Beyond a Social-cognitive Perspective on Doping - Towards an Integrative Model of Person-Situation Interactions

Doping als psychosoziales Verhalten stellt mehr als die bloße Verletzung von Anti-Doping-Regeln dar. Doping betrifft sowohl den (Hoch-)Leistungs- als auch den Breiten- und Freizeitsport. Für die Vorhersage von Doping haben Einstellungen einen nachweislich großen Einfluss, jedoch konnte bisher kein zufriedenstellendes theoretisches Modell, welches sowohl Personen- und Situationsfaktoren ausreichend berücksichtigt, gefunden werden. Die erste Publikation konzentriert sich auf methodische Fragen zur Erfassung impliziter Dopingeinstellungen. Dieser Beitrag, der auf duale Einstellungstheorien (z.B., Fazio, 1990) basiert, diskutiert die indirekte Messung von Dopingeinstellungen mittels Impliziten Assoziationstest (Greenwald et al., 1998). Die zweite Publikation stützt sich auf ein erweitertes Dopingverständnis und untersucht den Schmerzmittelkonsum in Abhängigkeit von Situations- und Personenfaktoren anhand der Annahmen von Rational-Choice-Theorie und Routine-Activity-Ansatz (Clarke & Cornish, 1985; Cohen & Felson, 1979). Abschließend wird der Einfluss von moralischen Entscheidungen auf Doping diskutiert (z. B. Ntoumanis et al., 2014). Das Ethische Dilemmatraining (Elbe & Brand, 2016) stellt eine neue Methode dar, um die moralische Entscheidungsfähigkeit zu steigern und moralische Werte und Überzeugungen zu stärken. Als integrierender theoretischer Rahmen wird die Situational Action Theory (z. B., Wikström, 2014) vorgeschlagen, welche sowohl die Interaktion von Personen- und Situationsfaktoren als auch die moralische Entscheidungsfindung miteinander verbindet. Weiterführende Implikationen für die Dopingforschung und -prävention werden diskutiert.:List of Publications III List of Figures IV List of Tables VI Abstract VII Zusammenfassung VIII 1 Introduction 1 1.1 Historical Overview on Doping in Sports 1 1.2 Defining Doping - Strengths and Weaknesses 3 1.2.1 World Anti-Doping Code 4 1.2.2 Limitations of WADA Code 6 1.2.3 Doping as (Deviant) Social Behavior 7 2 A Review on Current Research on Doping 11 2.1 Prevalence of Doping Elite and Recreational Sport 11 2.2 Doping and Legal and Illegal Substance (Mis-)Use 15 2.3 Doping and Related Personal and Situational Factors 19 3 Modelling Doping - A Theoretical Overview 21 3.1 A Summary of Relevant Theories on Doping 21 3.1.1 Theory of Planned Behavior 21 3.1.2 Sport Drug Control Model 22 3.1.3 Life Cycle Model 24 3.1.4 Trans-contextual Model of Avoid Doping 25 3.2 A Dual-process Perspective on Doping 27 3.3 A Person-Situation Perspective - Impact of Situation and Context 31 3.4 A Gateway to Doping 34 3.5 Implication for Further Theoretical Discussion 37 4 Aim of Thesis and General Research Questions 39 5 Publications 43 5.1 Publication Manuscript 1 43 5.2 Publication Manuscript 2 51 5.3 Publication Manuscript 3 61 6 General Discussion and Conclusion 79 6.1 Future Perspectives on Research of Doping Attitudes 79 6.2 A Different Understanding of the Person-Situation Interaction 81 6.3 Bridging the Gap - An Integrative Model of Person and Situation 82 6.3.1 Situational Action Theory (SAT) 82 6.3.2 SAT - New Implications for Doping Research 90 6.4 Future Implications and Challenges for Doping Prevention 95 6.5 Conclusion 97 7 References 101 8 Appendix 130 8.1 Thesis Statement of Originality 130 8.2 Statement of Authorship 131 8.3 Curriculum Vitae 132Doping - as a psychosocial behavior - is more than simply violating anti-doping rules and laws. Doping has become a part of high-performance and recreational sports. Attitudes toward doping among athletes have been sufficiently proven as an important impact factor. However, theoretical consideration of the person-situation mode with other relevant factors (e.g., moral disengagement or situational factors) into an integrated understanding of doping is still needed. The first study presented in this thesis focusses on methodological issues and the assessment of implicit doping attitudes. Based on dual process theories of attitudes (e.g., Fazio, 1990), the first paper discusses the indirect measurement of doping attitudes via the Implicit Association Test (Greenwald et al., 1998) as a tool to overcome limitations of self-reported attitudes. The second study presented here uses a broader understanding of doping and focuses on the parallelism of doping and doping-like behavior. The study analyzes the use of NSAID (non-steroidal anti-inflammatory drugs) in different intake situations. The influence of situation and person factors is tested by using the assumption of high- and low-cost situations from the Rational Choice Theory and Routine Activity Approach (e.g., Clarke & Cornish, 1985; Cohen & Felson, 1979). Finally, research has shown that moral decision-making has an impact on doping behavior (e.g., Ntoumanis et al., 2014). Ethical dilemma training (e.g., Elbe & Brand, 2016) may be employed as a new method to increase moral decision-making ability and to strengthen moral values and beliefs. Accordingly, the third research paper presented discusses this as a new approach to doping prevention. Overall, this thesis introduces Situational Action Theory ( e.g., Wikström, 2014) as an integrative theoretical approach, focussing on the person-situation interaction, as well as on moral decision-making. Further implications for doping research and for prevention are discussed.:List of Publications III List of Figures IV List of Tables VI Abstract VII Zusammenfassung VIII 1 Introduction 1 1.1 Historical Overview on Doping in Sports 1 1.2 Defining Doping - Strengths and Weaknesses 3 1.2.1 World Anti-Doping Code 4 1.2.2 Limitations of WADA Code 6 1.2.3 Doping as (Deviant) Social Behavior 7 2 A Review on Current Research on Doping 11 2.1 Prevalence of Doping Elite and Recreational Sport 11 2.2 Doping and Legal and Illegal Substance (Mis-)Use 15 2.3 Doping and Related Personal and Situational Factors 19 3 Modelling Doping - A Theoretical Overview 21 3.1 A Summary of Relevant Theories on Doping 21 3.1.1 Theory of Planned Behavior 21 3.1.2 Sport Drug Control Model 22 3.1.3 Life Cycle Model 24 3.1.4 Trans-contextual Model of Avoid Doping 25 3.2 A Dual-process Perspective on Doping 27 3.3 A Person-Situation Perspective - Impact of Situation and Context 31 3.4 A Gateway to Doping 34 3.5 Implication for Further Theoretical Discussion 37 4 Aim of Thesis and General Research Questions 39 5 Publications 43 5.1 Publication Manuscript 1 43 5.2 Publication Manuscript 2 51 5.3 Publication Manuscript 3 61 6 General Discussion and Conclusion 79 6.1 Future Perspectives on Research of Doping Attitudes 79 6.2 A Different Understanding of the Person-Situation Interaction 81 6.3 Bridging the Gap - An Integrative Model of Person and Situation 82 6.3.1 Situational Action Theory (SAT) 82 6.3.2 SAT - New Implications for Doping Research 90 6.4 Future Implications and Challenges for Doping Prevention 95 6.5 Conclusion 97 7 References 101 8 Appendix 130 8.1 Thesis Statement of Originality 130 8.2 Statement of Authorship 131 8.3 Curriculum Vitae 13

