Investigating causality in the association between vitamin D status and self-reported tiredness.

Self-reported tiredness or low energy, often referred to as fatigue, has been linked to low levels of circulating 25-hydroxyvitamin D (25OHD), a biomarker of vitamin D status. Although it is uncertain if the association is causal, fatigue is a common indication for testing, and correcting, low 25OHD-levels. We used two-sample Mendelian randomization to test for genetic evidence of a causal association between low 25OHD-levels and fatigue. Genetic-25OHD associations were estimated from the largest genome-wide association study of vitamin D to date, and genetic-fatigue associations were estimated in 327,478 individuals of European descent in UK Biobank, of whom 19,526 (5.96%) reported fatigue (tiredness or low energy nearly every day over the past two weeks). Using seven genome-wide significant 25OHD-reducing genetic variants, there was little evidence for a causal effect of 25OHD on fatigue (odds ratio for fatigue was 1.05 with 95% confidence interval of 0.87-1.27 per 1-SD decrease in log-transformed 25OHD). There was also little evidence of association between any individual 25OHD-reducing variant and fatigue. Our results suggest that a clinically relevant protective effect of 25OHD-levels on fatigue is unlikely. Therefore, vitamin D supplementation of the general population to raise 25OHD-levels is not likely to be useful in preventing fatigue.

Perinatal depression and omega-3 fatty acids: a Mendelian randomisation study.

BACKGROUND: There have been numerous studies investigating the association between omega-3 fatty acids (FAs) and depression, with mixed findings. We propose an approach which is largely free from issues such as confounding or reverse causality, to investigate this relationship using observational data from a pregnancy cohort. METHODS: The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort collected information on FA levels from antenatal blood samples and depressive symptoms at several time points during pregnancy and the postnatal period. Conventional epidemiological analyses were used in addition to a Mendelian randomisation (MR) approach to investigate the association between levels of two omega-3 FAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and perinatal onset depression, antenatal depression (AND) and postnatal depression (PND). RESULTS: Weak evidence of a positive association with both EPA (OR=1.07; 95% CI: 0.99-1.15) and DHA (OR=1.08; 95% CI: 0.98-1.19) with perinatal onset depression was found using a multivariable logistic regression adjusting for social class and maternal age. However, the strength of association was found to attenuate when using an MR analysis to investigate DHA. LIMITATIONS: Pleiotropy is a potential limitation in MR analyses; we assume that the genetic variants included in the instrumental variable are associated only with our trait of interest (FAs) and thus cannot influence the outcome via any other pathway. CONCLUSIONS: We found weak evidence of a positive association between omega-3 FAs and perinatal onset depression. However, without confirmation from the MR analysis, we are unable to draw conclusions regarding causality.