Results of our literature review reveal that the main ethical issues associated with GDR are related to the re-contact of research participants and the disclosure to them of their genetic information during the recruitment phase [1–4, 6, 7, 9, 14, 17]. Table 1 provides an overview of our analysis results including the ethical concerns identified, recommendations forwarded to address these, whether the current recommendations adequately address the ethical concerns raised under a broader utilization of GDR and the reasoning behind these determinations.

Table 1 Overview of ethical concerns in GDR and assessment whether current recommendations suffice for a broader use of GDR Full size table

Ethical concerns in GDR

GDR based on the secondary use of previously collected genotype data requires that the research participants be re-contacted for the purpose of recruitment into the study. Because genotypic information is the basis for the recruitment, GDR may implicitly result in researchers providing participants with some information about their genotype as well as other information related to their medical or health status [1]. However, providing such information during recruitment might violate the individual’s privacy and right not to know about their own genetic information [1–4]. It may also create anxiety and distress for the individual who might think that something is wrong about her health since she has been re-contacted [1, 2]. By contrast, not providing such information at recruitment may be perceived by the individual as a form of deception because she would not know why she has been enrolled in the study [1].

Issues surrounding the divulgence of genetic results are at the crux of the ethical considerations in GDR. Today, the return of research results from genetic studies to research participants is a highly debated topic among scientists, ethicists and policy makers [29–31]. Current guidelines typically sanction the return of genetic results if they are actionable or clinically useful for the research participants [18, 32–34]. However, to harness the full scientific potential of GDR designs, it is quite likely that the genetic selection criteria for recruiting participants will not meet the requirements of being actionable or clinically useful. Not providing genetic results may mask the reasons why participants have been enrolled in the study [1, 7], but disclosing genetic results requires certain types of guidance for the participant. This process is compounded when results are experimental, partly unreliable or uncertified and may have serious consequences for the research participants who may make further health-related decisions based on shallow scientific ground [1, 3, 5]. However, even when the results are verified in clinical labs, the finding of a rare variant could also have dramatic consequences for the individuals concerned because they may affect their health and make them the carriers of bad news for their family members [1, 4, 9].

Re-contact for recruitment into a GDR study may also put the individuals re-contacted and their relatives in a difficult situation, especially if the study design (e.g. case only study) allows outsiders to determine which genetic variant is under study [1, 2]. Finally, there is a risk that individuals with rare genetic variants may begin to feel overwhelmed if they receive numerous invitations to join GDR studies [1, 2]. This could, in the long term, discourage individuals from participating in research.

Published recommendations

A number of recommendations have been made to address the issues surrounding the return of genetic results described above and primarily focus on optimising the informed consent process and developing mechanisms for feedback of results to research participants. This is illustrated by recommendations to 1) include information about potential re-contact and future disclosure in the original consent [2, 6, 7, 12]; 2) offer participants the opportunity to choose whether or not they want to be re-contacted for future participation in GDR studies [2–4, 6, 7]; and 3) ensure that re-contact occurs by a known and trusted health professional [3, 4, 7].

In addition, it is recommended that independent governance bodies determine, in close co-operation with the Institutional Review Boards (IRB) of the original studies, which individuals to re-contact and how to re-contact them [2, 6, 7, 10]. Other recommendations include 1) choosing a study design which prevents the involuntary disclosure of information about the genetic profile of the research participants to the outside world, e.g. by adding randomly selected sub-groups in case-only studies [1]; 2) using less stringent parameters for the return of results to research participants than currently recommended in other genetic research [1, 3, 6, 7, 9, 15, 17] and 3) return of results according to specific criteria agreed upon in co-operation with the research participants [8, 15].

Finally, a general recommendation is that researchers who plan to conduct GDR studies should take into consideration the context of the research (e.g. was the original study conducted by different researchers than the follow-up GDR study?) and the relationship between the researchers and the individuals they plan to invite [5, 7, 9].

Do the recommendations suffice under a broader use of GDR?

Results from our conceptual analysis reveal that out of 15 recommendations proposed in the current literature only one may suffice in the context of a broader use of GDR. The recommendation to add randomly selected sub-groups in case-only studies to avoid risks of stigmatisation when individuals are invited to GDR studies may also be applicable when GDR studies are original studies and not follow-up studies. For each of the remaining fourteen recommendations, we found one or several reasons why the current recommendations would not suffice in a context of broader use of GDR designs. These reasons are reported in Table 1 and can be summarised as follows.

