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We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia., Competing Interests: EH, ED, GM, JB, NB, MB, AC, CC, DD, TD, GD, MG, AG, CG, HH, CH, VJ, RK, JK, GK, CM, AM, DM, KM, CM, IN, DQ, AR, BR, DS, ST, TT, JV, JW, EV, GB, LS, JM No competing interests declared, MD M Di Forti reports personal fees from Janssen, outside the submitted work. FG Fiona Gaughran has received honoraria from Lundbeck, Otsuka, and Sunovion. She has a family member with professional links to Lilly and GSK, including shares. KK Kaarina Kowalec has consulted with Emerald Lake Safety Ltd. (2017-2018) and has received speaker honoraria from Biogen/Fraser Health Multiple Sclerosis Clinic (2018). Both are unrelated to the work published here. JM James MacCabe has received research funding from H Lundbeck. MO Michael C O'Donovan is supported by a collaborative research grant from Takeda Pharmaceuticals. Takeda played no part in the conception, design, implementation, or interpretation of this study. PS PF Sullivan reports the following potentially competing financial interests. Current: Lundbeck (advisory committee, grant recipient). Past three years: Pfizer (scientific advisory board). DC David A Collier is a full time employee and stockholder of Eli Lilly and Company. RM Robin M Murray reports personal fees from Janssen, Lundbeck, Sunovion, Recordati and Otsuka, (© 2021, Hannon et al.)

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10 -6 , 1.7 × 10 - 9 , 3.5 × 10 -12 and 1.0 × 10 -4 , respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.