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1. Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Author

Georgiadis F, Larivière S, Glahn D, Hong LE, Kochunov P, Mowry B, Loughland C, Pantelis C, Henskens FA, Green MJ, Cairns MJ, Michie PT, Rasser PE, Catts S, Tooney P, Scott RJ, Schall U, Carr V, Quidé Y, Krug A, Stein F, Nenadić I, Brosch K, Kircher T, Gur R, Gur R, Satterthwaite TD, Karuk A, Pomarol-Clotet E, Radua J, Fuentes-Claramonte P, Salvador R, Spalletta G, Voineskos A, Sim K, Crespo-Facorro B, Tordesillas Gutiérrez D, Ehrlich S, Crossley N, Grotegerd D, Repple J, Lencer R, Dannlowski U, Calhoun V, Rootes-Murdy K, Demro C, Ramsay IS, Sponheim SR, Schmidt A, Borgwardt S, Tomyshev A, Lebedeva I, Höschl C, Spaniel F, Preda A, Nguyen D, Uhlmann A, Stein DJ, Howells F, Temmingh HS, Diaz Zuluaga AM, López Jaramillo C, Iasevoli F, Ji E, Homan S, Omlor W, Homan P, Kaiser S, Seifritz E, Misic B, Valk SL, Thompson P, van Erp TGM, Turner JA, Bernhardt B, and Kirschner M

Subjects
Humans, Adult, Female, Male, Cerebral Cortex pathology, Cerebral Cortex physiopathology, Nerve Net pathology, Nerve Net physiopathology, Nerve Net diagnostic imaging, Brain pathology, Brain physiopathology, Middle Aged, Neural Pathways physiopathology, Neural Pathways pathology, Young Adult, Schizophrenia pathology, Schizophrenia physiopathology, Connectome methods, Magnetic Resonance Imaging methods
Abstract

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia., (© 2024. The Author(s).)

Published
2024
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2. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Author

Schijven D, Postema MC, Fukunaga M, Matsumoto J, Miura K, de Zwarte SMC, van Haren NEM, Cahn W, Hulshoff Pol HE, Kahn RS, Ayesa-Arriola R, Ortiz-García de la Foz V, Tordesillas-Gutierrez D, Vázquez-Bourgon J, Crespo-Facorro B, Alnæs D, Dahl A, Westlye LT, Agartz I, Andreassen OA, Jönsson EG, Kochunov P, Bruggemann JM, Catts SV, Michie PT, Mowry BJ, Quidé Y, Rasser PE, Schall U, Scott RJ, Carr VJ, Green MJ, Henskens FA, Loughland CM, Pantelis C, Weickert CS, Weickert TW, de Haan L, Brosch K, Pfarr JK, Ringwald KG, Stein F, Jansen A, Kircher TTJ, Nenadić I, Krämer B, Gruber O, Satterthwaite TD, Bustillo J, Mathalon DH, Preda A, Calhoun VD, Ford JM, Potkin SG, Chen J, Tan Y, Wang Z, Xiang H, Fan F, Bernardoni F, Ehrlich S, Fuentes-Claramonte P, Garcia-Leon MA, Guerrero-Pedraza A, Salvador R, Sarró S, Pomarol-Clotet E, Ciullo V, Piras F, Vecchio D, Banaj N, Spalletta G, Michielse S, van Amelsvoort T, Dickie EW, Voineskos AN, Sim K, Ciufolini S, Dazzan P, Murray RM, Kim WS, Chung YC, Andreou C, Schmidt A, Borgwardt S, McIntosh AM, Whalley HC, Lawrie SM, du Plessis S, Luckhoff HK, Scheffler F, Emsley R, Grotegerd D, Lencer R, Dannlowski U, Edmond JT, Rootes-Murdy K, Stephen JM, Mayer AR, Antonucci LA, Fazio L, Pergola G, Bertolino A, Díaz-Caneja CM, Janssen J, Lois NG, Arango C, Tomyshev AS, Lebedeva I, Cervenka S, Sellgren CM, Georgiadis F, Kirschner M, Kaiser S, Hajek T, Skoch A, Spaniel F, Kim M, Kwak YB, Oh S, Kwon JS, James A, Bakker G, Knöchel C, Stäblein M, Oertel V, Uhlmann A, Howells FM, Stein DJ, Temmingh HS, Diaz-Zuluaga AM, Pineda-Zapata JA, López-Jaramillo C, Homan S, Ji E, Surbeck W, Homan P, Fisher SE, Franke B, Glahn DC, Gur RC, Hashimoto R, Jahanshad N, Luders E, Medland SE, Thompson PM, Turner JA, van Erp TGM, and Francks C

Subjects
Male, Female, Humans, Case-Control Studies, Brain diagnostic imaging, Cerebral Cortex, Magnetic Resonance Imaging methods, Functional Laterality, Schizophrenia diagnostic imaging
Abstract

