Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk

Fusion of metabolomics and proteomics data for biomarkers discovery: case study on the experimental autoimmune encephalomyelitis

Contains fulltext : 91843.pdf (publisher's version ) (Open Access)12 p

Birth Weight and Adult IQ, but Not Anxious-Depressive Psychopathology, Are Associated with Cortical Surface Area: A Study in Twins

BACKGROUND: Previous research suggests that low birth weight (BW) induces reduced brain cortical surface area (SA) which would persist until at least early adulthood. Moreover, low BW has been linked to psychiatric disorders such as depression and psychological distress, and to altered neurocognitive profiles. AIMS: We present novel findings obtained by analysing high-resolution structural MRI scans of 48 twins; specifically, we aimed: i) to test the BW-SA association in a middle-aged adult sample; and ii) to assess whether either depression/anxiety disorders or intellectual quotient (IQ) influence the BW-SA link, using a monozygotic (MZ) twin design to separate environmental and genetic effects. RESULTS: Both lower BW and decreased IQ were associated with smaller total and regional cortical SA in adulthood. Within a twin pair, lower BW was related to smaller total cortical and regional SA. In contrast, MZ twin differences in SA were not related to differences in either IQ or depression/anxiety disorders. CONCLUSION: The present study supports findings indicating that i) BW has a long-lasting effect on cortical SA, where some familial and environmental influences alter both foetal growth and brain morphology; ii) uniquely environmental factors affecting BW also alter SA; iii) higher IQ correlates with larger SA; and iv) these effects are not modified by internalizing psychopathology.This work was supported by the Spanish SAF2008-05674, European Twins Study Network on Schizophrenia Research Training Network (grant number EUTwinsS; MRTN-CT-2006-035987), the Catalan 2014SGR1636 and the PIM2010-ERN- 00642 in frame of ERA-NET NEURON. A. Córdova- Palomera was funded by The National Council for Science and Technology (CONACyT, Mexico). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Cardiovascular disease, risk factors and heart rate variability in the elderly general population: Design and objectives of the CARdiovascular disease, Living and Ageing in Halle (CARLA) Study

BACKGROUND: The increasing burden of cardiovascular diseases (CVD) in the ageing population of industrialized nations requires an intensive search for means of reducing this epidemic. In order to improve prevention, detection, therapy and prognosis of cardiovascular diseases on the population level in Eastern Germany, it is necessary to examine reasons for the East-West gradient of CVD morbidity and mortality, potential causal mechanisms and prognostic factors in the elderly. Psychosocial and nutritional factors have previously been discussed as possible causes for the unexplained part of the East-West gradient. A reduced heart rate variability appears to be associated with cardiovascular disease as well as with psychosocial and other cardiovascular risk factors and decreases with age. Nevertheless, there is a lack of population-based data to examine the role of heart rate variability and its interaction with psychosocial and nutritional factors regarding the effect on cardiovascular disease in the ageing population. There also is a paucity of epidemiological data describing the health situation in Eastern Germany. Therefore, we conduct a population-based study to examine the distribution of CVD, heart rate variability and CVD risk factors and their associations in an elderly East German population. This paper describes the design and objectives of the CARLA Study. METHODS/DESIGN: For this study, a random sample of 45–80 year-old inhabitants of the city of Halle (Saale) in Eastern Germany was drawn from the population registry. By the end of the baseline examination (2002–2005), 1750 study participants will have been examined. A multi-step recruitment strategy aims at achieving a 70 % response rate. Detailed information is collected on own and family medical history, socioeconomic, psychosocial, behavioural and biomedical factors. Medical examinations include anthropometric measures, blood pressure of arm and ankle, a 10-second and a 20-minute electrocardiogram, a general physical examination, an echocardiogram, and laboratory analyses of venous blood samples. On 200 participants, a 24-hour electrocardiogram is recorded. A detailed system of quality control ensures high data quality. A follow-up examination is planned. DISCUSSION: This study will help to elucidate pathways to CVD involving autonomic dysfunction and lifestyle factors which might be responsible for the CVD epidemic in some populations

Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty

Global ageing poses a substantial economic burden on health and social care costs. Enabling a greater proportion of older people to stay healthy for longer is key to the future sustainability of health, social and economic policy. Frailty and associated decrease in resilience plays a central role in poor health in later life. In this study, we present a population level assessment of the metabolic phenotype associated with frailty. Analysis of serum from 1191 older individuals (aged between 56 and 84 years old) and subsequent longitudinal validation (on 786 subjects) was carried out using liquid and gas chromatography-mass spectrometry metabolomics and stratified across a frailty index designed to quantitatively summarize vulnerability. Through multivariate regression and network modelling and mROC modeling we identified 12 significant metabolites (including three tocotrienols and six carnitines) that differentiate frail and non-frail phenotypes. Our study provides evidence that the dysregulation of carnitine shuttle and vitamin E pathways play a role in the risk of frailty

Heritability estimates for 361 blood metabolites across 40 genome-wide association studies

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2total), and the proportion of heritability captured by known metabolite loci (h2Metabolite-hits) for 309 lipids and 52 organic acids. Our study reveals significant differences in h2Metabolite-hits among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation have higher h2Metabolite-hits estimates than phosphatidylcholines with low degrees of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes