Georg Homuth - Academia.edu (original) (raw)

Papers by Georg Homuth

Research paper thumbnail of Genome-wide transcriptional profiling of the Bacillus subtilis cold-shock response

Microbiology (Reading, England), 2002

The transcriptome of Bacillus subtilis was analysed at different time points (30, 60 and 90 min) ... more The transcriptome of Bacillus subtilis was analysed at different time points (30, 60 and 90 min) after a temperature downshift from 37 to 18 degrees C using DNA macroarrays. This approach allowed the identification of around 50 genes exhibiting an increased mRNA level and around 50 genes exhibiting a decreased mRNA level under cold-shock conditions. Many of the repressed genes encode enzymes involved in the biosynthesis of amino acids, nucleotides and coenzymes, indicating metabolic adaptation of the cells to the decreased growth rate at the lower temperature. The strongest cold-inducible gene encodes fatty acid desaturase, which forms unsaturated fatty acids from saturated phospholipid precursors, thereby increasing membrane fluidity. The cold-shock-induced increase of mRNA levels of the classical cold-shock genes cspB, cspC and cspD could be verified. Furthermore, besides many genes encoding proteins of unknown function, some genes encoding ribosomal proteins were transcriptionall...

Research paper thumbnail of A thyroid hormone-independent molecular fingerprint of 3,5-diiodothyronine suggests a strong relation with coffee metabolism in humans

Thyroid

Background: In numerous studies based predominantly on rodent models, administration of 3,5-diiod... more 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 without adverse thyrotoxic side effects. However, the empirical evidence concerning the physiological relevance of endogenously produced 3,5-T2 in humans is comparatively poor. Therefore, to improve the understanding of 3,5-T2-related metabolic processes, we performed a comprehensive metabolomic study relating serum 3,5-T2 concentrations to plasma and urine metabolite levels within a large general population sample. Methods: Serum 3,5-T2 concentrations were determined for 856 participants of the population-based Study of Health in Pomerania-TREND (SHIP-TREND). Plasma and urine metabolome data were generated using mass spectrometry and nuclear magnetic resonance spectroscopy, allowing quantification of 613 and 578 metabolites in plasma and urine, respectively. To detect thyroid function-independent significant 3,5-T2-metabolite associations, linear regression analyses controlling for major confounders, including thyrotropin and free T4, were performed. The same analyses were carried out using a sample of 16 male healthy volunteers treated for 8 weeks with 250 lg/ day levothyroxine to induce thyrotoxicosis. Results: The specific molecular fingerprint of 3,5-T2 comprised 15 and 73 significantly associated metabolites in plasma and urine, respectively. Serum 3,5-T2 concentrations were neither associated with classical thyroid function parameters nor altered during experimental thyrotoxicosis. Strikingly, many metabolites related to coffee metabolism, including caffeine and paraxanthine, formed the clearest positively associated molecular signature. Importantly, these associations were replicated in the experimental human thyrotoxicosis model. Conclusion: The molecular fingerprint of 3,5-T2 demonstrates a clear and strong positive association of the serum levels of this TH metabolite with plasma levels of compounds indicating coffee consumption, therefore pointing to the liver as an organ, the metabolism of which is strongly affected by coffee. Furthermore, 3,5-T2 serum concentrations were found not to be directly TH dependent. Considering the beneficial health effects of 3,5-T2

Research paper thumbnail of ENIGMA and Global Neuroscience: A Decade of Large-Scale Studies of the Brain in Health and Disease across more than 40 Countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics thr... more This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics throughMeta Analysis) Consortium, a global alliance of over 1,400 scientists across 43 countries, studying the humanbrain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicatedgenetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), poolingworldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, andgenetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normalvariation due to sex and gender differences, or development and aging; still other WGs develop methodologicalpipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodalMRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studiesto date in schizop...

Research paper thumbnail of Interleukin 33 regulates Th2 T-cell differentiation and macrophage polarization during acute pancreatitis

Research paper thumbnail of Macrophage-derived cytokines of the IL1 family simultaneously regulate pro- and anti-inflammation during severe acute pancreatitis

Research paper thumbnail of Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

The American Journal of Human Genetics

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control b... more Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNAþ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p % 5EÀ04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p % 1EÀ03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p % 1EÀ06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis-and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

Research paper thumbnail of Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives

Scientific reports, Jan 26, 2017

Using oral contraceptives has been implicated in the aetiology of stress-related disorders like d... more Using oral contraceptives has been implicated in the aetiology of stress-related disorders like depression. Here, we followed the hypothesis that oral contraceptives deregulate the HPA-axis by elevating circulating cortisol levels. We report for a sample of 233 pre-menopausal women increased circulating cortisol levels in those using oral contraceptives. For women taking oral contraceptives, we observed alterations in circulating phospholipid levels and elevated triglycerides and found evidence for increased glucocorticoid signalling as the transcript levels of the glucocorticoid-regulated genes DDIT4 and FKBP5 were increased in whole blood. The effects were statistically mediated by cortisol. The associations of oral contraceptives with higher FKBP5 mRNA and altered phospholipid levels were modified by rs1360780, a genetic variance implicated in psychiatric diseases. Accordingly, the methylation pattern of FKBP5 intron 7 was altered in women taking oral contraceptives depending on ...

Research paper thumbnail of Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Nature communications, Oct 26, 2018

Thyroid dysfunction is an important public health problem, which affects 10% of the general popul... more Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge a...

Research paper thumbnail of Interplay between RGS2 and childhood adversities in predicting anxiety and depressive disorders: Findings from a general population sample

Research paper thumbnail of Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Nature communications, Sep 26, 2018

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a ... more The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

Research paper thumbnail of Functional abdominal pain and discomfort (IBS) is not associated with faecal microbiota composition in the general population

Research paper thumbnail of {"__content__"=>"Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.", "i"=>{"__content__"=>"MRPL38"}}

Stroke, Jan 12, 2018

White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cere... more White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating t...

Research paper thumbnail of Helicobacter pylori colonization and obesity - a Mendelian randomization study

Scientific reports, Jan 31, 2017

Obesity is associated with substantial morbidity, costs, and decreased life expectancy, and conti... more Obesity is associated with substantial morbidity, costs, and decreased life expectancy, and continues to rise worldwide. While etiological understanding is needed for prevention, epidemiological studies indicated that colonization with Helicobacter pylori (H. pylori) may affect body mass index (BMI), but with inconsistent results. Here, we examine the relationship between H. pylori colonization and BMI/obesity. Cross-sectional analyses were performed in two independent population-based cohorts of elderly from the Netherlands and Germany (n = 13,044). Genetic risk scores were conducted based on genetic loci associated with either H. pylori colonization or BMI/obesity. We performed a bi-directional Mendelian randomization. Meta-analysis of cross-sectional data revealed no association between anti-H. pylori IgG titer and BMI, nor of H. pylori positivity and BMI. Anti-H. pylori IgG titer was negatively associated with obesity (OR 0.99972; 95% CI 0.99946-0.99997, p = 0.03) and with obesi...

Research paper thumbnail of Meta-analysis of human genome-microbiome association studies: the MiBioGen consortium initiative

Microbiome, Jun 8, 2018

In recent years, human microbiota, especially gut microbiota, have emerged as an important yet co... more In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition s...

Research paper thumbnail of Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy

Nature communications, Jan 20, 2017

Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity ... more Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanis...

Research paper thumbnail of ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

Circulation. Genomic and precision medicine, 2018

QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricl... more QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement ...

Research paper thumbnail of Genome-wide gene-environment interaction in depression: A systematic evaluation of candidate genes: The childhood trauma working-group of PGC-MDD

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2018

Gene by environment (GxE) interaction studies have investigated the influence of a number of cand... more Gene by environment (GxE) interaction studies have investigated the influence of a number of candidate genes and variants for major depressive disorder (MDD) on the association between childhood trauma and MDD. Most of these studies are hypothesis driven and investigate only a limited number of SNPs in relevant pathways using differing methodological approaches. Here (1) we identified 27 genes and 268 SNPs previously associated with MDD or with GxE interaction in MDD and (2) analyzed their impact on GxE in MDD using a common approach in 3944 subjects of European ancestry from the Psychiatric Genomics Consortium who had completed the Childhood Trauma Questionnaire. (3) We subsequently used the genome-wide SNP data for a genome-wide case-control GxE model and GxE case-only analyses testing for an enrichment of associated SNPs. No genome-wide significant hits and no consistency among the signals of the different analytic approaches could be observed. This is the largest study for syste...

Research paper thumbnail of Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Circulation. Genomic and precision medicine, 2018

Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal h... more Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was...

Research paper thumbnail of Comprehensive Metabolic Profiling Reveals a Lipid-Rich Fingerprint of Free Thyroxine Far Beyond Classic Parameters

The Journal of clinical endocrinology and metabolism, May 1, 2018

Thyroid hormones are ubiquitously involved in human metabolism. However, the precise molecular pa... more Thyroid hormones are ubiquitously involved in human metabolism. However, the precise molecular patterns associated with alterations in thyroid hormones levels remain to be explored in detail. A number of recent studies took great advantage of metabolomics profiling to outline the metabolic actions of thyroid hormones in humans. Among 952 participants in the Study of Health in Pomerania, data on serum free thyroxine (FT4) and thyrotropin and comprehensive nontargeted metabolomics data from plasma and urine samples were available. Linear regression analyses were performed to assess the association between FT4 or thyrotropin and metabolite levels. After accounting for major confounders, 106 of 613 plasma metabolites were significantly associated with FT4. The associations in urine were minor (12 of 587). Most of the plasma metabolites consisted of lipid species, and subsequent analysis of highly resolved lipoprotein subclasses measured by proton nuclear magnetic resonance spectroscopy ...

Research paper thumbnail of Interplay between COMT Val158Met, childhood adversities and sex in predicting panic pathology: Findings from a general population sample

Journal of affective disorders, Jul 1, 2018

The single nucleotide polymorphism rs4680 of the catechol-O-methyltransferase (COMT) gene has bee... more The single nucleotide polymorphism rs4680 of the catechol-O-methyltransferase (COMT) gene has been implicated to be involved in the etiopathogenesis of panic. However, it remains unresolved whether rs4680 modifies the risk-association between early life stress and subsequent development of panic pathology. The genotype of rs4680 was determined for n = 2242 adults with European ancestry from the Study of Health in Pomerania (SHIP, a regional longitudinal cohort study from northeastern Germany). Lifetime fearful spells, panic attacks and panic disorder were assessed according to DSM-IV in 2007-2010 (when participants were aged 29-89) using the Munich Composite International Diagnostic Interview (DIA-X/M-CIDI). Childhood adversities were assessed with the Childhood Trauma Questionnaire (CTQ). Logistic regressions with interaction terms (adjusted for sex and age) revealed that rs4680 interacted with total childhood adversity, emotional abuse and physical abuse in predicting panic disord...

Research paper thumbnail of Genome-wide transcriptional profiling of the Bacillus subtilis cold-shock response

Microbiology (Reading, England), 2002

The transcriptome of Bacillus subtilis was analysed at different time points (30, 60 and 90 min) ... more The transcriptome of Bacillus subtilis was analysed at different time points (30, 60 and 90 min) after a temperature downshift from 37 to 18 degrees C using DNA macroarrays. This approach allowed the identification of around 50 genes exhibiting an increased mRNA level and around 50 genes exhibiting a decreased mRNA level under cold-shock conditions. Many of the repressed genes encode enzymes involved in the biosynthesis of amino acids, nucleotides and coenzymes, indicating metabolic adaptation of the cells to the decreased growth rate at the lower temperature. The strongest cold-inducible gene encodes fatty acid desaturase, which forms unsaturated fatty acids from saturated phospholipid precursors, thereby increasing membrane fluidity. The cold-shock-induced increase of mRNA levels of the classical cold-shock genes cspB, cspC and cspD could be verified. Furthermore, besides many genes encoding proteins of unknown function, some genes encoding ribosomal proteins were transcriptionall...

