Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
von Sandra Díaz ; Jens Kattge ; Johannes H. C. Cornelissen ; Ian J. Wright ; Sandra Lavorel ; Stéphane Dray ; Björn Reu ; Michael Kleyer ; Vanessa Minden ; Gerhard Zotz
Durch die Umsetzung niedervalenter Titankomplexe mit aromatischen N-Heterocyclen wurden eine Reihe neuartiger multinuklearer Titanocenkomplexe synthetisiert. Mittels spektroskopischer Untersuchungen und Einkristall-Röntgenstrukturanalyse wurden die Strukturen der stark luft- und feuchtigkeitsempfindlichen Verbindungen aufgeklärt und die folgenden Ergebnisse erhalten: Die Umsetzung niedervalenter Titanocenquellen mit linearen Brückenliganden führt zu tetranuklearen Titan(II)komplexen mit der Struktur 'molekularer Quadrate'. Analoge 'molekulare Rechtecke' sind durch die schrittweise Koordination von zwei verschiedenen Brückenliganden zugänglich. In anderen Reaktionen hingegen entstehen durch reduktive C-C-Kopplung und C-H-Aktivierung multinukleare Titanocenkomplexe höherer Oxidationsstufen, in denen die neuentstandenen, meist nicht mehr aromatischen Liganden die Titanzentren zu binuklearen, trinuklearen und oktanuklearen Einheiten verbrücken. <dt.>
A series of novel multinuclear titanocene complexes were synthesized from low-valent titanium compounds and aromatic N-heterocycles. Spectroscopic investigations and single crystal X-ray analyses revealed the structures of the highly air- and moisture-sensitive compounds and yielded the following results: the conversion of low-valent titanocene units with linear bridging ligands leads to tetranuclear titanium(II) complexes, which exhibit structures of 'molecular squares'. Analogous 'molecular rectangles' are available by stepwise coordination of two bridging ligands of different lengths. In contrast, other N-heterocyclic ligands are reduced by the low-valent titanium units and polynuclear complexes of higher oxidation states are formed by reductive C-C coupling reactions and C-H activation. In these complexes the newly formed and no longer aromatic ligands associate the titanium centres to binuclear, trinuclear and octanuclear units. <engl.>
