Common 'Inborn Errors' of Metabolism in the General Population

Inborn errors of metabolism (IEMs) are a group of disorders characterised by the toxic accumulation or deficiency of circulating molecules (‘metabolites’) caused by rare genetic mutations. Previous studies have identified select examples where common variants at genes known to cause rare Mendelian diseases, including IEMs (e.g. LPL, DBH, PPM1K), are linked to phenotypic consequences in the general population that also occur in patients with the corresponding rare disease. Advances in genetic and metabolic profiling at an epidemiological scale now provide an opportunity to systematically identify such examples in the population and characterise their downstream effects on health. To assess the value of untargeted metabolomic profiling for the study of common complex diseases, I identified candidate mediators of the association between weight gain and future type 2 diabetes risk based on untargeted, large-scale metabolomic profiling of a large prospective cohort. Integration of metabolomics, genetic profiling and comprehensive longitudinal follow up for a range of diseases together with the application of Bayesian and genetic epidemiological methods enabled the identification of 20 candidate mediators. These reflected genetic susceptibility to adiposity and insulin resistance and explained most of the increased T2D risk associated with weight gain. To systematically characterise the phenotypic effects of variation at IEM-causing genes, I identified sentinel variants at these genes associated with plasma metabolites affected in the corresponding IEM across the genome. Of the 202 ‘IEM familiar’ variants (IFVs) detected, 187 at 89 loci were not previously reported as pathogenic for the corresponding IEM in ClinVar and 51 of these were associated with extreme metabolite levels (97.5th percentile) or had non-additive effects on metabolite levels. Phenome-wide assessment identified 1,553 IFV-phenotype associations at 108 loci. Of the detected associations, 703 at 54 loci were of particular interest as the phenotype related to a symptom of the corresponding IEM. At 24 of these 54 loci, genetic colocalisation detected shared genetic signals for IEM-related metabolites and phenotypes. For example, in line with norepinephrine deficiency causing dizziness on standing in severe cases of rare orthostatic hypotension (OMIM #223360), I identified a genetic signal at the dopamine beta hydroxylase (DBH) locus associated with decreased levels of the downstream catecholamine vanillylmandelate in the general population (IFV EAF=0.074). This signal was shared with that for lower risk of hypertension (based on 462,933 participants in UK Biobank) and other blood pressure-related phenotypes with high posterior probability of colocalisation (PPcolocalisation=0.94, with >99% of the probability explained by the IFV). This work uses untargeted metabolomic profiling to identify underlying disease mechanisms and demonstrate the proof-of-principle that common variants can have similar health consequences to those caused by rare mutations at the same IEM gene.Wellcome Trust, Cambridge Trus

Hereditary Hemochromatosis Predisposes Mice to Yersinia pseudotuberculosis Infection Even in the Absence of the Type III Secretion System.

The iron overload disorder hereditary hemochromatosis (HH) predisposes humans to serious disseminated infection with pathogenic Yersinia as well as several other pathogens. Recently, we showed that the iron-sulfur cluster coordinating transcription factor IscR is required for type III secretion in Y. pseudotuberculosis by direct control of the T3SS master regulator LcrF. In E. coli and Yersinia, IscR levels are predicted to be regulated by iron bioavailability, oxygen tension, and oxidative stress, such that iron depletion should lead to increased IscR levels. To investigate how host iron overload influences Y. pseudotuberculosis virulence and the requirement for the Ysc type III secretion system (T3SS), we utilized two distinct murine models of HH: hemojuvelin knockout mice that mimic severe, early-onset HH as well as mice with the Hfe (C282Y∕C282Y) mutation carried by 10% of people of Northern European descent, associated with adult-onset HH. Hjv (-∕-) and Hfe (C282Y∕C282Y) transgenic mice displayed enhanced colonization of deep tissues by Y. pseudotuberculosis following oral inoculation, recapitulating enhanced susceptibility of humans with HH to disseminated infection with enteropathogenic Yersinia. Importantly, HH mice orally infected with Y. pseudotuberculosis lacking the T3SS-encoding virulence plasmid, pYV, displayed increased deep tissue colonization relative to wildtype mice. Consistent with previous reports using monocytes from HH vs. healthy donors, macrophages isolated from Hfe (C282Y∕C282Y) mice were defective in Yersinia uptake compared to wildtype macrophages, indicating that the anti-phagocytic property of the Yersinia T3SS plays a less important role in HH animals. These data suggest that Yersinia may rely on distinct virulence factors to cause disease in healthy vs. HH hosts

Reduced specificity of autobiographical memory and depression: The role of executive control

It has been widely established that depressed mood states and clinical depression, as well as a range of other psychiatric disorders, are associated with a relative difficulty in accessing specific autobiographical information in response to emotion-related cue words on an Autobiographical Memory Test (AMT; J. M. G. Williams and K. Broadbent, 1986). In 8 studies the authors examined the extent to which this relationship is a function of impaired executive control associated with these mood states and clinical disorders. Studies 1-4 demonstrated that performance on the AMT is associated with performance on measures of executive control, independent of depressed mood. Furthermore, Study 1 showed that executive control (as measured by verbal fluency) mediated the relationship between both depressed mood and a clinical diagnosis of eating disorder and AMT performance. Using a stratified sample in Study 5, the authors confirmed the positive association between depressed mood and impaired performance on the AMT. Studies 6-8 involved experimental manipulations of the parameters of the AMT designed to further indicate that reduced executive control is to a significant extent driving the relationship between depressed mood and AMT performance. The potential role of executive control in accounting for other aspects of the AMT literature is discussed

Rare and common genetic determinants of metabolic individuality and their effects on human health.

Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships