Gabi Kastenmüller

Gabi Kastenmüller
Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) | HZM · Institute of Bioinformatics and Systems Biology

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357
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Publications

Publications (357)
Article
Full-text available
Food intake triggers extensive changes in the blood metabolome. The kinetics of these changes depend on meal composition and on intrinsic, health-related characteristics of each individual, making the assessment of changes in the postprandial metabolome an opportunity to assess someone's metabolic status. To enable the usage of dietary challenges a...
Article
Full-text available
Introduction: Alzheimer's disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in the brain has been missing. Methods: We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correl...
Preprint
Metabolome reflects the interplay of genome and exposome at molecular level and thus can provide deep insights into the pathogenesis of a complex disease like major depression. To identify metabolites associated with depression we performed a metabolome-wide association analysis in 13,596 participants from five European population-based cohorts cha...
Article
Full-text available
In recent years, bile acids (BA) have received great interest due to their pleiotropic biological activity and the presence of plasma membrane-bound and nuclear receptors. Moreover, BA in blood have been identified by metabolite screening approaches as biomarkers that are associated with various diseases and even with a human longevity phenotype. W...
Article
Older adults experience a higher prevalence of multiple chronic conditions (MCCs). Establishing the presence and pattern of MCCs in individuals or populations is important for healthcare delivery, research, and policy. This report describes four emerging approaches and discusses their potential applications for enhancing assessment, treatment, and...
Article
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Genome-wide association studies (GWAS) with non-targeted metabolomics have identified many genetic loci of biomedical interest. However, metabolites with a high degree of missingness, such as drug metabolites and xenobiotics, are often excluded from such studies due to a lack of statistical power and higher uncertainty in their quantification. Here...
Article
Full-text available
Resistance training promotes metabolic health and stimulates muscle hypertrophy, but the precise routes by which resistance exercise (RE) conveys these health benefits are largely unknown. Aim: To investigate how acute RE affects human skeletal muscle metabolism. Methods: We collected vastus lateralis biopsies from six healthy male untrained vo...
Article
Background Altered metabolism of acylcarnitines – transporting fatty acids to mitochondria – may link cellular energy dysfunction to depression. We examined the potential causal role of acylcarnitine metabolism in depression by leveraging genomics and Mendelian randomization. Methods Summary statistics were obtained from large GWAS: the Fenland St...
Poster
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Dried blood spots (DBS) are an alternative sampling method to blood plasma sampling. In contrast to blood plasma sampling, DBS are low-volume capillary blood samples obtained via pricking and collection on paper cards. DBS require less space and no cooling which is advantageous for exercise tests in the field. The aim of this project was to compare...
Preprint
Experimental models shows that bioenergetic homeostasis changes with increasing age based on apolipoprotein E (APOE) gene. However, such link with dementia remains unclear in population. We used H1-NMR metabolome in blood from 118,021 random-selected participants in UK Biobank (n=118,021 individuals), and identified 56 metabolites associated with t...
Article
Background Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Neth...
Article
Full-text available
Depression constitutes a leading cause of disability worldwide. Despite extensive research on its interaction with psychobiological factors, associated pathways are far from being elucidated. Metabolomics, assessing the final products of complex biochemical reactions, has emerged as a valuable tool for exploring molecular pathways. We conducted a m...
Article
Alzheimer’s disease (AD) related neurodegeneration has been correlated with metabolic dysfunction. Sphingomyelins (SM), a class of lipids found in the cell membranes especially myelin sheath, have been shown to be disrupted in AD and in other neurodegenerative diseases. Ceramides, the simplest of the sphingolipids, are known to be associated with A...
Article
Increasing evidence suggests a role for gut microbiome in pathogenesis of neurological disorders including Alzheimer’s disease. Gut bacteria produce a large number of metabolites that become part of the human blood metabolome. We hypothesized that the effect of gut microbiome on Alzheimer’s disease is through certain metabolites derived or influenc...
Article
There is compelling evidence implying critical role of gut‐brain axis in neuropsychiatric diseases including Alzheimer’s disease (AD). Consequently, microbially‐derived metabolites, e.g., secondary bile acids, have been shown to be altered in blood, faecal and brain tissues of AD patients. The presence of these microbially‐derived products in brain...
Article
There is increasing interest in early metabolic changes in dementia, which may reflect the effects of genetic determinants of dementia, medical history and co‐morbidity, environmental risk factors, and aging. We studied the relation of blood‐based metabolites to the risk of dementia. The analyses are conducted in 121,389 participants of the UK Biob...
Article
Full-text available
The apolipoprotein E gene (APOE) genotype is the first and strongest genetic risk factor for late‐onset Alzheimer’s disease and has emerged as a novel therapeutic target for AD. The encoded protein (Apolipoprotein E, APOE) is well‐known to be involved in lipoprotein transport and metabolism, but its effect on lipid metabolic pathways and the potent...
Article
Background: Impairment of brain glucose metabolism has been frequently described in Alzheimer's disease (AD). Moreover, the strongest predictor of the lifetime incidence of AD is the ε4 allele of APOE, a protein involved in lipid metabolism. These connections between AD and metabolism provide motivation to perform an in-depth metabolic profiling o...
Article
Background: L-carnitine is present in the mammalian cells as free carnitine (FC) and acylcarnitine and the adult human brain contains almost 10% of long chain acylcarnitine. Acylcarnitines are functionally involved in β-oxidation of fatty acids and are also known for their role in neuroprotection. Levels of plasma acylcarnitines are known to decre...
Article
Background: Alzheimer's disease (AD) is a devastating neurodegenerative disorder for which there currently are no disease-modifying treatments available. To accelerate the path to effective intervention strategies, drug repositioning - the application of available compounds in a novel disease context - has gained increasing attention as a promisin...
Preprint
Full-text available
INTRODUCTION Alzheimer’s disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in brain has been missing. METHODS We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated wit...
Preprint
Full-text available
Resistance training promotes metabolic health and stimulates muscle hypertrophy, but the precise routes by which resistance exercise (RE) conveys these health benefits is largely unknown. Aim: To investigate how acute RE affects human skeletal muscle metabolism. Methods: We collected vastus lateralis biopsies from six healthy male untrained volunte...
Article
Full-text available
Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD‐specific met...
Article
Introduction In the era of personalized medicine with more and more patient specific targeted therapies being used, we need reliable, dynamic, faster, and sensitive biomarkers both to track the causes of disease and to develop and evolve therapies during the course of treatment. Metabolomics recently has shown substantial evidence to support its em...
Article
Detangling gene-disease connections Many diseases are at least partially due to genetic causes that are not always understood or targetable with specific treatments. To provide insight into the biology of various human diseases as well as potential leads for therapeutic development, Pietzner et al . undertook detailed, genome-wide proteogenomic map...
Preprint
Full-text available
INTRODUCTION: Embedding single-omics disease associations into the wider context of multi-level molecular changes in Alzheimer's disease (AD) remains one central challenge in AD research. METHODS: Results from numerous AD-specific omics studies from AMP-AD, NIAGADS, and other initiatives were integrated into a comprehensive network resource and com...
Preprint
Full-text available
We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species that are putatively in the mechanistic pathway to coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 phenotyped individuals from the Busselton Health Study. In our...
Preprint
Full-text available
Background: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Net...
Preprint
Full-text available
Dysregulation of sphingomyelin (SM) and ceramide metabolism have been implicated in Alzheimer’s Disease (AD). Genome-wide and transcriptome wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with AD. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to...
Article
Full-text available
Background Periodontitis is among the most common chronic diseases worldwide, and it is one of the main reasons for tooth loss. Comprehensive profiling of the metabolite content of the saliva can enable the identification of novel pathways associated with periodontitis and highlight non-invasive markers to facilitate time and cost-effective screeni...
Article
Full-text available
Metabolomics in the Alzheimer’s Disease Neuroimaging Initiative cohort provides a powerful tool for mapping biochemical changes in Alzheimer’s disease, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-β deposition in Alzheimer’s disease. We examined 140 serum metabolites and their assoc...
Article
Full-text available
Objective: Technological advances have brought a steady increase in the availability of various types of omics data, from genomics to metabolomics. Integrating these multi-omics data is a chance and challenge for systems biology; yet, tools to fully tap their potential remain scarce. Methods: We present here a fully unsupervised and versatile co...
Article
Full-text available
Human metabolism is highly variable. At one end of the spectrum, defects of enzymes, transporters, and metabolic regulation result in metabolic diseases such as diabetes mellitus or inborn errors of metabolism. At the other end of the spectrum, favorable genetics and years of training combine to result in physiologically extreme forms of metabolism...
Article
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Multimorbidity, the simultaneous presence of multiple chronic conditions, is an increasing global health problem and research into its determinants is of high priority. We used baseline untargeted plasma metabolomics profiling covering >1,000 metabolites as a comprehensive readout of human physiology to characterize pathways associated with and acr...
Article
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Biological exploration of early biomarkers for chronic kidney disease (CKD) in (pre)diabetic individuals is crucial for personalized management of diabetes. Here, we evaluated two candidate biomarkers of incident CKD (sphingomyelin (SM) C18:1 and phosphatidylcholine diacyl (PC aa) C38:0) concerning kidney function in hyperglycemic participants of t...
Article
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A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21370-6
Article
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In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10−10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insuli...
Article
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Recent advances in high-throughput technologies have enabled the profiling of multiple layers of a biological system, including DNA sequence data (genomics), RNA expression levels (transcriptomics), and metabolite levels (metabolomics). This has led to the generation of vast amounts of biological data that can be integrated in so-called multi-omics...