Whole-genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes.

Initial results from sequencing studies suggest that there are relatively few low-frequency (<5%) variants associated with large effects on common phenotypes. We performed low-pass whole-genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: (i) that sequencing would detect single low-frequency-large effect variants that explained similar amounts of phenotypic variance as single common variants, and (ii) that some common variant associations could be explained by low-frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant-common phenotype associations-11 132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11 657 229 high-quality variants of which 6 129 221 and 5 528 008 were common and low frequency (<5%), respectively, low frequency-large effect associations comprised 7% of detectable cis-gene expression traits [89 of 1314 cis-eQTLs at P < 1 × 10(-06) (false discovery rate ∼5%)] and one of eight biomarker associations at P < 8 × 10(-10). Very few (30 of 1232; 2%) common variant associations were fully explained by low-frequency variants. Our data show that whole-genome sequencing can identify low-frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low-frequency variants of large effect

Channel-like slippage modes in the human anion/proton exchanger ClC-4

The ClC family encompasses two classes of proteins with distinct transport functions: anion channels and transporters. ClC-type transporters usually mediate secondary active anion–proton exchange. However, under certain conditions they assume slippage mode behavior in which proton and anion transport are uncoupled, resulting in passive anion fluxes without associated proton movements. Here, we use patch clamp and intracellular pH recordings on transfected mammalian cells to characterize exchanger and slippage modes of human ClC-4, a member of the ClC transporter branch. We found that the two transport modes differ in transport mechanisms and transport rates. Nonstationary noise analysis revealed a unitary transport rate of 5 × 105 s−1 at +150 mV for the slippage mode, indicating that ClC-4 functions as channel in this mode. In the exchanger mode, unitary transport rates were 10-fold lower. Both ClC-4 transport modes exhibit voltage-dependent gating, indicating that there are active and non-active states for the exchanger as well as for the slippage mode. ClC-4 can assume both transport modes under all tested conditions, with exchanger/channel ratios determined by the external anion. We propose that binding of transported anions to non-active states causes transition from slippage into exchanger mode. Binding and unbinding of anions is very rapid, and slower transitions of liganded and non-liganded states into active conformations result in a stable distribution between the two transport modes. The proposed mechanism results in anion-dependent conversion of ClC-type exchanger into an anion channel with typical attributes of ClC anion channels

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

This is the final version of the article. Available from the publisher via the DOI in this record.Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.This work was generously funded by an award to DM, TF, AM, LH and CB by the Medical Research Council MR/M023095/1. This research has been conducted using the UK Biobank Resource, under application 1417. The authors wish to thank the UK Biobank participants and coordinators for this unique dataset. S.E.J. is funded by the Medical Research Council (grant: MR/M005070/1). J.T. is funded by a Diabetes Research and Wellness Foundation Fellowship. R.B. is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. M.A.T., M.N.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant: 104150/Z/14/Z). A.R.W. H.Y., and T.M.F. are supported by the European Research Council grant: 323195:GLUCOSEGENES-FP7-IDEAS-ERC. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Framingham Heart Study is supported by Contract No. N01-HC-25195 and HHSN268201500001I and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). The phenotypegenotype association analyses were supported by National Institute of Aging R01AG29451. This work has made use of the resources provided by the University of Exeter Science Strategy and resulting Systems Biology initiative. Primarily these include high-performance computing facilities managed by Konrad Paszkiewicz of the College of Environmental and Life Sciences and Pete Leggett of the University of Exeter Academics services unit

A meta-analysis of gene expression signatures of blood pressure and hypertension.

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension

A meta-analysis of gene expression signatures of blood pressure and hypertension

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%-9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension

Vitamin C and infectious diseases

Non peer reviewe

Framework and baseline examination of the German National Cohort (NAKO)

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19–74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2–3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4–5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10654-022-00890-5

A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension

Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p&lt;0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms