Showing papers by "Henry Völzke published in 2015"

Common genetic variants influence human subcortical brain structures.

Abstract: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Abstract: Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

The transcriptional landscape of age in human peripheral blood

Abstract: Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

Abstract: Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Metabolic syndrome across Europe: Different clusters of risk factors

Abstract: Background: Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se - are associated with accelerated arterial ageing and with cardiovascular (CV) events. To investigate whether the distribution of clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and one cohort from the USA in the MARE (Metabolic syndrome and Arteries REsearch) Consortium. Methods: In accordance with the ATP III criteria, MetS was defined as an alteration three or more of the following five components: elevated glucose (G), fasting glucose >= 110 mg/dl; low HDL cholesterol, = 150 mg/dl; elevated blood pressure (B), >= 130/ >= 85 mmHg; abdominal obesity (W), waist circumference >102 cm for men or >88 cm for women. Results: MetS had a 24.3% prevalence (8468 subjects: 23.9% in men vs. 24.6% in women, p < 0.001) with an age-associated increase in its prevalence in all the cohorts. The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p < 0.0001) and in men and women (p < 0.0001). In details, the cluster TBW was observed in 12% of the subjects with MetS, but was far more common in the cohorts from the UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and the USA (2.5%). The cluster GBW accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal: 31.4, 18.4, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania: 7.6, 9.4, and 9.6% respectively). Conclusions: The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries. (Less)

Whole-Body MR Imaging in the German National Cohort: Rationale, Design, and Technical Background.

Abstract: To identify and establish novel imaging-based biomarkers of risk, the German National Cohort MR imaging study is designed as a prospective cohort study that will enroll 30 000 participants and will apply a highly standardized study set with respect to technical equipment, quality management, and algorithms for the management of incidental findings.

Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis.

Abstract: Objective: The objective was to determine the risk of stroke associated with subclinical hypothyroidism. Data Sources and Study Selection: Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data on thyroid function and stroke outcome. Euthyroidism was defined as TSH levels of 0.45–4.49 mIU/L, and subclinical hypothyroidism was defined as TSH levels of 4.5–19.9 mIU/L with normal T4 levels. Data Extraction and Synthesis: We collected individual participant data on 47 573 adults (3451 subclinical hypothyroidism) from 17 cohorts and followed up from 1972–2014 (489 192 person-years). Age- and sex-adjusted pooled hazard ratios (HRs) for participants with subclinical hypothyroidism compared to euthyroidism were 1.05 (95% confidence interval [CI], 0.91–1.21) for stroke events (combined fatal and nonfatal st...

Pancreatic Steatosis Demonstrated at MR Imaging in the General Population: Clinical Relevance

Abstract: High pancreatic fat content is related to older age, greater body mass index, and lower serum lipase activity but not to the endocrine function of the gland.

Diagnosed thyroid disorders are associated with depression and anxiety.

Abstract: Associations between thyroid diseases and depression have been described since the 1960s but there is a lack of population-based studies investigating associations of thyroid diseases with depression and anxiety defined by gold-standard methods. Thus, the aim was to investigate the association of diagnosed thyroid disorders, serum thyroid-stimulating hormone (TSH) levels, and anti-thyroid-peroxidase antibodies (TPO-abs) with depression and anxiety. We used data from 2142 individuals, who participated in the first follow-up of the Study of Health in Pomerania (SHIP-1) and in the Life-Events and Gene-Environment Interaction in Depression (LEGEND). DSM-VI diagnoses of major depression disorder and anxiety were defined using the Munich-Composite International Diagnostic Interview; the Beck depression inventory (BDI-II) was used for the assessment of current depressive symptoms. Thyroid diseases were assessed by interviews and by biomarkers and were associated with depression and anxiety using Poisson regression adjusted for age, sex, marital status, educational level, smoking status, BMI, and the log-transformed time between SHIP-1 and LEGEND. Untreated diagnosed hypothyroidism was positively associated with the BDI-II-score and with anxiety, while untreated diagnosed hyperthyroidism was significantly related to MDD during the last 12 months. Serum TSH levels and TPO-Abs were not significantly associated with depression and anxiety. In sub-analyses, distinct interactions were found between childhood maltreatment and thyroid disorders in modifying the association on depression and anxiety disorders. Our results substantiate evidence that diagnosed untreated hypothyroidism is associated with depression and anxiety, and that diagnosed untreated hyperthyroidism is associated with depression.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study

Abstract: Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality.

Abstract: Genome-wide association studies with metabolic traits (mGWAS) uncovered many genetic variants that influence human metabolism. These genetically influenced metabotypes (GIMs) contribute to our metabolic individuality, our capacity to respond to environmental challenges, and our susceptibility to specific diseases. While metabolic homeostasis in blood is a well investigated topic in large mGWAS with over 150 known loci, metabolic detoxification through urinary excretion has only been addressed by few small mGWAS with only 11 associated loci so far. Here we report the largest mGWAS to date, combining targeted and non-targeted 1H NMR analysis of urine samples from 3,861 participants of the SHIP-0 cohort and 1,691 subjects of the KORA F4 cohort. We identified and replicated 22 loci with significant associations with urinary traits, 15 of which are new (HIBCH, CPS1, AGXT, XYLB, TKT, ETNPPL, SLC6A19, DMGDH, SLC36A2, GLDC, SLC6A13, ACSM3, SLC5A11, PNMT, SLC13A3). Two-thirds of the urinary loci also have a metabolite association in blood. For all but one of the 6 loci where significant associations target the same metabolite in blood and urine, the genetic effects have the same direction in both fluids. In contrast, for the SLC5A11 locus, we found increased levels of myo-inositol in urine whereas mGWAS in blood reported decreased levels for the same genetic variant. This might indicate less effective re-absorption of myo-inositol in the kidneys of carriers. In summary, our study more than doubles the number of known loci that influence urinary phenotypes. It thus allows novel insights into the relationship between blood homeostasis and its regulation through excretion. The newly discovered loci also include variants previously linked to chronic kidney disease (CPS1, SLC6A13), pulmonary hypertension (CPS1), and ischemic stroke (XYLB). By establishing connections from gene to disease via metabolic traits our results provide novel hypotheses about molecular mechanisms involved in the etiology of diseases.

Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects, and an increased risk for chronic pancreatitis: a genetic association study

Abstract: Objective Serum lipase activities above the threefold upper reference limit indicate acute pancreatitis. We investigated whether high lipase activity—within the reference range and in the absence of pancreatitis—are associated with genetic single nucleotide polymorphisms (SNP), and whether these identified SNPs are also associated with clinical pancreatitis. Methods Genome-wide association studies (GWAS) on phenotypes ‘serum lipase activity’ and ‘high serum lipase activity’ were conducted including 3966 German volunteers from the population-based Study-of-Health-in-Pomerania (SHIP). Lead SNPs associated on a genome-wide significance level were replicated in two cohorts, 1444 blood donors and 1042 pancreatitis patients. Results Initial discovery GWAS detected SNPs within or near genes encoding the ABO blood group specifying transferases A/B ( ABO ), Fucosyltransferase-2 ( FUT2 ), and Chymotrypsinogen-B2 ( CTRB2 ), to be significantly associated with lipase activity levels in asymptomatic subjects. Replication analyses in blood donors confirmed the association of FUT-2 non-secretor status (OR=1.49; p=0.012) and ABO blood-type-B (OR=2.48; p=7.29×10 −8 ) with high lipase activity levels. In pancreatitis patients, significant associations were found for FUT-2 non-secretor status (OR=1.53; p=8.56×10 −4 ) and ABO -B (OR=1.69, p=1.0×10 −4 ) with chronic pancreatitis, but not with acute pancreatitis. Conversely, carriers of blood group O were less frequently affected by chronic pancreatitis (OR=0.62; p=1.22×10 −05) and less likely to have high lipase activity levels (OR=0.59; p=8.14×10 −05 ). Conclusions These are the first results indicating that ABO blood type-B as well as FUT2 non-secretor status are common population-wide risk factors for developing chronic pancreatitis. They also imply that, even within the reference range, elevated lipase activities may indicate subclinical pancreatic injury in asymptomatic subjects.