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Published
2023
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3. Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Author

Constantinides C, Han LKM, Alloza C, Antonucci LA, Arango C, Ayesa-Arriola R, Banaj N, Bertolino A, Borgwardt S, Bruggemann J, Bustillo J, Bykhovski O, Calhoun V, Carr V, Catts S, Chung YC, Crespo-Facorro B, Díaz-Caneja CM, Donohoe G, Plessis SD, Edmond J, Ehrlich S, Emsley R, Eyler LT, Fuentes-Claramonte P, Georgiadis F, Green M, Guerrero-Pedraza A, Ha M, Hahn T, Henskens FA, Holleran L, Homan S, Homan P, Jahanshad N, Janssen J, Ji E, Kaiser S, Kaleda V, Kim M, Kim WS, Kirschner M, Kochunov P, Kwak YB, Kwon JS, Lebedeva I, Liu J, Mitchie P, Michielse S, Mothersill D, Mowry B, de la Foz VO, Pantelis C, Pergola G, Piras F, Pomarol-Clotet E, Preda A, Quidé Y, Rasser PE, Rootes-Murdy K, Salvador R, Sangiuliano M, Sarró S, Schall U, Schmidt A, Scott RJ, Selvaggi P, Sim K, Skoch A, Spalletta G, Spaniel F, Thomopoulos SI, Tomecek D, Tomyshev AS, Tordesillas-Gutiérrez D, van Amelsvoort T, Vázquez-Bourgon J, Vecchio D, Voineskos A, Weickert CS, Weickert T, Thompson PM, Schmaal L, van Erp TGM, Turner J, Cole JH, Dima D, and Walton E

Subjects
Adult, Humans, Male, Adolescent, Young Adult, Middle Aged, Aged, Female, Prospective Studies, Magnetic Resonance Imaging, Brain pathology, Aging, Schizophrenia
Abstract

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I 2  = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions., (© 2022. The Author(s).)

Published
2023
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4. Mapping genomic loci implicates genes and synaptic biology in schizophrenia.