Research paper thumbnail of A thyroid hormone-independent molecular fingerprint of 3,5-diiodothyronine suggests a strong relation with coffee metabolism in humans

Thyroid

Background: In numerous studies based predominantly on rodent models, administration of 3,5-diiod... more 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 without adverse thyrotoxic side effects. However, the empirical evidence concerning the physiological relevance of endogenously produced 3,5-T2 in humans is comparatively poor. Therefore, to improve the understanding of 3,5-T2-related metabolic processes, we performed a comprehensive metabolomic study relating serum 3,5-T2 concentrations to plasma and urine metabolite levels within a large general population sample. Methods: Serum 3,5-T2 concentrations were determined for 856 participants of the population-based Study of Health in Pomerania-TREND (SHIP-TREND). Plasma and urine metabolome data were generated using mass spectrometry and nuclear magnetic resonance spectroscopy, allowing quantification of 613 and 578 metabolites in plasma and urine, respectively. To detect thyroid function-independent significant 3,5-T2-metabolite associations, linear regression analyses controlling for major confounders, including thyrotropin and free T4, were performed. The same analyses were carried out using a sample of 16 male healthy volunteers treated for 8 weeks with 250 lg/ day levothyroxine to induce thyrotoxicosis. Results: The specific molecular fingerprint of 3,5-T2 comprised 15 and 73 significantly associated metabolites in plasma and urine, respectively. Serum 3,5-T2 concentrations were neither associated with classical thyroid function parameters nor altered during experimental thyrotoxicosis. Strikingly, many metabolites related to coffee metabolism, including caffeine and paraxanthine, formed the clearest positively associated molecular signature. Importantly, these associations were replicated in the experimental human thyrotoxicosis model. Conclusion: The molecular fingerprint of 3,5-T2 demonstrates a clear and strong positive association of the serum levels of this TH metabolite with plasma levels of compounds indicating coffee consumption, therefore pointing to the liver as an organ, the metabolism of which is strongly affected by coffee. Furthermore, 3,5-T2 serum concentrations were found not to be directly TH dependent. Considering the beneficial health effects of 3,5-T2

Research paper thumbnail of ENIGMA and Global Neuroscience: A Decade of Large-Scale Studies of the Brain in Health and Disease across more than 40 Countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics thr... more This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics throughMeta Analysis) Consortium, a global alliance of over 1,400 scientists across 43 countries, studying the humanbrain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicatedgenetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), poolingworldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, andgenetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normalvariation due to sex and gender differences, or development and aging; still other WGs develop methodologicalpipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodalMRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studiesto date in schizop...

Research paper thumbnail of Interleukin 33 regulates Th2 T-cell differentiation and macrophage polarization during acute pancreatitis

Research paper thumbnail of Macrophage-derived cytokines of the IL1 family simultaneously regulate pro- and anti-inflammation during severe acute pancreatitis

Research paper thumbnail of Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

The American Journal of Human Genetics

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control b... more Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNAþ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p % 5EÀ04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p % 1EÀ03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p % 1EÀ06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis-and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

Research paper thumbnail of Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives

Scientific reports, Jan 26, 2017

Using oral contraceptives has been implicated in the aetiology of stress-related disorders like d... more Using oral contraceptives has been implicated in the aetiology of stress-related disorders like depression. Here, we followed the hypothesis that oral contraceptives deregulate the HPA-axis by elevating circulating cortisol levels. We report for a sample of 233 pre-menopausal women increased circulating cortisol levels in those using oral contraceptives. For women taking oral contraceptives, we observed alterations in circulating phospholipid levels and elevated triglycerides and found evidence for increased glucocorticoid signalling as the transcript levels of the glucocorticoid-regulated genes DDIT4 and FKBP5 were increased in whole blood. The effects were statistically mediated by cortisol. The associations of oral contraceptives with higher FKBP5 mRNA and altered phospholipid levels were modified by rs1360780, a genetic variance implicated in psychiatric diseases. Accordingly, the methylation pattern of FKBP5 intron 7 was altered in women taking oral contraceptives depending on ...

