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Vitamin B 12 deficiency is common among older adults. However, the most commonly used marker of deficiency, total serum vitamin B 12 (B 12 ), is not sensitive enough to diagnose true deficiency in a significant proportion of the population. The combined indicator of B 12 status (cB 12 ), formulated as a composite score of various biomarkers of vitamin B 12 status (which also accounts for low folate status and age) has been shown to offer a more robust and powerful test to diagnose B 12 deficiency. There are no epidemiological studies of cB 12 variability in older adults. We carried out a twin study to characterize the relative contribution of heritable (h 2 ) and environmental factors to the observed variability in cB 12 score in an adult and older adult population (n=378). Furthermore, we tested for association between variability in cB 12 and candidate polymorphisms and genes previously associated with B 12 biomarker levels characterized in silico the mechanism linking the genetic variants and cB 12 variability. We found the variability in cB 12 and its constituents to be highly heritable (h 2 =55%-64%). The single nucleotide polymorphism rs291466 in HIBCH, previously associated with variation in MMA, was significantly associated with cB 12 (R 2 =5%, P=5E-04). Furthermore, variants in MTRR, MMAB and MUT, underlying inborn errors of B 12 metabolism, were nominally associated with variation in cB 12 . Pathway accompanied by expression quantitative trait loci analysis revealed that HIBCH rs291466 influences the concentration of MMA via the valine degradation pathway. Our study provides etiological insight into how B 12 deficiency can manifest into impaired mitochondrial function through perturbations in mitochondrial "fuel" usage., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study investigated the potential genetic mechanisms which underlie adipose tissue mitochondrial dysfunction in Type 2 diabetes (T2D), by systematically identifying nuclear-encoded mitochondrial genes (NEMGs) among the genes regulated by T2D-associated genetic loci. The target genes of these 'disease loci' were identified by mapping genetic loci associated with both disease and gene expression levels (expression quantitative trait loci, eQTL) using high resolution genetic maps, with independent estimates co-locating to within a small genetic distance. These co-locating signals were defined as T2D-eQTL and the target genes as T2D cis- genes. In total, 763 cis- genes were associated with T2D-eQTL, of which 50 were NEMGs. Independent gene expression datasets for T2D and insulin resistant cases and controls confirmed that the cis- genes and cis- NEMGs were enriched for differential expression in cases, providing independent validation that genetic maps can identify informative functional genes. Two additional results were consistent with a potential role of T2D-eQTL in regulating the 50 identified cis- NEMGs in the context of T2D risk: (1) the 50 cis- NEMGs showed greater differential expression compared to other NEMGs and (2) other NEMGs showed a trend towards significantly decreased expression if their expression levels correlated more highly with the subset of 50 cis- NEMGs. These 50 cis -NEMGs, which are differentially expressed and associated with mapped T2D disease loci, encode proteins acting within key mitochondrial pathways, including some of current therapeutic interest such as the metabolism of branched-chain amino acids, GABA and biotin. [ABSTRACT FROM AUTHOR]