Emily Bassett

Mendelian imputation is a promising method for imputing missing parental genotypes and estimating direct and indirect genetic effects. While the method has clear scientific benefits, so far there has been little reflection on its legal and ethical implications. In this perspective, we discuss these considerations and provide recommendations on transparent use of this method. We argue that imputed genotypes should be considered identifiable, personal data, and that using these data requires informed consent. We distinguish different scenarios where consent may be missing, such as an individual previously not having been contacted for consent, or a person who was contacted but did not reply or did not wish to participate. Informed consent is important across all these scenarios as it allows individuals to decide whether they want to participate in a study. In addition, transparent communication on how people’s data are used is important for public perception of science, and a failure to communicate this may contribute to mistrust. We discuss potential harmful applications of Mendelian imputation, and how robust regulatory frameworks guiding Institutional Review Boards on novel advanced methods such as Mendelian imputation are currently missing. This complicates decision making, especially when researchers argue for public interest as a lawful basis for foregoing consent. We end with a set of recommendations for (1) future genetic research projects for which Mendelian imputation will be possible; (2) research that has already been conducted using this method; and (3) the inclusion of ethical considerations in the publication of novel techniques/analyses.

Vitamin D deficiency has been linked to various chronic pain conditions. However, randomized trials of vitamin D supplementation have had mixed results. In contrast, systematic reviews of randomized trials indicate a protective effect of vitamin D supplementation on depression. We undertake a Mendelian randomization investigation in UK Biobank, a study of UK residents aged 40-65 at recruitment. We perform linear and non-linear Mendelian randomization analyses for four outcomes: fibromyalgia, clinical fatigue, chronic widespread pain, and probable lifetime major depression. We use genetic variants from four gene regions with known links to vitamin D biology as instruments. In linear analyses, genetically-predicted levels of 25-hydroxyvitamin D [25(OH)D], a clinical marker of vitamin D status, were not associated with fibromyalgia (odds ratio [OR] per 10 nmol/L higher 25(OH)D 1.02, 95% confidence interval [CI] 0.93, 1.12), clinical fatigue (OR 0.99, 95% CI 0.94, 1.05), chronic widespread pain (OR 0.95, 95% CI 0.89, 1.02), or probable lifetime major depression (OR 0.97, 95% CI 0.93, 1.01). In non-linear analyses, an association was observed between genetically-predicted 25(OH)D levels and depression in the quintile of the population with the lowest 25(OH)D levels (OR 0.75, 95% CI 0.59, 0.94); associations were null in other strata. Our findings suggest that population-wide vitamin D supplementation will not substantially reduce pain or depression; however, targeted supplementation of deficient individuals may reduce risk of depression.

Vitamin D deficiency has been linked to various chronic pain conditions. However, randomized trials of vitamin D supplementation have had mixed results. In contrast, systematic reviews of randomized trials indicate a protective effect of vitamin D supplementation on depression. We undertake a Mendelian randomization investigation in UK Biobank, a study of UK residents aged 40-65 at recruitment. We perform linear and non-linear Mendelian randomization analyses for four outcomes: fibromyalgia, clinical fatigue, chronic widespread pain, and probable lifetime major depression. We use genetic variants from four gene regions with known links to vitamin D biology as instruments. In linear analyses, genetically-predicted levels of 25-hydroxyvitamin D [25(OH)D], a clinical marker of vitamin D status, were not associated with fibromyalgia (odds ratio [OR] per 10 nmol/L higher 25(OH)D 1.02, 95% confidence interval [CI] 0.93, 1.12), clinical fatigue (OR 0.99, 95% CI 0.94, 1.05), chronic widespread pain (OR 0.95, 95% CI 0.89, 1.02), or probable lifetime major depression (OR 0.97, 95% CI 0.93, 1.01). In non-linear analyses, an association was observed between genetically-predicted 25(OH)D levels and depression in the quintile of the population with the lowest 25(OH)D levels (OR 0.78, 95% CI 0.64, 0.94); associations were null in other strata. Our findings suggest that population-wide vitamin D supplementation will not substantially reduce pain or depression; however, targeted supplementation of deficient individuals may reduce risk of depression.