Article
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Shared metabolomic patterns at delivery have been suggested to underlie the mother-to-child transmission of adverse metabolic health. This study aimed to investigate whether mothers with gestational diabetes mellitus (GDM) and their offspring show similar metabolomic patterns several years postpartum. Targeted metabolomics (including 137 metabolite...
Article
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Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identif...
Article
Early and precise identification of individuals with prediabetes and type 2 diabetes (T2D) at risk for progressing to chronic kidney disease (CKD) is essential to prevent complications of diabetes. Here, we identify and evaluate prospective metabolite biomarkers and the best set of predictors of CKD in the longitudinal, population-based Cooperative...
Article
Accumulating evidence suggests that Alzheimer’s disease (AD) patients display metabolic dysfunction. Metabolomics is a powerful tool for studying metabolic pathways by mapping biochemical changes in AD, yet little is known about the association between circulating metabolites in blood and the “A/T/N” (amyloid‐β, tau, neurodegeneration) biomarkers f...
Article
The metabolic basis of Alzheimer’s Disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis remain elusive. In this study, we systematically interrogated metabolomics, genetics, proteomics, and clinical data from the matched subjects in the Alzheimer’s Disease Neuroimaging Initiative...
Article
Dysregulation of lipid metabolism is as an important – and modifiable – risk factor for the initiation and progression of Alzheimer’s disease (AD). Although lipid metabolism is established as crucial to numerous biological processes, the genetic factors that influence inter‐individual variation are still not well understood. To address this issue,...
Article
Alzheimer’s disease (AD) is an untreatable neurodegenerative disorder that represents a major global health burden. Large investments in the generation and analysis of increasing amounts of multi‐omics data have provided us with multi‐layered molecular imprints of pathogenic processes in AD. To identify the most promising targets for translating th...
Article
Full-text available
Metabolomics can be a tool to identify dietary biomarkers. However, reported food-metabolite associations have been inconsistent, and there is a need to explore further associations. Our aims were to confirm previously reported food-metabolite associations and to identify novel food-metabolite associations. We conducted a cross-sectional analysis o...
Article
Full-text available
Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of prima...
Article
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Least absolute shrinkage and selection operator (LASSO) regression is often applied to select the most promising set of single nucleotide polymorphisms (SNPs) associated with a molecular phenotype of interest. While the penalization parameter λ restricts the number of selected SNPs and the potential model overfitting, the least-squares loss functio...
Preprint
Full-text available
Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid "in...
Article
Full-text available
Late-onset Alzheimer’s disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum meta...
Article
Full-text available
Objective While metabolic dysfunction occurs in several pulmonary arterial hypertension (PAH) animal models, its role in the human hypertensive right ventricle (RV) and lung is not well characterised. We investigated whether circulating metabolite concentrations differ across the hypertensive RV and/or the pulmonary circulation, and correlate with...
Article
Full-text available
Background: Exercise changes the concentrations of many metabolites, which are small molecules (< 1.5 kDa) metabolized by the reactions of human metabolism. In recent years, especially mass spectrometry-based metabolomics methods have allowed researchers to measure up to hundreds of metabolites in a single sample in a non-biased fashion. To summar...
Article
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The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function....
Article
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Obesity is one of the major risk factor for cardiovascular and metabolic diseases. A disproportional accumulation of fat at visceral (VAT) compared to subcutaneous sites (SAT) has been suspected as a key detrimental event. We used non-targeted metabolomics profiling to reveal metabolic pathways associated with higher VAT or SAT amount among subject...
Preprint
The steadily increasing amount of newly generated omics data of various types from genomics to metabolomics is a chance and a challenge to systems biology. To fully use its potential, one key is the meaningful integration of different types of omics. We here present a fully unsupervised and versatile correlation-based method, termed Correlation gui...
Article
Full-text available
Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the reg...
Article
Full-text available
Alzheimer’s disease (AD) is the most common cause of dementia. The mechanism of disease development and progression is not well understood, but increasing evidence suggests multifactorial etiology, with a number of genetic, environmental, and aging-related factors. There is a growing body of evidence that metabolic defects may contribute to this co...
Preprint
Full-text available
Correlation networks are commonly used to statistically extract biological interactions between omics markers. Network edge selection is typically based on the significance of the underlying correlation coefficients. A statistical cutoff, however, is not guaranteed to capture biological reality, and heavily depends on dataset properties such as sam...
Article
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Background: In numerous studies based predominantly on rodent models, administration of 3,5-diiodo-L-thyronine (3,5-T2), a metabolite of the thyroid hormones (TH) thyroxine (T4) and triiodo-L-thyronine (T3), was reported to cause beneficial health effects, including reversal of steatohepatosis and prevention of insulin resistance, in most instances...