Understanding the Genetic Architecture of Vitamin Status Biomarkers in the Genome-Wide Association Study Era: Biological Insights and Clinical Significance

Abstract

Vitamins play an intrinsic role in human health and are targets for clinical intervention through dietary or pharmacological approaches. Biomarkers of vitamin status are complex traits, measurable phenotypes that arise from an interplay between dietary and other environmental factors with a genetic component that is polygenic, meaning many genes are plausibly involved. Studying these genetic influences will improve our knowledge of fundamental vitamin biochemistry, refine estimates of the effects of vitamins on human health, and may in future prove clinically actionable. Here, we evaluate genetic studies of circulating and excreted biomarkers of vitamin status in the era of hypothesis-free genome-wide association studies (GWAS) that have provided unprecedented insights into the genetic architecture of these traits. We found that the most comprehensive and well-powered GWAS currently available were for circulating status biomarkers of vitamin A, C, D, and a subset of the B vitamins (B₉ and B₁₂). The biology implicated by GWAS of measured biomarkers of each vitamin is then discussed, both in terms of key genes and higher-order processes. Across all major vitamins, there were genetic signals revealed by GWAS that could be directly linked with known vitamin biochemistry. We also outline how genetic variants associated with vitamin status biomarkers have been already extensively used to estimate causal effects of vitamins on human health outcomes, which is particularly important given the large number of randomized control trials of vitamin related interventions with null findings. Finally, we discuss the current evidence for the clinical applicability of findings from vitamin GWAS, along with future directions for the field to maximize the utility of these data.

Keywords: Genome-wide association studies; Mendelian randomization; nutritional epidemiology; polygenic scores; vitamin status biomarkers.

FIGURE 1

Examples of the utility of pursuing genome-wide association studies (GWAS) of biomarkers of vitamin status. GWAS of vitamin status may be both biologically and clinically informative for several reasons, four of which are briefly summarized in the above figure and discussed further throughout the review. GWAS, genome-wide association studies.

FIGURE 2

Putative mechanism of key common variants associated with vitamin A compounds from GWAS. Provitamin A carotenoids such as β-carotene can be cleaved into two retinaldehyde (two molecules) in a reaction catalyzed by the enzyme Beta-Carotene 15,15′-monooxygenase 1 encoded by BCO1. Variation physically mapped to BCO1 associated with circulating β-carotene at genome-wide significance has been suggested experimentally to reduce the efficiency of enzymatic conversion to retinaldehyde [32]. As a result, this signal is associated with a small-to-moderate increase in circulating β-carotene. Common variation in RBP4, which encodes the primary circulating transporter of retinol, retinol binding protein 4, is associated with circulating retinol at genome-wide significance. The same causal variant has been estimated to underly both circulating RBP4 expression and circulating retinol (colocalization) [28], suggesting that the allele which decreases RBP4 abundance in turn decreases retinol transport from the liver. RBP4 complexes with transthyretin (encoded by TTR) to stabilize the complex and prevent excessive renal filtration of RBP4. Variation mapped to TTR has also been associated with circulating retinol, and while the effect of these variants on expression or function of TTR has not been fully resolved, it is logical that retinol decreasing alleles would impact TTR abundance or function, therefore, resulting in increased renal filtration of RBP4 bound retinol. Chemical formulas sourced from PubChem (https://pubchem.ncbi.nlm.nih.gov/). GWAS, genome-wide association studies.

FIGURE 3

Schematic of how genetic variants associated with circulating vitamin C can be used for causal inference via Mendelian randomization. The rs33972313 missense variant in the transporter SLC23A1 is directly mechanistically linked to circulating vitamin C, whereby each T allele is associated with reduced plasma vitamin C (∼−0.36 SD in the largest GWAS). As a result, this T allele could be characterized as a genetic proxy of circulating vitamin C and be considered an instrumental variable, given certain assumptions are met [15]. As this variant will be randomly inherited in the population under Mendel’s laws, a causal estimate of the effect of vitamin C can be inferred through the ratio of the association of this allele with an outcome trait of interest (for example, disease risk) relative to its association with circulating vitamin C.

FIGURE 4

Using polygenic scores to predict circulating 25(OH)D concentrations and its implications of personalized supplementation. The genetic predisposition for higher or lower circulating 25(OH)D can be indexed in an individual using a polygenic score (PGS). Specifically, this summates the alleles carried by an individual weighted by their effect size (association with 25(OH)D) derived from a GWAS conducted in an individual sample. To render these scores interpretable at an individual level, they need to be scaled relative to the distribution (for example, mean and standard deviation) of this score in a comparable population. Individuals who score low after scaling, highlighted on the kernel density estimation plot in this figure using an arbitrary threshold of the lowest 20% of the population, have a lower genetically predicted 25(OH)D than most of the population. This information could be utilized to personalize supplement dosage such that those with low polygenic scores receive higher dosages, as well as receive more pervasive monitoring in clinical situations 25(OH)D is a clinically important sequala, such as malabsorptive conditions.