Methodology used in studies reporting chronic kidney disease prevalence : a systematic literature review

Abstract: Background. Many publications report the prevalence of chronic kidney disease (CKD) in the general population. Comparisons across studies are hampered as CKD prevalence estimations are influenced b ...

Carotid Intima Media Thickness Progression and Risk of Vascular Events in People With Diabetes: Results From the PROG-IMT Collaboration

Abstract: OBJECTIVECarotid intima-media thickness (CIMT) is a marker of subclinical organ damage and predicts cardiovascular disease (CVD) events in the general population. It has also been associated with vascular risk in people with diabetes. However, the association of CIMT change in repeated examinations with subsequent CVD events is uncertain, and its use as a surrogate end point in clinical trials is controversial. We aimed at determining the relation of CIMT change to CVD events in people with diabetes.RESEARCH DESIGN AND METHODSIn a comprehensive meta-analysis of individual participant data, we collated data from 3,902 adults (age 33-92 years) with type 2 diabetes from 21 population-based cohorts. We calculated the hazard ratio (HR) per standard deviation (SD) difference in mean common carotid artery intima-media thickness (CCA-IMT) or in CCA-IMT progression, both calculated from two examinations on average 3.6 years apart, for each cohort, and combined the estimates with random-effects meta-analysis.RESULTSAverage mean CCA-IMT ranged from 0.72 to 0.97 mm across cohorts in people with diabetes. The HR of CVD events was 1.22 (95% CI 1.12-1.33) per SD difference in mean CCA-IMT, after adjustment for age, sex, and cardiometabolic risk factors. Average mean CCA-IMT progression in people with diabetes ranged between -0.09 and 0.04 mm/year. The HR per SD difference in mean CCA-IMT progression was 0.99 (0.91-1.08).CONCLUSIONSDespite reproducing the association between CIMT level and vascular risk in subjects with diabetes, we did not find an association between CIMT change and vascular risk. These results do not support the use of CIMT progression as a surrogate end point in clinical trials in people with diabetes.

Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts.

Abstract: Importance Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD). Objective To assess the association between differences in thyroid function within the reference range and CHD risk. Design, Setting, and Participants Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55 412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline. Exposures Thyroid function as expressed by serum thyrotropin levels at baseline. Main Outcomes and Measures Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status. Results Among 55 412 individuals, 1813 people (3.3%) died of CHD during 643 183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48 875 individuals (9.5%) experienced a first-time CHD event during 533 408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results. Conclusions and Relevance Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.

The association between lower educational attainment and depression owing to shared genetic effects? Results in ~25,000 subjects.

Abstract: An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14,949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15,138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884,105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on ~120,000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status.

Pre‐diabetes and well‐controlled diabetes are not associated with periodontal disease: the SHIP Trend Study

Abstract: Aim To examine associations of pre-diabetes and well-controlled diabetes with periodontitis. Materials and Methods The Study of Health in Pomerania (SHIP)-Trend is a cross-sectional survey in North-Eastern Germany including 3086 participants (49.4% men; age 20–82 years). Clinical attachment loss (CAL) and periodontal probing depth (PPD) were assessed applying a random half-mouth protocol. The number of teeth was determined. Pre-diabetes comprised impaired fasting glucose and impaired glucose tolerance. Previously known diabetes was defined as well controlled if glycated haemoglobin (HbA1c) was <7.0%. Participants were categorized as follows: normal glucose tolerance (NGT), pre-diabetes, newly detected type 2 diabetes (T2DM), known T2DM with HbA1c<7.0% and known T2DM with HbA1c≥7.0%. Results Pre-diabetes was neither associated with mean CAL and PPD in multivariable adjusted linear regression models nor with edentulism (OR = 1.09 (95%-CI: 0.69-1.71)) and number of teeth (OR = 0.96 (95%-CI: 0.75–1.22), lowest quartile versus higher quartiles) in logistic regression models. Associations with mean CAL and edentulism were stronger in poorly controlled previously known diabetes than in well-controlled previously known diabetes (for edentulism: OR = 2.19 (95%-CI: 1.18–4.05), and OR = 1.40 (95%-CI: 0.82–2.38), respectively, for comparison with NGT). Conclusions Periodontitis and edentulism were associated with poorly controlled T2DM, but not with pre-diabetes and well-controlled diabetes.

Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure.

Abstract: In two large genome-wide association studies, an intergenic single-nucleotide polymorphism (SNP; rs7294919) involved in TESC gene regulation has been associated with hippocampus volume. Further characterization of neurobiological effects of the TESC gene is warranted using multimodal brain-wide structural and functional imaging. Voxel-based morphometry (VBM8) was used in two large, well-characterized samples of healthy individuals of West-European ancestry (Munster sample, N=503; SHIP-TREND, N=721) to analyze associations between rs7294919 and local gray matter volume. In subsamples, white matter fiber structure was investigated using diffusion tensor imaging (DTI) and limbic responsiveness was measured by means of functional magnetic resonance imaging (fMRI) during facial emotion processing (N=220 and N=264, respectively). Furthermore, gene x environment (G × E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF-α, BDNF and 5-HTTLPR/rs25531) were explored. We demonstrated highly significant effects of rs7294919 on hippocampal gray matter volumes in both samples. In whole-brain analyses, no other brain areas except the hippocampal formation and adjacent temporal structures were associated with rs7294919. There were no genotype effects on DTI and fMRI results, including functional connectivity measures. No G × E interaction with childhood maltreatment was found in both samples. However, an interaction between rs7294919 and rs2299403 in the Reelin gene was found that withstood correction for multiple comparisons. We conclude that rs7294919 exerts highly robust and regionally specific effects on hippocampal gray matter structures, but not on other neuropsychiatrically relevant imaging markers. The biological interaction between TESC and RELN pointing to a neurodevelopmental origin of the observed findings warrants further mechanistic investigations.

Prevalence trends in lifestyle-related risk factors.

Abstract: The disease burden in the German population shows considerable regional variation (1). After the reunification of Germany it was found that life expectancy was substantially lower in the east than in the west. Moreover, there were geographical differences within the old East Germany, with the lowest life expectancy in the northeast (2). Against this backdrop, a research center for community medicine was set up at the University of Greifswald in the mid-1990s (3). The population project Study of Health in Pomerania (SHIP) investigates to what extent the high mortality in the northeastern German population can be explained by the risk-factor profile in that part of the country. The SHIP investigators did indeed find a pronounced cardiometabolic risk factor and disease burden in the region. The following risk factors and diseases were higher than in any other part of Germany and occupied alarmingly high positions in international comparisons (4– 10): Alcohol consumption Obesity Metabolic syndrome Diabetes mellitus Arterial hypertension Gallstone disease Social trends in recent years can be expected to impact on age- and sex-specific prevalence of risk factors and diseases in northeastern Germany. Unemployment has gone down and medical care structures have been improved (11). At the federal level, laws to protect non-smokers have been enacted and taxes on tobacco have been raised. Furthermore, various programs are promoting increased physical exercise, healthy nutrition, and reduction of other behaviors that are deleterious to health (12). It would be interesting to discover to what extent these developments have affected the prevalence of common risk factors and diseases in northeastern Germany. Following analysis of the data from a first population sample between 1997 and 2001 (SHIP-0), a second, independent sample of the population of West Pomerania (SHIP-Trend) was investigated a decade later. One of the central goals of SHIP-Trend was to identify the trends in prevalence of common risk factors and diseases in northeastern Germany. This article focuses both on harmful behaviors such as smoking, alcohol consumption, and physical inactivity and on obesity and diabetes mellitus.

