作者
Marisol Herrera-Rivero,Karina Gutiérrez-Fragoso,Anbupalam Thalamuthu,Azmeraw T. Amare,Mazda Adli,Kazufumi Akiyama,Nirmala Akula,Raffaella Ardau,Bárbara Arias,Jean‐Michel Aubry,Lena Backlund,Frank Bellivier,Antonio Benabarre,Susanne Bengesser,Bhattacharjee Abesh,Joanna M. Biernacka,Armin Birner,Micah Cearns,Pablo Cervantes,Hsi‐Chung Chen,Caterina Chillotti,Sven Cichon,Scott Clark,Francesc Colom,Cristiana Cruceanu,Piotr M. Czerski,Nina Dalkner,Franziska Degenhardt,Maria Del Zompo,J. Raymond DePaulo,Bruno Étain,P. Falkai,Ewa Ferensztajn‐Rochowiak,Andreas J. Forstner,Josef Frank,Louise Frisén,Mark A. Frye,Janice M. Fullerton,Carla Gallo,Sébastien Gard,Julie Garnham,Fernando S. Goes,Maria Grigoroiu-Serbǎnescu,Paul Grof,Ryota Hashimoto,Roland Hasler,Joanna Twarowska-Hauser,Urs Heilbronner,Stefan Herms,Per Hoffmann,Liping Hou,Yi‐Hsiang Hsu,Stéphane Jamain,Esther Jiménez,Jean‐Pierre Kahn,Layla Kassem,Takeshi Kato,John R. Kelsoe,Sarah Kittel-Schneider,Po-Hsiu Kuo,Joachim Kurtz,Ichiro Kusumi,Barbara König,Gonzalo Laje,Mikael Landén,Catharina Lavebratt,Marion Leboyer,Susan G. Leckband,Mario Maj,Mirko Manchia,Cynthia Marie-Claire,Lina Martinsson,Michael J. McCarthy,Susan L. McElroy,Vincent Millischer,Marina Mitjans,Francis M. Mondimore,Palmiero Monteleone,Caroline M. Nievergelt,Tomáš Novák,Markus M. Nöthen,Claire O’Donovan,Norio Ozaki,Sergi Papiol,Andrea Pfennig,Claudia Pisanu,James B. Potash,Andreas Reif,Eva Reininghaus,Hélène Richard-Lepouriel,Gloria Roberts,Guy A. Rouleau,Janusz Rybakowski,Martin Schalling,Peter R. Schofield,Klaus Oliver Schubert,Eva C. Schulte,Barbara Schweizer,Giovanni Severino,Tatyana Shekhtman
摘要
Abstract The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi + Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1x10 − 4 values, including HAS3 , CNTNAP5 and NFIB . Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4 , XKR4 , NRXN1 , NRG1/3 and GRK5 . Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.