The individuals invited to enroll in an original GDR study may not be prepared to receive such an invitation

Current recommendations presuppose that, at some point in time, an informed consent process has taken place between researchers and participants; a process during which information about potential future enrolment in GDR studies has been provided and the opportunity for participants to indicate whether they want to be involved in future GDR has been given. Recommendations also suggest that re-contact should be undertaken by a known professional such as the principal investigator of the study to which the participant was originally recruited. However, this type of individual informed consent process may not systematically take place in conjunction with the generation of genotypic information. An example would be genotyping conducted through standard health care where informed consent may not have been required. Individuals who are not aware that genetic information exists about them will probably be totally unprepared if contacted for participation in a GDR study [14]. Even individuals who have previous knowledge about their genotype from DTC genetic testing services may not be aware that their genetic information potentially could have been sold to or shared with other private companies or researchers [25]. Thus, unexpected contact may come as a surprise and provoke anger if the individuals contacted do not want to know about own genetic information and do not want their relatives to know [1, 3, 4, 9].

The individuals invited to enroll in an original GDR study may not be prepared to receive genetic research results

When individuals who have participated in previous research are re-contacted for participation in a GDR study, they already have some knowledge about what a research study entails and what participating in research means. They have taken the initiative to participate in research and may have received some basic information related to the genetic research aims by the investigators of the original study. Things may be different for individuals who are not re-contacted but contacted for the first time; individuals who have never participated in research before and may not know anything about genetic research. There is currently no empirical evidence on the effects of receiving genetic results without having been prepared to it. One could argue that the disclosure of genetic research results to research participants normally does not trigger such distress as shown in recent studies [35, 36]. However, the recipients of genetic results who participated in those studies already had a relationship with the researchers or were aware of the presence of a genetic variant in their family through a relative’s participation in research or illness. If individuals are recruited into original GDR studies through e.g. their health care system or directly by a private company, such a relationship and awareness may not exist.

Current recommendations also encourage applying a lower threshold than usual for feedback of results from GDR [1, 3, 6, 7, 9, 15, 17]. A sound feedback process that respects the perspectives and wishes of participants typically requires taking into consideration the context of the research and the relationship between the researcher and the research participant [8, 15]. However, if as we postulate, GDR designs were used more broadly, it would not always be possible for researchers to make such an assessment because they may not know anything about the individual’s previous involvement in research.

The establishment of independent governance bodies to coordinate all GDR research projects may be too challenging

The current recommendations encourage the establishment of independent governance bodies, e.g. centralised ethics or data access committees, by the projects generating genetic information to manage all data access requests, protect the privacy and confidentiality of datasets and determine which individuals can be contacted and by whom. The objective of establishing these committees is to avoid harassing individuals by inviting them to multiple studies as could be the case, for example, for individuals carrying a rare genetic variant, and ensure that ethical standards are respected [2, 7, 10]. Creation of such committees raises several sets of questions. First, questions related to the legal authority of these committees may emerge. For instance, under which legal framework, national or international, would these committees be established and operate? Could these committees have authority both over publicly financed research projects and private companies? As an example, DTC genetic testing companies currently do not operate under the same legal framework as publicly funded research projects [37] and, although attempts to regulate their activities have been made, they still benefit from a rather loose legal framework [38]. Unless international regulation requires that DTC genetic testing companies follow the same rules (and report to the same centralised committees) as publicly funded research projects, it is quite unlikely that they will do so.

Second, questions related to the scientific authority of these committees may emerge. How could these committees for instance make decisions regarding data access requests from numerous public and private actors? To do so would probably require that the committees have extensive knowledge about all research projects previously undergone, which individuals have participated in which research projects and which have not, which have consented to re-contact and which have not, which have already been invited in previous GDR studies, and which have not etc. Such a high level of co-ordination could maybe be possible between publicly-funded institutions within a specific research collaboration or geographic area [10] but seem quite unrealistic to expect when both publicly funded research projects and a myriad of private companies are involved.