The combined effects of alcohol consumption and body mass index on hepatic steatosis in a general population sample of European men and women

Abstract: SummaryBackground Research on the association between alcohol consumption and hepatic steatosis revealed conflictive results. Aim To investigate the associations between average daily alcohol consumption and binge drinking with hepatic steatosis, and to analyse combined effects of average daily alcohol consumption and binge drinking with body mass index (BMI) on hepatic steatosis. Methods Data from the population-based Study of Health in Pomerania (SHIP) conducted in north-east Germany comprising 4009 adults were used. Alcohol consumption was assessed by self-report. Serum carbohydrate-deficient transferrin (CDT) was analysed as biomarker for alcohol consumption. Hepatic steatosis was diagnosed by ultrasonography. Results Analyses revealed a dose–response relationship between average daily alcohol consumption and hepatic steatosis in men starting with a consumption of 20 g of alcohol per day [adjusted odds ratio (OR) compared to abstainers 1.53; 95% confidence interval (CI) 1.15–2.05]. Using CDT as alternative exposure variable confirmed these results. Binge drinking was associated with hepatic steatosis in men (adjusted OR of binge drinkers compared to nonbinge drinkers 1.36, 95% CI 1.06–1.74). The likelihood of having hepatic steatosis increased in men and women with increasing levels of average daily alcohol consumption in combination with overweight or obesity. Similarly, binge drinking in combination with overweight or obesity enhanced the likelihood of having hepatic steatosis. Conclusions Overweight or obesity substantially enhanced the effect of high levels of average daily alcohol consumption and binge drinking on hepatic steatosis in the present study population. This finding underlines the necessity to screen for multiple risk factors in the prevention of hepatic steatosis.

Shift of the TSH reference range with improved iodine supply in Northeast Germany

Abstract: Objective: Germany was iodine deficient until the mid-1990s when a nationwide iodine fortification program became effective. It is expected that after a longer period of sufficient iodine supply, median TSH values in the general population will shift to the right. Hence, the previous TSH reference range does not reflect the current TSH distribution in the general population of Germany. Thus, we aimed to establish a new reference range for serum TSH levels. Design and methods: We used data from the Study of Health in Pomerania TREND, a population-based study including 4420 individuals. The reference population consisted of 1596 individuals without diagnosed thyroid diseases or thyroid-related findings in ultrasound and serum analysis. Serum TSH levels were measured by an immunochemiluminescent procedure on a Siemens Dimension Vista. Results: The overall reference range for TSH was 0.49 mIU/l (95% CIZ0.44; 0.53)–3.29 mIU/l (95% CIZ3.08; 3.50). The lower reference limit differed significantly by sex, whereas the upper reference limit showed no significant difference between males and females. Age was significantly associated with the 2.5th TSH percentile in males but not in females, whereas age was significantly associated in males and females for the 97.5th TSH percentile. Conclusions: We demonstrate a shift toward the right of the TSH reference range in comparison with data from the same study region 10 years earlier, which is likely due to the improved iodine supply of the study region. Our study indicates that TSH reference limits are dependent on past and current iodine supply of populations.

Endogenous Androgens and Sex Hormone-Binding Globulin in Women and Risk of Metabolic Syndrome and Type 2 Diabetes.

