Joana A. Revez

Background: Various vitamins and minerals have been implicated in the aetiology of depression. Objective: To estimate the effects of micronutrient exposures on major depressive disorder (MDD) and recurrent depression (rMDD) using Mendelian randomisation (MR), a method using genetic data to estimate causal effects given certain assumptions. Methods: We undertook a comprehensive bidirectional MR study of multiple micronutrient exposures on MDD and rMDD. Summary statistics were obtained from the Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWASs) of MDD (cases = 116,209; controls = 314,566) and rMDD (cases = 17,451; controls = 62,482). Results: None of the micronutrients with available genetic instruments were strongly associated with MDD or rMDD using traditional MR methods. However, using methods to increase analytical power by accounting for genetically correlated variants (e.g., cIVW) highlighted five micronutrients with possible causal effects. Point estimates for rMDD were the largest magnitude, with three micronutrients suggestive of a protective effect: serum iron (OR_cIVW 0.90 per SD increase; 95% CI 0.85–0.95; p = 0.0003); erythrocyte copper (OR_cIVW 0.97; 95% CI 0.95–0.99; p = 0.0004); and 25(OH) vitamin D (OR_cIVW 0.81; 0.66–0.99; p = 0.04). Apparent adverse effects of increased selenium on the risk of MDD (OR_cIVW 1.03; 95% CI 1.02–1.05; p = 0.0003) and rMDD (OR_cIVW 1.08; 95% CI 1.00–1.08; p = 0.06), and serum magnesium on rMDD (OR_cIVW 1.21; 1.01–1.44; p = 0.04); were less consistent between methods and may be driven by pleiotropy. Conclusions: Our results suggest weak evidence for a protective effect of iron, copper and 25(OH)D on major depressive outcomes, with mixed evidence for selenium and magnesium. There was no evidence to support a causal effect of any other micronutrients on MDD or rMDD, although genetic instruments were lacking, with insufficient power to detect small but important effects. Future micronutrient supplementation trials should ensure ample statistical power given modest causal effect estimates and consider potential risks of supplementation, as some micronutrient effect estimates suggested potential harm in excess.

Background: Various vitamins and minerals have been implicated in the aetiology of depression. Objective: To estimate the effects of micronutrient exposures on major depressive disorder (MDD) and recurrent depression (rMDD) using Mendelian randomization (MR). Methods: We undertook a comprehensive bidirectional MR study of multiple micronutrient exposures on MDD and rMDD. Summary statistics were obtained from the Psychiatric Genomics Consortium (PGC) genome wide association studies (GWASs) of MDD (cases = 116,209; controls = 314,566), and rMDD (cases=17,451; controls=62,482). Results: None of the micronutrients with available genetic instruments were strongly associated with MDD or rMDD using traditional MR methods. However, using methods to increase analytical power by accounting for genetically correlated variants (e.g. cIVW), highlighted five micronutrients with possible causal effects. Point estimates for rMDD were the largest magnitude, with three micronutrients suggestive of a protective effect: serum iron (OR_cIVW 0.90 per SD increase; 95% CI 0.85- 0.95; p=0.0003); erythrocyte copper (OR_cIVW 0.97; 95% CI 0.95- 0.99; p=0.0004); and 25(OH) vitamin D (OR_cIVW 0.81; 0.66- 0.99; p=0.04). Apparent adverse effects of increased selenium on the risk of MDD (OR_cIVW 1.03; 95% CI 1.02-1.05; p=0.0003) and rMDD (OR_cIVW 1.08; 95% CI 1.00-1.08; p=0.06), and serum magnesium on rMDD (OR_cIVW 1.21; 1.01- 1.44; p=0.04); were less consistent between methods and may be driven by pleiotropy. Conclusions: Our results suggest weak evidence for a protective effect of iron, copper and 25(OH)D on major depressive outcomes, with mixed evidence for selenium and magnesium. There was no evidence to support a causal effect of any other micronutrients on MDD or rMDD, although genetic instruments were lacking, with insufficient power to detect small but important effects. Future micronutrient supplementation trials should ensure ample statistical power given modest causal effect estimates, and consider potential risks of supplementation, as some micronutrient effect estimates suggested potential harm in excess.

While it is known that vitamin D deficiency is associated with adverse bone outcomes, it remains unclear whether low vitamin D status may increase the risk of a wider range of health outcomes. We had the opportunity to explore the association between common genetic variants associated with both 25 hydroxyvitamin D (25OHD) and the vitamin D binding protein (DBP, encoded by the GC gene) with a comprehensive range of health disorders and laboratory tests in a large academic medical center. We used summary statistics for 25OHD and DBP to generate polygenic scores (PGS) for 66,482 participants with primarily European ancestry and 13,285 participants with primarily African ancestry from the Vanderbilt University Medical Center Biobank (BioVU). We examined the predictive properties of PGS_25OHD, and two scores related to DBP concentration with respect to 1322 health-related phenotypes and 315 laboratory-measured phenotypes from electronic health records. In those with European ancestry: (a) the PGS_25OHD and PGS_DBP scores, and individual SNPs rs4588 and rs7041 were associated with both 25OHD concentration and 1,25 dihydroxyvitamin D concentrations; (b) higher PGS_25OHD was associated with decreased concentrations of triglycerides and cholesterol, and reduced risks of vitamin D deficiency, disorders of lipid metabolism, and diabetes. In general, the findings for the African ancestry group were consistent with findings from the European ancestry analyses. Our study confirms the utility of PGS and two key variants within the GC gene (rs4588 and rs7041) to predict the risk of vitamin D deficiency in clinical settings and highlights the shared biology between vitamin D-related genetic pathways a range of health outcomes.

Vitamin D status–a complex trait influenced by environmental and genetic factors–is tightly associated with skin colour and ancestry. Yet very few studies have investigated the genetic underpinnings of vitamin D levels across diverse ancestries, and the ones that have, relied on small sample sizes, resulting in inconclusive results. Here, we conduct genome-wide association studies (GWAS) of 25 hydroxyvitamin D (25OHD)–the main circulating form of vitamin D–in 442,435 individuals from four broad genetically-determined ancestry groups represented in the UK Biobank: European (N = 421,867), South Asian (N = 9,983), African (N = 8,306) and East Asian (N = 2,279). We identify a new genetic determinant of 25OHD (rs146759773) in individuals of African ancestry, which was not detected in previous analysis of much larger European cohorts due to low minor allele frequency. We show genome-wide significant evidence of dominance effects in 25OHD that protect against vitamin D deficiency. Given that key events in the synthesis of 25OHD occur in the skin and are affected by pigmentation levels, we conduct GWAS of 25OHD stratified by skin colour and identify new associations. Lastly, we test the interaction between skin colour and variants associated with variance in 25OHD levels and identify two loci (rs10832254 and rs1352846) whose association with 25OHD differs in individuals of distinct complexions. Collectively, our results provide new insights into the complex relationship between 25OHD and skin colour and highlight the importance of diversity in genomic studies. Despite the much larger rates of vitamin D deficiency that we and others report for ancestry groups with dark skin (e.g., South Asian), our study highlights the importance of considering ancestral background and/or skin colour when assessing the implications of low vitamin D.

The vitamin D binding protein (DBP), encoded by the group-specific component (GC) gene, is a component of the vitamin D system. In a genome-wide association study of DBP concentration in 65,589 neonates we identify 26 independent loci, 17 of which are in or close to the GC gene, with fine-mapping identifying 2 missense variants on chromosomes 12 and 17 (within SH2B3 and GSDMA, respectively). When adjusted for GC haplotypes, we find 15 independent loci distributed over 10 chromosomes. Mendelian randomization analyses identify a unidirectional effect of higher DBP concentration and (a) higher 25-hydroxyvitamin D concentration, and (b) a reduced risk of multiple sclerosis and rheumatoid arthritis. A phenome-wide association study confirms that higher DBP concentration is associated with a reduced risk of vitamin D deficiency. Our findings provide valuable insights into the influence of DBP on vitamin D status and a range of health outcomes.

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of Streptococcus salivarius DSM 13084/ATCC BAA 1024 as a technological additive (functional group: acidity regulators) in feed for dogs and cats. The additive is intended for use at a proposed minimum concentration of 1 × 10¹¹ CFU/l or kg liquid feed for dogs and cats. Due to the lack of adequate data, the FEEDAP Panel could not conclude on the safety of the additive for the target species. The additive was considered a respiratory sensitiser, but not irritant to skin. No conclusions could be drawn on the potential of the additive to be an eye irritant or a skin sensitiser. No environmental risk assessment is necessary for the use of the additive in feeds for pets. The Panel concluded that the additive has the potential to be efficacious in feeds for dogs and cats at the proposed conditions of use.

The genetic regulation of post-prandial glucose levels is poorly understood. Here, we characterise the genetic architecture of blood glucose variably measured within 0 and 24 h of fasting in 368,000 European ancestry participants of the UK Biobank. We found a near-linear increase in the heritability of non-fasting glucose levels over time, which plateaus to its fasting state value after 5 h post meal (h² = 11%; standard error: 1%). The genetic correlation between different fasting times is > 0.77, suggesting that the genetic control of glucose is largely constant across fasting durations. Accounting for heritability differences between fasting times leads to a ~16% improvement in the discovery of genetic variants associated with glucose. Newly detected variants improve the prediction of fasting glucose and type 2 diabetes in independent samples. Finally, we meta-analysed summary statistics from genome-wide association studies of random and fasting glucose (N = 518,615) and identified 156 independent SNPs explaining 3% of fasting glucose variance. Altogether, our study demonstrates the utility of random glucose measures to improve the discovery of genetic variants associated with glucose homeostasis, even in fasting conditions.

The vitamin D binding protein (DBP), encoded by the group-specific component ( GC ) gene, is a much-studied component of the vitamin D system. In a genome-wide association study of DBP concentration in 65,589 neonates, we identified 26 independent loci, 17 of which were in or close to the GC gene, with fine-mapping identifying 2 loci on chromosomes 12 and 17 (missense variants within SH2B3 and GSDMA, respectively). When adjusted for key GC haplotypes, we found 15 independent loci distributed over 10 chromosomes. Mendelian randomization analyses found evidence consistent with a unidirectional, causal effect of higher DBP concentration and (a) higher 25 hydroxyvitamin D (25OHD) concentration, and (b) a reduced risk of multiple sclerosis and rheumatoid arthritis. A phenome-wide association study in an external dataset confirmed that higher DBP concentration was associated with higher 25OHD concentration and a reduced risk of vitamin D deficiency. Our study provides new insights into the influence of DBP on vitamin D status and a range of health outcomes.