Author

Trubetskoy V, Pardiñas AF, Qi T, Panagiotaropoulou G, Awasthi S, Bigdeli TB, Bryois J, Chen CY, Dennison CA, Hall LS, Lam M, Watanabe K, Frei O, Ge T, Harwood JC, Koopmans F, Magnusson S, Richards AL, Sidorenko J, Wu Y, Zeng J, Grove J, Kim M, Li Z, Voloudakis G, Zhang W, Adams M, Agartz I, Atkinson EG, Agerbo E, Al Eissa M, Albus M, Alexander M, Alizadeh BZ, Alptekin K, Als TD, Amin F, Arolt V, Arrojo M, Athanasiu L, Azevedo MH, Bacanu SA, Bass NJ, Begemann M, Belliveau RA, Bene J, Benyamin B, Bergen SE, Blasi G, Bobes J, Bonassi S, Braun A, Bressan RA, Bromet EJ, Bruggeman R, Buckley PF, Buckner RL, Bybjerg-Grauholm J, Cahn W, Cairns MJ, Calkins ME, Carr VJ, Castle D, Catts SV, Chambert KD, Chan RCK, Chaumette B, Cheng W, Cheung EFC, Chong SA, Cohen D, Consoli A, Cordeiro Q, Costas J, Curtis C, Davidson M, Davis KL, de Haan L, Degenhardt F, DeLisi LE, Demontis D, Dickerson F, Dikeos D, Dinan T, Djurovic S, Duan J, Ducci G, Dudbridge F, Eriksson JG, Fañanás L, Faraone SV, Fiorentino A, Forstner A, Frank J, Freimer NB, Fromer M, Frustaci A, Gadelha A, Genovese G, Gershon ES, Giannitelli M, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JI, González Peñas J, González-Pinto A, Gopal S, Gratten J, Green MF, Greenwood TA, Guillin O, Gülöksüz S, Gur RE, Gur RC, Gutiérrez B, Hahn E, Hakonarson H, Haroutunian V, Hartmann AM, Harvey C, Hayward C, Henskens FA, Herms S, Hoffmann P, Howrigan DP, Ikeda M, Iyegbe C, Joa I, Julià A, Kähler AK, Kam-Thong T, Kamatani Y, Karachanak-Yankova S, Kebir O, Keller MC, Kelly BJ, Khrunin A, Kim SW, Klovins J, Kondratiev N, Konte B, Kraft J, Kubo M, Kučinskas V, Kučinskiene ZA, Kusumawardhani A, Kuzelova-Ptackova H, Landi S, Lazzeroni LC, Lee PH, Legge SE, Lehrer DS, Lencer R, Lerer B, Li M, Lieberman J, Light GA, Limborska S, Liu CM, Lönnqvist J, Loughland CM, Lubinski J, Luykx JJ, Lynham A, Macek M Jr, Mackinnon A, Magnusson PKE, Maher BS, Maier W, Malaspina D, Mallet J, Marder SR, Marsal S, Martin AR, Martorell L, Mattheisen M, McCarley RW, McDonald C, McGrath JJ, Medeiros H, Meier S, Melegh B, Melle I, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mitjans M, Molden E, Molina E, Molto MD, Mondelli V, Moreno C, Morley CP, Muntané G, Murphy KC, Myin-Germeys I, Nenadić I, Nestadt G, Nikitina-Zake L, Noto C, Nuechterlein KH, O'Brien NL, O'Neill FA, Oh SY, Olincy A, Ota VK, Pantelis C, Papadimitriou GN, Parellada M, Paunio T, Pellegrino R, Periyasamy S, Perkins DO, Pfuhlmann B, Pietiläinen O, Pimm J, Porteous D, Powell J, Quattrone D, Quested D, Radant AD, Rampino A, Rapaport MH, Rautanen A, Reichenberg A, Roe C, Roffman JL, Roth J, Rothermundt M, Rutten BPF, Saker-Delye S, Salomaa V, Sanjuan J, Santoro ML, Savitz A, Schall U, Scott RJ, Seidman LJ, Sharp SI, Shi J, Siever LJ, Sigurdsson E, Sim K, Skarabis N, Slominsky P, So HC, Sobell JL, Söderman E, Stain HJ, Steen NE, Steixner-Kumar AA, Stögmann E, Stone WS, Straub RE, Streit F, Strengman E, Stroup TS, Subramaniam M, Sugar CA, Suvisaari J, Svrakic DM, Swerdlow NR, Szatkiewicz JP, Ta TMT, Takahashi A, Terao C, Thibaut F, Toncheva D, Tooney PA, Torretta S, Tosato S, Tura GB, Turetsky BI, Üçok A, Vaaler A, van Amelsvoort T, van Winkel R, Veijola J, Waddington J, Walter H, Waterreus A, Webb BT, Weiser M, Williams NM, Witt SH, Wormley BK, Wu JQ, Xu Z, Yolken R, Zai CC, Zhou W, Zhu F, Zimprich F, Atbaşoğlu EC, Ayub M, Benner C, Bertolino A, Black DW, Bray NJ, Breen G, Buccola NG, Byerley WF, Chen WJ, Cloninger CR, Crespo-Facorro B, Donohoe G, Freedman R, Galletly C, Gandal MJ, Gennarelli M, Hougaard DM, Hwu HG, Jablensky AV, McCarroll SA, Moran JL, Mors O, Mortensen PB, Müller-Myhsok B, Neil AL, Nordentoft M, Pato MT, Petryshen TL, Pirinen M, Pulver AE, Schulze TG, Silverman JM, Smoller JW, Stahl EA, Tsuang DW, Vilella E, Wang SH, Xu S, Adolfsson R, Arango C, Baune BT, Belangero SI, Børglum AD, Braff D, Bramon E, Buxbaum JD, Campion D, Cervilla JA, Cichon S, Collier DA, Corvin A, Curtis D, Forti MD, Domenici E, Ehrenreich H, Escott-Price V, Esko T, Fanous AH, Gareeva A, Gawlik M, Gejman PV, Gill M, Glatt SJ, Golimbet V, Hong KS, Hultman CM, Hyman SE, Iwata N, Jönsson EG, Kahn RS, Kennedy JL, Khusnutdinova E, Kirov G, Knowles JA, Krebs MO, Laurent-Levinson C, Lee J, Lencz T, Levinson DF, Li QS, Liu J, Malhotra AK, Malhotra D, McIntosh A, McQuillin A, Menezes PR, Morgan VA, Morris DW, Mowry BJ, Murray RM, Nimgaonkar V, Nöthen MM, Ophoff RA, Paciga SA, Palotie A, Pato CN, Qin S, Rietschel M, Riley BP, Rivera M, Rujescu D, Saka MC, Sanders AR, Schwab SG, Serretti A, Sham PC, Shi Y, St Clair D, Stefánsson H, Stefansson K, Tsuang MT, van Os J, Vawter MP, Weinberger DR, Werge T, Wildenauer DB, Yu X, Yue W, Holmans PA, Pocklington AJ, Roussos P, Vassos E, Verhage M, Visscher PM, Yang J, Posthuma D, Andreassen OA, Kendler KS, Owen MJ, Wray NR, Daly MJ, Huang H, Neale BM, Sullivan PF, Ripke S, Walters JTR, and O'Donovan MC

Subjects
Alleles, Genetic Predisposition to Disease genetics, Genomics, Humans, Polymorphism, Single Nucleotide genetics, Genome-Wide Association Study, Schizophrenia genetics
Abstract

Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2022
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5. Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort.