Abstract: Context and Objectives: The association of endogenous androgens and sex hormone–binding globulin (SHBG) with metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) mostly 23562 refers to small and selected study samples with immunoassay-based measurements. Thus, we investigated the association of hormone levels with MetS and T2DM in women from a large population-based sample. Design, Setting, and Participants: A total of 2077 women from the Study of Health in Pomerania were assessed at baseline (N = 3160, 1997–2001) and 5-year follow-up (N = 1711, 2002–2006). Main Outcomes and Measures: We investigated associations of total testosterone (T) and androstenedione measured by liquid chromatography-tandem mass spectrometry, SHBG by immunoassay, and free T and free androgen index with MetS and T2DM. Results: Baseline prevalence of MetS and T2DM was 23.1% (N = 365) and 9.5% (N = 196), with an incidence of 17.7 and 7.0 per 1.000 person-years, respectively. Cross-sectional analyses yielded inverse associati...

Association between serum thyroid-stimulating hormone levels and serum lipids in children and adolescents: a population-based study of german youth.

Abstract: Context: No studies have examined the association between TSH and lipid profiles of healthy children and adolescents in the general population. Objective: The objective was to investigate the association between TSH and lipid profiles. Design: We used a population-based cross-sectional study design and analyzed our results using multivariable regression models. Setting: The study was conducted in Germany. Participants: We analyzed data from 6622 children (ages 3–10 y) and 6134 adolescents (ages 11–17 y) drawn from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Intervention: Not applicable. Main Outcome Measures: Blood samples were collected, and serum TSH levels were measured using the electrochemiluminescence method. High and low serum TSH levels were defined according to age-specific reference limits for the assay. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels were determined...

Rare coding variants and X-linked loci associated with age at menarche

Abstract: More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

Fully Automated Glottis Segmentation in Endoscopic Videos Using Local Color and Shape Features of Glottal Regions

Abstract: Exact analysis of glottal vibration patterns is indispensable for the assessment of laryngeal pathologies. Increasing demand of voice related examination and large amount of data provided by high-speed laryngoscopy and stroboscopy call for automatic assistance in research and patient care. Automatic glottis segmentation is necessary to assist glottal vibration pattern analysis, but unfortunately proves to be very challenging. Previous glottis segmentation approaches hardly consider characteristic glottis features as well as inhomogeneity of glottal regions and show serious drawbacks in their application for diagnostic purposes. We developed a fully automated glottis segmentation framework that extracts a set of glottal regions in endoscopic videos by using a flexible thresholding technique combined with a refining level set method that incorporates prior glottis shape knowledge. A novel descriptor for glottal regions is presented to remove potential nonglottal fake regions that show glottis-like shape properties. Knowledge of local color distributions is incorporated into Bayesian probability image generation. Glottal regions are then tracked frame-by-frame in probability images with a region-based level set segmentation strategy. Principal component analysis of pixel coordinates is applied to determine glottal orientation in each frame and to remove nonglottal regions if erroneous regions are included. The framework shows very promising results concerning segmentation accuracy and processing times and is applicable for both stroboscopic and high-speed videos.

A Genetic Risk Score for Thyroid Peroxidase Antibodies Associates With Clinical Thyroid Disease in Community-Based Populations

Abstract: Context: Antibodies against thyroid peroxidase (TPOAbs) are detected in 90% of all patients with Hashimoto thyroiditis, the most common cause of hypothyroidism. Hypothyroidism is associated with a range of adverse outcomes. The current knowledge of its genetic underpinnings is limited. Objective: The purpose of this study was to identify novel genetic variants associated with TPOAb concentrations and positivity using genome-wide association data and to characterize their association with thyroid function and disease. Design, Setting, and Participants: We studied European ancestry participants of 3 independent prospective population-based studies: Atherosclerosis Risk In Communities study (n = 7524), Study of Health in Pomerania (n = 3803), and Study of Health in Pomerania-TREND (n = 887). Exposure: Single nucleotide polymorphisms (SNPs), individually and combined into a genetic risk score (GRS), were examined. Main Outcomes: The main outcomes were TPOAb concentrations and positivity, thyroid hormone conce...