participants for follow-up studies could significantly advance the pace of genomic research on the functional significance of human genetic variation (McGuire and McGuire 2008). Genotype-driven recruitment, however, presents considerable ethical challenges. It is inextricably linked to the complex and much-debated issue of disclosing individual research results to participants: When individuals are recontacted, what if anything should they be told about the genotype that led to their being recontacted? There is a fundamental tension between avoiding the disclosure of potentially unwanted and uncertain information, and avoiding deception when explaining to prospective participants the purpose of the research and why they have been identified as eligible to participate. To resolve this tension, McGuire and McGuire (2008) suggested that, when recontacted, participants should be told that the follow-up study is genotype-driven and what that means, what the genotype and biological pathway of interest is, that half of the participants are controls without the targeted gene variants, and that an invitation to participate is not contingent on the presence of any known phenotype. Here, we report our experiences and participants' reactions when we implemented a similar approach.