Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic... Show moreGenome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8,9,10,11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases. Show less
Li-Gao, R.; Hughes, D.A.; Klinken, J.B. van; Mutsert, R. de; Rosendaal, F.R.; Mook-Kanamori, D.O.; ... ; Dijk, K.W. van 2021
Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We examined the genetics of variation... Show moreHumans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We examined the genetics of variation in concentrations of postprandial metabolites (t = 150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity (NEO) study (n = 5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (beta [SE] -0.23 [0.03], P = 2.15 x 10(-19)). In addition, the ANKRD55 locus led by rs458741:C showed strong associations with extremely large VLDL (XXLVLDL) particle response (XXLVLDL total cholesterol: beta [SE] 0.17 [0.03], P = 5.76 x 10(-10); XXLVLDL cholesterol ester: beta [SE] 0.17 [0.03], P = 9.74 x 10(-10)), which also revealed strong associations with body composition and diabetes in the UK Biobank (P < 5 x 10(-8)). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-beta, Matsuda insulin sensitivity index, and HbA(1c) in the NEO study implied the role of chylomicron synthesis in diabetes (with false discovery rate-corrected q <0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of the ANKRD55 locus underlying diabetes. Show less
Ruifang, L.G.; Hughes, D.A.; Cessie, S. le; Mutsert, R. de; Heijer, M. den; Rosendaal, F.R.; ... ; Mook-Kanamori, D.O. 2019
We describe the novel association in a girl of nephrotic syndrome due to focal segmental glomerulosclerosis, bilateral sensorineural deafness, basal ganglia calcification, bilateral retinopathy... Show moreWe describe the novel association in a girl of nephrotic syndrome due to focal segmental glomerulosclerosis, bilateral sensorineural deafness, basal ganglia calcification, bilateral retinopathy similar to that seen in Coats' disease, with de novo duplication of a subtelomeric region of chromosome 4q35. The chromosomal duplication was identified during investigation of a possible association with features of fascio-scapulo-humeral dystrophy (FSHD). This duplication has not previously been reported with FSGS and adds to the expanding number of genetic associations with steroid-resistant nephrotic syndrome. Show less
Anticoagulant therapy with coumarin derivatives is often sub- or supra-therapeutic, resulting in an increased risk of thromboembolic events or hemorrhage, respectively. Pharmacogenetic-guided... Show moreAnticoagulant therapy with coumarin derivatives is often sub- or supra-therapeutic, resulting in an increased risk of thromboembolic events or hemorrhage, respectively. Pharmacogenetic-guided dosing has been proposed as an effective way of reducing bleeding rates. Clinical trials to confirm the safety, efficacy and effectiveness of this strategy are ongoing, but in addition, it is also necessary to consider the cost effectiveness of this strategy. This article describes the findings of a systematic review of published cost effectiveness analyses of pharmacogenetic-guided dosing of coumarin derivatives. Similarities and differences in the approaches used were examined and the quality of the analyses was assessed. The results of the analyses are not sufficient to determine whether or not pharmacogenetic-guided dosing of coumarins is cost effective. More reliable cost effectiveness estimates need to become available before it is possible to recommend whether or not this strategy should be applied in clinical practice. Show less