Research paper thumbnail of Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Nature communications, Oct 26, 2018

Thyroid dysfunction is an important public health problem, which affects 10% of the general popul... more Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge a...

Research paper thumbnail of Interplay between RGS2 and childhood adversities in predicting anxiety and depressive disorders: Findings from a general population sample

Research paper thumbnail of Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Nature communications, Sep 26, 2018

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a ... more The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

Research paper thumbnail of Functional abdominal pain and discomfort (IBS) is not associated with faecal microbiota composition in the general population

Research paper thumbnail of {"__content__"=>"Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.", "i"=>{"__content__"=>"MRPL38"}}

Stroke, Jan 12, 2018

White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cere... more White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating t...

Research paper thumbnail of Helicobacter pylori colonization and obesity - a Mendelian randomization study

Scientific reports, Jan 31, 2017

Obesity is associated with substantial morbidity, costs, and decreased life expectancy, and conti... more Obesity is associated with substantial morbidity, costs, and decreased life expectancy, and continues to rise worldwide. While etiological understanding is needed for prevention, epidemiological studies indicated that colonization with Helicobacter pylori (H. pylori) may affect body mass index (BMI), but with inconsistent results. Here, we examine the relationship between H. pylori colonization and BMI/obesity. Cross-sectional analyses were performed in two independent population-based cohorts of elderly from the Netherlands and Germany (n = 13,044). Genetic risk scores were conducted based on genetic loci associated with either H. pylori colonization or BMI/obesity. We performed a bi-directional Mendelian randomization. Meta-analysis of cross-sectional data revealed no association between anti-H. pylori IgG titer and BMI, nor of H. pylori positivity and BMI. Anti-H. pylori IgG titer was negatively associated with obesity (OR 0.99972; 95% CI 0.99946-0.99997, p = 0.03) and with obesi...

Research paper thumbnail of Meta-analysis of human genome-microbiome association studies: the MiBioGen consortium initiative

Microbiome, Jun 8, 2018

In recent years, human microbiota, especially gut microbiota, have emerged as an important yet co... more In recent years, human microbiota, especially gut microbiota, have emerged as an important yet complex trait influencing human metabolism, immunology, and diseases. Many studies are investigating the forces underlying the observed variation, including the human genetic variants that shape human microbiota. Several preliminary genome-wide association studies (GWAS) have been completed, but more are necessary to achieve a fuller picture. Here, we announce the MiBioGen consortium initiative, which has assembled 18 population-level cohorts and some 19,000 participants. Its aim is to generate new knowledge for the rapidly developing field of microbiota research. Each cohort has surveyed the gut microbiome via 16S rRNA sequencing and genotyped their participants with full-genome SNP arrays. We have standardized the analytical pipelines for both the microbiota phenotypes and genotypes, and all the data have been processed using identical approaches. Our analysis of microbiome composition s...

Research paper thumbnail of Genome-wide association study identifies the SERPINB gene cluster as a susceptibility locus for food allergy

Nature communications, Jan 20, 2017

Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity ... more Genetic factors and mechanisms underlying food allergy are largely unknown. Due to heterogeneity of symptoms a reliable diagnosis is often difficult to make. Here, we report a genome-wide association study on food allergy diagnosed by oral food challenge in 497 cases and 2387 controls. We identify five loci at genome-wide significance, the clade B serpin (SERPINB) gene cluster at 18q21.3, the cytokine gene cluster at 5q31.1, the filaggrin gene, the C11orf30/LRRC32 locus, and the human leukocyte antigen (HLA) region. Stratifying the results for the causative food demonstrates that association of the HLA locus is peanut allergy-specific whereas the other four loci increase the risk for any food allergy. Variants in the SERPINB gene cluster are associated with SERPINB10 expression in leukocytes. Moreover, SERPINB genes are highly expressed in the esophagus. All identified loci are involved in immunological regulation or epithelial barrier function, emphasizing the role of both mechanis...

Research paper thumbnail of ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals

Circulation. Genomic and precision medicine, 2018

QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricl... more QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement ...

Research paper thumbnail of Genome-wide gene-environment interaction in depression: A systematic evaluation of candidate genes: The childhood trauma working-group of PGC-MDD

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2018

Gene by environment (GxE) interaction studies have investigated the influence of a number of cand... more Gene by environment (GxE) interaction studies have investigated the influence of a number of candidate genes and variants for major depressive disorder (MDD) on the association between childhood trauma and MDD. Most of these studies are hypothesis driven and investigate only a limited number of SNPs in relevant pathways using differing methodological approaches. Here (1) we identified 27 genes and 268 SNPs previously associated with MDD or with GxE interaction in MDD and (2) analyzed their impact on GxE in MDD using a common approach in 3944 subjects of European ancestry from the Psychiatric Genomics Consortium who had completed the Childhood Trauma Questionnaire. (3) We subsequently used the genome-wide SNP data for a genome-wide case-control GxE model and GxE case-only analyses testing for an enrichment of associated SNPs. No genome-wide significant hits and no consistency among the signals of the different analytic approaches could be observed. This is the largest study for syste...

Research paper thumbnail of Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Circulation. Genomic and precision medicine, 2018

Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal h... more Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was...

Research paper thumbnail of Comprehensive Metabolic Profiling Reveals a Lipid-Rich Fingerprint of Free Thyroxine Far Beyond Classic Parameters

The Journal of clinical endocrinology and metabolism, May 1, 2018

Thyroid hormones are ubiquitously involved in human metabolism. However, the precise molecular pa... more Thyroid hormones are ubiquitously involved in human metabolism. However, the precise molecular patterns associated with alterations in thyroid hormones levels remain to be explored in detail. A number of recent studies took great advantage of metabolomics profiling to outline the metabolic actions of thyroid hormones in humans. Among 952 participants in the Study of Health in Pomerania, data on serum free thyroxine (FT4) and thyrotropin and comprehensive nontargeted metabolomics data from plasma and urine samples were available. Linear regression analyses were performed to assess the association between FT4 or thyrotropin and metabolite levels. After accounting for major confounders, 106 of 613 plasma metabolites were significantly associated with FT4. The associations in urine were minor (12 of 587). Most of the plasma metabolites consisted of lipid species, and subsequent analysis of highly resolved lipoprotein subclasses measured by proton nuclear magnetic resonance spectroscopy ...

Research paper thumbnail of Interplay between COMT Val158Met, childhood adversities and sex in predicting panic pathology: Findings from a general population sample

Journal of affective disorders, Jul 1, 2018

The single nucleotide polymorphism rs4680 of the catechol-O-methyltransferase (COMT) gene has bee... more The single nucleotide polymorphism rs4680 of the catechol-O-methyltransferase (COMT) gene has been implicated to be involved in the etiopathogenesis of panic. However, it remains unresolved whether rs4680 modifies the risk-association between early life stress and subsequent development of panic pathology. The genotype of rs4680 was determined for n = 2242 adults with European ancestry from the Study of Health in Pomerania (SHIP, a regional longitudinal cohort study from northeastern Germany). Lifetime fearful spells, panic attacks and panic disorder were assessed according to DSM-IV in 2007-2010 (when participants were aged 29-89) using the Munich Composite International Diagnostic Interview (DIA-X/M-CIDI). Childhood adversities were assessed with the Childhood Trauma Questionnaire (CTQ). Logistic regressions with interaction terms (adjusted for sex and age) revealed that rs4680 interacted with total childhood adversity, emotional abuse and physical abuse in predicting panic disord...