Adaptive Emotionsregulation im Kontext der Major Depression

Defizite in der adaptiven ER und damit assoziierte erhöhte negativer Affekte gelten als Risikofaktoren für die Entstehung und Aufrechterhaltung depressiver Episoden. Eine Verbesserung von Kompetenzen im Bereich der adaptiven ER sollte Personen helfen, negative Affekte bei Bedarf zu reduzieren und könnte so der Entstehung, Aufrechterhaltung und Wiederkehr von MDD entgegenwirken. Ziel der vorliegenden Dissertation war die Identifikation von Ansatzpunkten zur Verbesserung der adaptiven ER bei aktuell und ehemals depressiven Personen. Ein Schwerpunkt wurde dabei auf das Konstrukt der mitfühlenden Selbstunterstützung gelegt. In einer querschnittlichen Studie untersuchten wir die Hypothese häufiger Selbstkritik und seltener mitfühlender Selbstunterstützung und Selbstbestätigung als stabiler Vulnerabilitätsfaktoren, die über akute Phasen der Major Depression hinaus bestehen bleiben (Studie 1). Wie erwartet berichteten sowohl aktuell als auch ehemals depressive Personen im Vergleich zu gesunden und zuvor nicht depressiven Personen von häufigerer Selbstkritik und seltenerer mitfühlender Selbstunterstützung und Selbstbestätigung. In einer experimentellen Studie untersuchten wir die Effektivität mitfühlender Selbstunterstützung zur Reduktion depressiver Stimmung bei aktuell, ehemals und gesunden, zuvor nicht depressiven Personen (Studie 2). Über die Gruppen hinweg war mitfühlende Selbstunterstützung effektiver als eine Wartebedingung und emotionale Akzeptanz. Bei ehemals depressiven und gesunden, zuvor nicht depressiven Personen war mitfühlende Selbstunterstützung zudem effektiver als kognitive Neubewertung. In einer längsschnittlichen Studie untersuchten wir prospektive Zusammenhänge zwischen verschiedenen, potentiell relevanten Komponenten der adaptiven ER (inklusive Aufmerksamkeit, Klarheit, Körperwahrnehmung, Verstehen, Modifikation, Akzeptanz, Toleranz, mitfühlender Selbstunterstützung und Konfrontationsbereitschaft) und einer nachfolgenden Reduktion negativen Affekts über den Verlauf der Depressionsbehandlung (Studie 3). In einem latenten Veränderungsmodell sagten der Gesamtwert sowie die folgenden Komponenten eine Abnahme negativen Affekts vorher: das Verstehen der Ursachen negativer Affekte, die selbsteingeschätzte Fähigkeit zur Modifikation negativer Affekte, emotionale Akzeptanz und Toleranz sowie die zielbezogene Konfrontationsbereitschaft mit belastenden Situationen. In einer randomisiert-kontrollierten Studie soll getestet werden, inwieweit eine Verbesserung mitfühlender Selbstunterstützung und weiterer vermeintlich relevanter Komponenten der adaptiven ER durch gezielte Interventionen bei Personen mit Major Depression zu einer Verbesserung der psychischen Gesundheit, inklusive einer Reduktion depressiver Symptome, beiträgt (Studie 4).Zukünftige Studien werden darüber hinaus zeigen müssen, inwieweit Interventionen zur Verbesserung der adaptiven ER bei ehemals depressiven sowie gesunden, zuvor nicht depressiven Personen zu einer Reduktion des Risikos für die Entstehung und Wiederkehr von Major Depression beitragen können

Malaria Host Candidate Genes Validated by Association With Current, Recent, and Historical Measures of Transmission Intensity

Background: Human malaria susceptibility is determined by multiple genetic factors. It is unclear, however, which genetic variants remain important over time. Methods: Genetic associations of 175 high-quality polymorphisms within several malaria candidate genes were examined in a sample of 8096 individuals from northeast Tanzania using altitude, seroconversion rates, and parasite rates as proxies of historical, recent, and current malaria transmission intensity. A principal component analysis was used to derive 2 alternative measures of overall malaria propensity of a location across different time scales. Results: Common red blood cell polymorphisms (ie, hemoglobin S, glucose-6-phosphate dehydrogenase, and α-thalassemia) were the only ones to be associated with all 3 measures of transmission intensity and the first principal component. Moderate associations were found between some immune response genes (ie, IL3 and IL13) and parasite rates, but these could not be reproduced using the alternative measures of malaria propensity. Conclusions: We have demonstrated the potential of using altitude and seroconversion rate as measures of malaria transmission capturing medium- to long-term time scales to detect genetic associations that are likely to persist over time. These measures also have the advantage of minimizing the deleterious effects of random factors affecting parasite rates on the respective association signals

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Genome-Wide Association Studies of Serum Magnesium, Potassium, and Sodium Concentrations Identify Six Loci Influencing Serum Magnesium Levels

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using $\sim$2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant $(p<5 \times 10^{-8})$ or suggestive associations $(p<4 \times 10^{-7})$ were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding $(p<4 \times 10^{-7})$. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels

Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)

Genome-Wide Association Studies of Serum Magnesium, Potassium, and Sodium Concentrations Identify Six Loci Influencing Serum Magnesium Levels

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ∼2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5×10−8) or suggestive associations (p<4×10−7) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4×10−7. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Abstract: Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria