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The authors acknowledge the financial support the Scottish Government's Rural and Environmental Sciences and Analytical Services (RESAS) in order to complete some of the soil and pore water sample analysis as well as the Czech Ministry of Education, Youth and Sports (COST CZ LD13068), the Czech Science Foundation (GAČR 14-02183P) and EU COST actionFP1407 ('ModWoodLife') short term scientific mission grant in order to complete the column leaching test. ; Peer reviewed ; Postprint

Published online ; Journal Article ; This is the final version of the article. Available from Nature Publishing Group via the DOI in this record. ; Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10(-21)), left fusiform gyrus (d=-0.288; P=8.25 × 10(-21)) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10(-19)). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.Molecular Psychiatry advance online publication, 2 May 2017; doi:10.1038/mp.2017.73. ; The ENIGMA Bipolar Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PMT). We thank the members of the International Group for the Study of Lithium Treated Patients (IGSLi) and Costa Rica/Colombia Consortium for Genetic Investigation of Bipolar Endophenotypes. We also thank research funding sources: The Halifax studies have been supported by grants from Canadian Institutes of Health Research (103703, 106469, 64410 and 142255), the Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship to TH. TOP is supported by the Research Council of Norway (223273, 213837, 249711), the South East Norway Health Authority (2017-112), the Kristian Gerhard Jebsen Stiftelsen (SKGJ‐MED‐008) and the European Community's Seventh Framework Programme (FP7/2007–2013), grant agreement no. 602450 (IMAGEMEND). Cardiff is supported by the National Centre for Mental Health (NCMH), Bipolar Disorder Research Network (BDRN) and the 2010 NARSAD Young Investigator Award (ref. 17319) to XC. The Paris sample is supported by the French National Agency for Research (ANR MNP 2008 to the 'VIP' project) and by the Fondation pour la Recherche Médicale (2014 Bio-informarcis grant). The St. Göran bipolar project (SBP) is supported by grants from the Swedish Medical Research Council, the Swedish foundation for Strategic Research, the Swedish Brain foundation and the Swedish Federal Government under the LUA/ALF agreement. The Malt-Oslo sample is supported by the South East Norway Health Authority and by generous unrestricted grants from Mrs. Throne-Holst. The UT Houston sample is supported by NIH grant, MH085667. The UCLA-BP study is supported by NIH grants R01MH075007, R01MH095454, P30NS062691 (to NBF), K23MH074644-01 (to CEB) and K08MH086786 (to SF). Data collection for the UMCU sample is funded by the NIMH R01 MH090553 (PI Ophoff). The Oxford/Newcastle sample was funded by the Brain Behavior Research Foundation and Stanley Medical Research Institute. The University of Barcelona sample is supported by the CIBERSAM, the Spanish Ministry of Economy and Competitiveness (PI 12/00910), and the Comissionat per a Universitats i Recerca del DIUE de la Generalitat de Catalunya (2014 SGR 398). The KCL group is supported by a MRC Fellowship MR/J008915/1 (PI Kempton). The NUIG sample was supported by the Health Research Board (HRA_POR/2011/100). The Sydney sample was funded by the Australian National Medical and Health Research Council (Program Grant 1037196; project grant 1066177) and the Lansdowne Foundation and supported by philanthropic donations from Janette O'Neil and Paul and Jenny Reid. SF was supported by the National Institute of Mental Health under grant R01MH104284. DD is partially supported by a NARSAD 2014 Young Investigator Award (Leichtung Family Investigator) and a Psychiatric Research Trust grant (2014). The Münster Sample was funded by the German Research Foundation (DFG), grant FOR2107, DA1151/5-1 to UD. The Penn sample was funded by NIH grants K23MH098130 (to TDS), K23MH085096 (to DHW), R01MH107703 (to TDS) and R01MH101111 (to DHW), as well as support from the Brain and Behavior Research Foundation. The Tulsa studies were supported by the William K. Warren Foundation. Partial support was also received from the NIMH (K01MH096077). The Pittsburgh sample was funded by 5R01MH076971 (PI Phillips) and the Pittsburgh Foundation (Phillips). The Sao Paulo (Brazil) studies have been supported by grants from FAPESP-Brazil (#2009/14891-9, 2010/18672-7, 2012/23796-2 and 2013/03905-4), CNPq-Brazil (#478466/2009 and 480370/2009), the Wellcome Trust (UK) and the Brain & Behavior Research Foundation (2010 NARSAD Independent Investigator Award granted to GFB). MB and AP received support from the German Federal Ministry of Education and Research (BMBF) within the framework of the BipolLife research network on bipolar disorders. Data from the AMC was supported by the Organization for Health Research and Development (ZonMw), program Mental Health, education of investigators in mental health (OOG; #100-002-034). MMR used the e-Bioinfra Gateway to analyze data from the AMC (see Shahand et al. (2012): A grid-enabled gateway for biomedical data analysis. Journal of Grid Computing 1–18). The CliNG study sample was partially supported by the Deutsche Forschungsgemeinschaft (DFG) via the Clinical Research Group 241 'Genotype-phenotype relationships and neurobiology of the longitudinal course of psychosis', TP2 (PI Gruber; http://www.kfo241.de; grant number GR 1950/5-1). The FIDMAG Germànes Hospitalàries Research Foundation sample is supported by the Comissionat per a Universitats i Recerca del DIUE de la Generalitat de Catalunya (2014-SGR-1573) and several grants funded by Instituto de Salud Carlos III (Co-funded by European Regional Development Fund/European Social Fund) "Investing in your future"): Miguel Servet Research Contract (CPII16/00018 to E. P.-C.), Sara Borrell Contract grant (CD16/00264 to M.F.-V.) and Research Projects (PI14/01148 to E.P.-C. and PI15/00277 to E.C.-R.).

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