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Hou, Liping ; Bergen, Sarah E. ; Akula, Nirmala ; Song, Jie ; Hultman, Christina M. ; Landén, Mikael ; Adli, Mazda ; Alda, Martin ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Badner, Judith A. ; Barrett, Thomas B. ; Bauer, Michael ; Baune, Bernhard T. ; Bellivier, Frank ; Benabarre Hernandez, Antonio ; Bengesser, Susanne ; Berrettini, Wade H. ; Bhattacharjee, Abesh Kumar ; Biernacka, Joanna ; Birner, Armin ; Bloss, Cinnamon S. ; Brichant-Petitjean, Clara ; Bui, Elise T. ; Byerley, William ; Cervantes, Pablo ; Chillotti, Caterina ; Cichon, Sven ; Colom, Francesc ; Coryell, William ; Craig, David W. ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Davis, Tony ; Dayer, Alexandre ; Degenhardt, Franziska ; Del Zompo, Maria ; DePaulo, J. Raymond ; Edenberg, Howard J. ; Étain, Bruno ; Falkai, Peter ; Foroud, Tatiana ; Forstner, Andreas Josef ; Frisén, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Gershon, Elliot S. ; Goes, Fernando S. ; Greenwood, Tiffany A. ; Grigoroiu-Serbanescu, Maria ; Hauser, Joanna ; Heilbronner, Urs ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hipolito, Maria ; Hitturlingappa, Shashi ; Hoffmann, Per ; Hofmann, Andrea ; Jamain, Stephane ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Kliwicki, Sebastian ; Koller, Daniel L. ; König, Barbara ; Lackner, Nina ; Laje, Gonzalo ; Lang, Maren ; Lavebratt, Catharina ; Lawson, William B. ; Leboyer, Marion ; Leckband, Susan G. ; Liu, Chunyu ; Maaser, Anna ; Mahon, Pamela B. ; Maier, Wolfgang ; Maj, Mario ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan L. ; McInnis, Melvin G. ; McKinney, Rebecca ; Mitchell, Philip B. ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Mühleisen, Thomas W. ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; Nurnberger, John I. ; Nwulia, Evaristus A. ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Propping, Peter ; Reif, Andreas ; Reininghaus, Eva ; Rice, John ; Rietschel, Marcella ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Scheftner, William A. ; Schofield, Peter R. ; Schork, Nicholas J. ; Schulze, Thomas Gerd ; Schumacher, Johannes ; Schweizer, Barbara W. ; Severino, Giovanni ; Shekhtman, Tatyana ; Shilling, Paul D. ; Simhandl, Christian ; Slaney, Claire M. ; Smith, Erin N. ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Streit, Fabian ; Strohmaier, Jana ; Szelinger, Szabolcs ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Vieta, Eduard ; Volkert, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Zhang, Peng ; Zollner, Sebastian ; McMahon, Francis J.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Le Clerc, Sigrid ; Lombardi, Laura ; Amare, Azmeraw T. ; Schubert, Klaus Oliver ; Hou, Liping ; Clark, Scott R. ; Papiol, Sergi ; Cearns, Micah ; Heilbronner, Urs ; Degenhardt, Franziska ; Tekola-Ayele, Fasil ; Hsu, Yi-Hsiang ; Shekhtman, Tatyana ; Adli, Mazda ; Akula, Nirmala ; Akiyama, Kazufumi ; Ardau, Raffaella ; Arias, Bárbara ; Aubry, Jean-Michel ; Backlund, Lena ; Bhattacharjee, Abesh Kumar ; Bellivier, Frank ; Benabarre, Antonio ; Bengesser, Susanne ; Biernacka, Joanna ; Birner, Armin ; Brichant-Petitjean, Clara ; Cervantes, Pablo ; Chen, Hsi-Chung ; Chillotti, Caterina ; Cichon, Sven ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Dalkner, Nina ; Dayer, Alexandre ; Baune, Bernhard T. ; Del Zompo, Maria ; DePaulo, J. Raymond ; Étain, Bruno ; Jamain, Stephane ; Falkai, Peter ; Forstner, Andreas Josef ; Frisen, Louise ; Frye, Mark A. ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Goes, Fernando S. ; Grigoroiu-Serbanescu, Maria ; Grof, Paul ; Hashimoto, Ryota ; Hauser, Joanna ; Herms, Stefan ; Hoffmann, Per ; Jiménez, Esther ; Kahn, Jean-Pierre ; Kassem, Layla ; Kuo, Po-Hsiu ; Kato, Tadafumi ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Ferensztajn-Rochowiak, Ewa ; König, Barbara ; Kusumi, Ichiro ; Laje, Gonzalo ; Landén, Mikael ; Lavebratt, Catharina ; Leckband, Susan G. ; Tortorella, Alfonso ; Manchia, Mirko ; Martinsson, Lina ; McCarthy, Michael J. ; McElroy, Susan ; Colom, Francesc ; Millischer, Vincent ; Mitjans, Marina ; Mondimore, Francis Mark ; Monteleone, Palmiero ; Nievergelt, Caroline M. ; Nöthen, Markus Maria ; Novák, Tomas ; O'Donovan, Claire ; Ozaki, Norio ; Ösby, Urban ; Pfennig, Andrea ; Potash, James B. ; Reif, Andreas ; Reininghaus, Eva ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Schofield, Peter R. ; Schweizer, Barbara W. ; Severino, Giovanni ; Shilling, Paul D. ; Shimoda, Katzutaka ; Simhandl, Christian ; Slaney, Claire M. ; Pisanu, Claudia ; Squassina, Alessio ; Stamm, Thomas ; Stopkova, Pavla ; Maj, Mario ; Turecki, Gustavo ; Vieta, Eduard ; Veeh, Julia ; Witt, Stephanie H. ; Wright, Adam ; Zandi, Peter P. ; Mitchell, Philip B. ; Bauer, Michael ; Alda, Martin ; Rietschel, Marcella ; McMahon, Francis J. ; Schulze, Thomas Gerd ; Spadoni, Jean-Louis ; Boukouaci, Wahid ; Richard, Jean-Romain ; Le Corvoisier, Philippe ; Barrau, Caroline ; Zagury, Jean-François ; Leboyer, Marion ; Tamouza, Ryad
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Lamparter, Julia ; Schmidtmann, Irene ; Schuster, Alexander K. ; Siouli, Angeliki ; Wasielica-Poślednik, Joanna Katarzyna ; Mirshahi, Alireza ; Höhn, René ; Unterrainer, Josef ; Wild, Philipp ; Binder, Harald ; Lackner, Karl Johannes ; Beutel, Manfred ; Münzel, Thomas ; Pfeiffer, Norbert ; Hoffmann, Esther Maria
Background: Glaucoma is a neurodegenerative disease, leading to thinning of the retinal nerve fibre layer (RNFL). The exact influence of ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFL thickness (RNFLT) is unknown and was analysed in a subgroup of the Gutenberg Health Study (GHS).
Methods: Global peripapillary RNFLT was measured in 3224 eyes of 1973 subjects (49% female) using spectral-domain optical coherence tomography (SD-OCT). The association of age, sex, ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFLT was analysed using Pearson correlation coefficient and fitting a linear mixed model.
Results: In the univariable analysis highest correlations were found for axial length (r = -0.27), spherical equivalent (r = 0.24), and glaucoma (r = -0.15) (p<0.0001, respectively). Other significant correlations with RNFLT were found for age, sex, intraocular pressure, systemic hypertension and systolic blood pressure, previous eye surgery, cholesterol, homocysteine, history of coronary artery disease, history of myocardial infarction, apnoea, diabetes and alcohol intake, p<0.05, respectively. Body length, body weight, BMI, diastolic blood pressure, blood glucose, HbA1c, history of apoplexy, cognitive function, peripheral artery disease, tinnitus, migraine, nicotine intake, central corneal thickness, and pseudophakia were not significantly correlated with RNFLT. The regression model revealed a significant relationship between RNFLT and age in decades (p<0.02), spherical equivalent (p<0.0001), axial length (p<0.0001), glaucoma (p<0.0001), tinnitus (p = 0.04), apnoea (p = 0.047), homocysteine (p = 0.05) and alcohol intake >10g/d for women and >20g/d for men (p = 0.02). Glaucoma, apnoea, higher homocysteine, higher alcohol intake and higher axial length as well as age were related to decreased RNFLT while higher spherical equivalent or history for tinnitus were related to thicker RNFL.
Conclusion: RNFLT is related to age, ocular parameters and lifestyle factors. Considering these parameters in normative databases could improve the evaluation of peripapillary RNFLT. It is necessary to evaluate if a reduction of alcohol intake as well as the therapy of apnea or high homocysteine levels could positively influence RNFLT.