Author

Liu X, Low SK, Atkins JR, Wu JQ, Reay WR, Cairns HM, Green MJ, Schall U, Jablensky A, Mowry B, Michie PT, Catts SV, Henskens F, Pantelis C, Loughland C, Boddy AV, Tooney PA, Scott RJ, Carr VJ, and Cairns MJ

Subjects
Australia, Cohort Studies, Frizzled Receptors genetics, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide genetics, Genome-Wide Association Study, Schizophrenia genetics
Abstract

Objectives: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories., Methods: We performed a case-control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome., Results: The strongest finding ( p  = 2.01 × 10 -6 , odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance ( p  = 2.78 × 10 -6 )., Conclusion: The identification of FZD1 , as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.

Published
2020
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6. Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

Author

van Erp TGM, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, Pearlson GD, Yao N, Fukunaga M, Hashimoto R, Okada N, Yamamori H, Clark VP, Mueller BA, de Zwarte SMC, Ophoff RA, van Haren NEM, Andreassen OA, Gurholt TP, Gruber O, Kraemer B, Richter A, Calhoun VD, Crespo-Facorro B, Roiz-Santiañez R, Tordesillas-Gutiérrez D, Loughland C, Catts S, Fullerton JM, Green MJ, Henskens F, Jablensky A, Mowry BJ, Pantelis C, Quidé Y, Schall U, Scott RJ, Cairns MJ, Seal M, Tooney PA, Rasser PE, Cooper G, Shannon Weickert C, Weickert TW, Hong E, Kochunov P, Gur RE, Gur RC, Ford JM, Macciardi F, Mathalon DH, Potkin SG, Preda A, Fan F, Ehrlich S, King MD, De Haan L, Veltman DJ, Assogna F, Banaj N, de Rossi P, Iorio M, Piras F, Spalletta G, Pomarol-Clotet E, Kelly S, Ciufolini S, Radua J, Murray R, Marques TR, Simmons A, Borgwardt S, Schönborn-Harrisberger F, Riecher-Rössler A, Smieskova R, Alpert KI, Bertolino A, Bonvino A, Di Giorgio A, Neilson E, Mayer AR, Yun JY, Cannon DM, Lebedeva I, Tomyshev AS, Akhadov T, Kaleda V, Fatouros-Bergman H, Flyckt L, Rosa PGP, Serpa MH, Zanetti MV, Hoschl C, Skoch A, Spaniel F, Tomecek D, McIntosh AM, Whalley HC, Knöchel C, Oertel-Knöchel V, Howells FM, Stein DJ, Temmingh HS, Uhlmann A, Lopez-Jaramillo C, Dima D, Faskowitz JI, Gutman BA, Jahanshad N, Thompson PM, and Turner JA

Subjects
Brain, Humans, Magnetic Resonance Imaging, Brain Diseases, Schizophrenia
Published
2019
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7. Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium.

Author

van Erp TGM, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, Pearlson GD, Yao N, Fukunaga M, Hashimoto R, Okada N, Yamamori H, Bustillo JR, Clark VP, Agartz I, Mueller BA, Cahn W, de Zwarte SMC, Hulshoff Pol HE, Kahn RS, Ophoff RA, van Haren NEM, Andreassen OA, Dale AM, Doan NT, Gurholt TP, Hartberg CB, Haukvik UK, Jørgensen KN, Lagerberg TV, Melle I, Westlye LT, Gruber O, Kraemer B, Richter A, Zilles D, Calhoun VD, Crespo-Facorro B, Roiz-Santiañez R, Tordesillas-Gutiérrez D, Loughland C, Carr VJ, Catts S, Cropley VL, Fullerton JM, Green MJ, Henskens FA, Jablensky A, Lenroot RK, Mowry BJ, Michie PT, Pantelis C, Quidé Y, Schall U, Scott RJ, Cairns MJ, Seal M, Tooney PA, Rasser PE, Cooper G, Shannon Weickert C, Weickert TW, Morris DW, Hong E, Kochunov P, Beard LM, Gur RE, Gur RC, Satterthwaite TD, Wolf DH, Belger A, Brown GG, Ford JM, Macciardi F, Mathalon DH, O'Leary DS, Potkin SG, Preda A, Voyvodic J, Lim KO, McEwen S, Yang F, Tan Y, Tan S, Wang Z, Fan F, Chen J, Xiang H, Tang S, Guo H, Wan P, Wei D, Bockholt HJ, Ehrlich S, Wolthusen RPF, King MD, Shoemaker JM, Sponheim SR, De Haan L, Koenders L, Machielsen MW, van Amelsvoort T, Veltman DJ, Assogna F, Banaj N, de Rossi P, Iorio M, Piras F, Spalletta G, McKenna PJ, Pomarol-Clotet E, Salvador R, Corvin A, Donohoe G, Kelly S, Whelan CD, Dickie EW, Rotenberg D, Voineskos AN, Ciufolini S, Radua J, Dazzan P, Murray R, Reis Marques T, Simmons A, Borgwardt S, Egloff L, Harrisberger F, Riecher-Rössler A, Smieskova R, Alpert KI, Wang L, Jönsson EG, Koops S, Sommer IEC, Bertolino A, Bonvino A, Di Giorgio A, Neilson E, Mayer AR, Stephen JM, Kwon JS, Yun JY, Cannon DM, McDonald C, Lebedeva I, Tomyshev AS, Akhadov T, Kaleda V, Fatouros-Bergman H, Flyckt L, Busatto GF, Rosa PGP, Serpa MH, Zanetti MV, Hoschl C, Skoch A, Spaniel F, Tomecek D, Hagenaars SP, McIntosh AM, Whalley HC, Lawrie SM, Knöchel C, Oertel-Knöchel V, Stäblein M, Howells FM, Stein DJ, Temmingh HS, Uhlmann A, Lopez-Jaramillo C, Dima D, McMahon A, Faskowitz JI, Gutman BA, Jahanshad N, Thompson PM, and Turner JA

Subjects
Adolescent, Adult, Age of Onset, Aged, Brain diagnostic imaging, Case-Control Studies, Child, Female, Frontal Lobe diagnostic imaging, Frontal Lobe pathology, Humans, Linear Models, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Prefrontal Cortex diagnostic imaging, Prefrontal Cortex pathology, Severity of Illness Index, Temporal Lobe diagnostic imaging, Temporal Lobe pathology, Young Adult, Brain pathology, Schizophrenia diagnostic imaging, Schizophrenia pathology
Abstract

Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group., Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide., Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset., Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Published
2018
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8. White Matter Disruptions in Schizophrenia Are Spatially Widespread and Topologically Converge on Brain Network Hubs.

Author

Klauser P, Baker ST, Cropley VL, Bousman C, Fornito A, Cocchi L, Fullerton JM, Rasser P, Schall U, Henskens F, Michie PT, Loughland C, Catts SV, Mowry B, Weickert TW, Shannon Weickert C, Carr V, Lenroot R, Pantelis C, and Zalesky A

Subjects
Adolescent, Adult, Aged, Cerebral Cortex diagnostic imaging, Corpus Callosum diagnostic imaging, Female, Gyrus Cinguli diagnostic imaging, Humans, Male, Middle Aged, Neural Pathways diagnostic imaging, Thalamus diagnostic imaging, Young Adult, Connectome methods, Diffusion Tensor Imaging methods, Nerve Net diagnostic imaging, Psychotic Disorders diagnostic imaging, Schizophrenia diagnostic imaging, White Matter diagnostic imaging
Abstract

White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain's fiber bundles., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2017
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9. Evaluating complex medical treatment options: a case report.

Author

Fernando I, Henskens F, and Talebian M

Subjects
Aged, Antipsychotic Agents therapeutic use, Female, Humans, Software, Clozapine therapeutic use, Decision Making, Patient Participation, Schizophrenia drug therapy
Abstract

Objective: Complex treatment decisions can be suboptimal due to lack of a reliable decision-making model, a need this paper aims to meet., Method: A model for making complex treatment decisions is introduced., Results: The utility of the proposed method is demonstrated by making a complex treatment decision involving evaluation of clozapine treatment in a treatment-resistant patient., Conclusion: The proposed method implemented as a software tool can provide a framework for shared decision-making involving the patient.

Published
2017
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10. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

Author

Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, Antaki D, Shetty A, Holmans PA, Pinto D, Gujral M, Brandler WM, Malhotra D, Wang Z, Fajarado KVF, Maile MS, Ripke S, Agartz I, Albus M, Alexander M, Amin F, Atkins J, Bacanu SA, Belliveau RA Jr, Bergen SE, Bertalan M, Bevilacqua E, Bigdeli TB, Black DW, Bruggeman R, Buccola NG, Buckner RL, Bulik-Sullivan B, Byerley W, Cahn W, Cai G, Cairns MJ, Campion D, Cantor RM, Carr VJ, Carrera N, Catts SV, Chambert KD, Cheng W, Cloninger CR, Cohen D, Cormican P, Craddock N, Crespo-Facorro B, Crowley JJ, Curtis D, Davidson M, Davis KL, Degenhardt F, Del Favero J, DeLisi LE, Dikeos D, Dinan T, Djurovic S, Donohoe G, Drapeau E, Duan J, Dudbridge F, Eichhammer P, Eriksson J, Escott-Price V, Essioux L, Fanous AH, Farh KH, Farrell MS, Frank J, Franke L, Freedman R, Freimer NB, Friedman JI, Forstner AJ, Fromer M, Genovese G, Georgieva L, Gershon ES, Giegling I, Giusti-Rodríguez P, Godard S, Goldstein JI, Gratten J, de Haan L, Hamshere ML, Hansen M, Hansen T, Haroutunian V, Hartmann AM, Henskens FA, Herms S, Hirschhorn JN, Hoffmann P, Hofman A, Huang H, Ikeda M, Joa I, Kähler AK, Kahn RS, Kalaydjieva L, Karjalainen J, Kavanagh D, Keller MC, Kelly BJ, Kennedy JL, Kim Y, Knowles JA, Konte B, Laurent C, Lee P, Lee SH, Legge SE, Lerer B, Levy DL, Liang KY, Lieberman J, Lönnqvist J, Loughland CM, Magnusson PKE, Maher BS, Maier W, Mallet J, Mattheisen M, Mattingsdal M, McCarley RW, McDonald C, McIntosh AM, Meier S, Meijer CJ, Melle I, Mesholam-Gately RI, Metspalu A, Michie PT, Milani L, Milanova V, Mokrab Y, Morris DW, Müller-Myhsok B, Murphy KC, Murray RM, Myin-Germeys I, Nenadic I, Nertney DA, Nestadt G, Nicodemus KK, Nisenbaum L, Nordin A, O'Callaghan E, O'Dushlaine C, Oh SY, Olincy A, Olsen L, O'Neill FA, Van Os J, Pantelis C, Papadimitriou GN, Parkhomenko E, Pato MT, Paunio T, Perkins DO, Pers TH, Pietiläinen O, Pimm J, Pocklington AJ, Powell J, Price A, Pulver AE, Purcell SM, Quested D, Rasmussen HB, Reichenberg A, Reimers MA, Richards AL, Roffman JL, Roussos P, Ruderfer DM, Salomaa V, Sanders AR, Savitz A, Schall U, Schulze TG, Schwab SG, Scolnick EM, Scott RJ, Seidman LJ, Shi J, Silverman JM, Smoller JW, Söderman E, Spencer CCA, Stahl EA, Strengman E, Strohmaier J, Stroup TS, Suvisaari J, Svrakic DM, Szatkiewicz JP, Thirumalai S, Tooney PA, Veijola J, Visscher PM, Waddington J, Walsh D, Webb BT, Weiser M, Wildenauer DB, Williams NM, Williams S, Witt SH, Wolen AR, Wormley BK, Wray NR, Wu JQ, Zai CC, Adolfsson R, Andreassen OA, Blackwood DHR, Bramon E, Buxbaum JD, Cichon S, Collier DA, Corvin A, Daly MJ, Darvasi A, Domenici E, Esko T, Gejman PV, Gill M, Gurling H, Hultman CM, Iwata N, Jablensky AV, Jönsson EG, Kendler KS, Kirov G, Knight J, Levinson DF, Li QS, McCarroll SA, McQuillin A, Moran JL, Mowry BJ, Nöthen MM, Ophoff RA, Owen MJ, Palotie A, Pato CN, Petryshen TL, Posthuma D, Rietschel M, Riley BP, Rujescu D, Sklar P, St Clair D, Walters JTR, Werge T, Sullivan PF, O'Donovan MC, Scherer SW, Neale BM, and Sebat J

Subjects
Case-Control Studies, Female, Genetic Predisposition to Disease, Genotype, Humans, Male, Risk Factors, DNA Copy Number Variations genetics, Genetic Loci genetics, Genetic Markers genetics, Genome-Wide Association Study, Schizophrenia genetics
Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10 -15 ), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10 -6 ). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10 -11 ) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10 -5 ). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Published
2017
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11. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.

Author

Mehta D, Tropf FC, Gratten J, Bakshi A, Zhu Z, Bacanu SA, Hemani G, Magnusson PK, Barban N, Esko T, Metspalu A, Snieder H, Mowry BJ, Kendler KS, Yang J, Visscher PM, McGrath JJ, Mills MC, Wray NR, Lee SH, Andreassen OA, Bramon E, Bruggeman R, Buxbaum JD, Cairns MJ, Cantor RM, Cloninger CR, Cohen D, Crespo-Facorro B, Darvasi A, DeLisi LE, Dinan T, Djurovic S, Donohoe G, Drapeau E, Escott-Price V, Freimer NB, Georgieva L, de Haan L, Henskens FA, Joa I, Julià A, Khrunin A, Lerer B, Limborska S, Loughland CM, Macek M Jr, Magnusson PK, Marsal S, McCarley RW, McIntosh AM, McQuillin A, Melegh B, Michie PT, Morris DW, Murphy KC, Myin-Germeys I, Olincy A, Van Os J, Pantelis C, Posthuma D, Quested D, Schall U, Scott RJ, Seidman LJ, Toncheva D, Tooney PA, Waddington J, Weinberger DR, Weiser M, and Wu JQ

Subjects
Adult, Alleles, Cohort Studies, Denmark, Female, Genetic Predisposition to Disease genetics, Humans, Phenotype, Pregnancy, Risk, Birth Order, Genome-Wide Association Study, Maternal Age, Schizophrenia genetics
Abstract

Importance: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age., Objective: To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets., Design, Setting, and Participants: This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study., Main Outcomes and Measures: We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age., Results: We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014., Conclusions and Relevance: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Published
2016
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12. Australian Schizophrenia Research Bank: a database of comprehensive clinical, endophenotypic and genetic data for aetiological studies of schizophrenia.

Author

Loughland C, Draganic D, McCabe K, Richards J, Nasir A, Allen J, Catts S, Jablensky A, Henskens F, Michie P, Mowry B, Pantelis C, Schall U, Scott R, Tooney P, and Carr V

Subjects
Adolescent, Adult, Aged, Australia epidemiology, Brain diagnostic imaging, Female, Humans, Male, Marital Status, Middle Aged, Psychiatric Status Rating Scales, Radiography, Schizophrenia blood, Schizophrenia diagnostic imaging, Schizophrenia etiology, Schizophrenia genetics, Schizophrenic Psychology, Socioeconomic Factors, Young Adult, Databases, Factual statistics & numerical data, Schizophrenia epidemiology
Abstract

Objective: This article describes the establishment of the Australian Schizophrenia Research Bank (ASRB), which operates to collect, store and distribute linked clinical, cognitive, neuroimaging and genetic data from a large sample of people with schizophrenia and healthy controls., Method: Recruitment sources for the schizophrenia sample include a multi-media national advertising campaign, inpatient and community treatment services and non-government support agencies. Healthy controls have been recruited primarily through multi-media advertisements. All participants undergo an extensive diagnostic and family history assessment, neuropsychological evaluation, and blood sample donation for genetic studies. Selected individuals also complete structural MRI scans., Results: Preliminary analyses of 493 schizophrenia cases and 293 healthy controls are reported. Mean age was 39.54 years (SD = 11.1) for the schizophrenia participants and 37.38 years (SD = 13.12) for healthy controls. Compared to the controls, features of the schizophrenia sample included a higher proportion of males (cases 65.9%; controls 46.8%), fewer living in married or de facto relationships (cases 16.1%; controls 53.6%) and fewer years of education (cases 13.05, SD = 2.84; controls 15.14, SD = 3.13), as well as lower current IQ (cases 102.68, SD = 15.51; controls 118.28, SD = 10.18). These and other sample characteristics are compared to those reported in another large Australian sample (i.e. the Low Prevalence Disorders Study), revealing some differences that reflect the different sampling methods of these two studies., Conclusion: The ASRB is a valuable and accessible schizophrenia research facility for use by approved scientific investigators. As recruitment continues, the approach to sampling for both cases and controls will need to be modified to ensure that the ASRB samples are as broadly representative as possible of all cases of schizophrenia and healthy controls.

Published
2010
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13. Virtual Ontogeny of Cortical Growth Preceding Mental Illness

Author

Patel, Yash, Shin, Jean, Abé, Christoph, Agartz, Ingrid, Alloza, Clara, Alnæs, Dag, Ambrogi, Sonia, Antonucci, Linda A, Arango, Celso, Arolt, Volker, Auzias, Guillaume, Ayesa-Arriola, Rosa, Banaj, Nerisa, Banaschewski, Tobias, Bandeira, Cibele, Başgöze, Zeynep, Cupertino, Renata Basso, Bau, Claiton HD, Bauer, Jochen, Baumeister, Sarah, Bernardoni, Fabio, Bertolino, Alessandro, Bonnin, Caterina Del Mar, Brandeis, Daniel, Brem, Silvia, Bruggemann, Jason, Bülow, Robin, Bustillo, Juan R, Calderoni, Sara, Calvo, Rosa, Canales-Rodríguez, Erick J, Cannon, Dara M, Carmona, Susanna, Carr, Vaughan J, Catts, Stanley V, Chenji, Sneha, Chew, Qian Hui, Coghill, David, Connolly, Colm G, Conzelmann, Annette, Craven, Alexander R, Crespo-Facorro, Benedicto, Cullen, Kathryn, Dahl, Andreas, Dannlowski, Udo, Davey, Christopher G, Deruelle, Christine, Díaz-Caneja, Covadonga M, Dohm, Katharina, Ehrlich, Stefan, Epstein, Jeffery, Erwin-Grabner, Tracy, Eyler, Lisa T, Fedor, Jennifer, Fitzgerald, Jacqueline, Foran, William, Ford, Judith M, Fortea, Lydia, Fuentes-Claramonte, Paola, Fullerton, Janice, Furlong, Lisa, Gallagher, Louise, Gao, Bingchen, Gao, Si, Goikolea, Jose M, Gotlib, Ian, Goya-Maldonado, Roberto, Grabe, Hans J, Green, Melissa, Grevet, Eugenio H, Groenewold, Nynke A, Grotegerd, Dominik, Gruber, Oliver, Haavik, Jan, Hahn, Tim, Harrison, Ben J, Heindel, Walter, Henskens, Frans, Heslenfeld, Dirk J, Hilland, Eva, Hoekstra, Pieter J, Hohmann, Sarah, Holz, Nathalie, Howells, Fleur M, Ipser, Jonathan C, Jahanshad, Neda, Jakobi, Babette, Jansen, Andreas, Janssen, Joost, Jonassen, Rune, Kaiser, Anna, Kaleda, Vasiliy, Karantonis, James, King, Joseph A, Kircher, Tilo, Kochunov, Peter, Koopowitz, Sheri-Michelle, Landén, Mikael, Landrø, Nils Inge, and Lawrie, Stephen

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Psychology, Neurosciences, Genetics, Mental Health, Serious Mental Illness, Mental Illness, Women's Health, Brain Disorders, Preterm, Low Birth Weight and Health of the Newborn, Pregnancy, Pediatric, Perinatal Period - Conditions Originating in Perinatal Period, Behavioral and Social Science, Prevention, Schizophrenia, 2.1 Biological and endogenous factors, 2.3 Psychological, social and economic factors, Neurological, Reproductive health and childbirth, Mental health, Good Health and Well Being, Attention Deficit Disorder with Hyperactivity, Autism Spectrum Disorder, Bipolar Disorder, Cerebral Cortex, Child, Depressive Disorder, Major, Female, Humans, Infant, Newborn, Magnetic Resonance Imaging, Premature Birth, Cortical growth, Cortical surface area, Mental illness, Neurodevelopment, Neurogenesis, Psychiatric disorders, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences
Abstract

BackgroundMorphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life.MethodsInterregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed.ResultsAcross the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth.ConclusionsOur findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

Published
2022

14. Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA

Author

Radua, Joaquim, Vieta, Eduard, Shinohara, Russell, Kochunov, Peter, Quidé, Yann, Green, Melissa J, Weickert, Cynthia S, Weickert, Thomas, Bruggemann, Jason, Kircher, Tilo, Nenadić, Igor, Cairns, Murray J, Seal, Marc, Schall, Ulrich, Henskens, Frans, Fullerton, Janice M, Mowry, Bryan, Pantelis, Christos, Lenroot, Rhoshel, Cropley, Vanessa, Loughland, Carmel, Scott, Rodney, Wolf, Daniel, Satterthwaite, Theodore D, Tan, Yunlong, Sim, Kang, Piras, Fabrizio, Spalletta, Gianfranco, Banaj, Nerisa, Pomarol-Clotet, Edith, Solanes, Aleix, Albajes-Eizagirre, Anton, Canales-Rodríguez, Erick J, Sarro, Salvador, Di Giorgio, Annabella, Bertolino, Alessandro, Stäblein, Michael, Oertel, Viola, Knöchel, Christian, Borgwardt, Stefan, du Plessis, Stefan, Yun, Je-Yeon, Kwon, Jun Soo, Dannlowski, Udo, Hahn, Tim, Grotegerd, Dominik, Alloza, Clara, Arango, Celso, Janssen, Joost, Díaz-Caneja, Covadonga, Jiang, Wenhao, Calhoun, Vince, Ehrlich, Stefan, Yang, Kun, Cascella, Nicola G, Takayanagi, Yoichiro, Sawa, Akira, Tomyshev, Alexander, Lebedeva, Irina, Kaleda, Vasily, Kirschner, Matthias, Hoschl, Cyril, Tomecek, David, Skoch, Antonin, van Amelsvoort, Therese, Bakker, Geor, James, Anthony, Preda, Adrian, Weideman, Andrea, Stein, Dan J, Howells, Fleur, Uhlmann, Anne, Temmingh, Henk, López-Jaramillo, Carlos, Díaz-Zuluaga, Ana, Fortea, Lydia, Martinez-Heras, Eloy, Solana, Elisabeth, Llufriu, Sara, Jahanshad, Neda, Thompson, Paul, Turner, Jessica, van Erp, Theo, collaborators, ENIGMA Consortium, Glahn, David, Pearlson, Godfrey, Hong, Elliot, Krug, Axel, Carr, Vaughan, Tooney, Paul, Cooper, Gavin, Rasser, Paul, Michie, Patricia, Catts, Stanley, Gur, Raquel, Gur, Ruben, Yang, Fude, Fan, Fengmei, Chen, Jingxu, and Guo, Hua

Subjects
Brain Disorders, Biomedical Imaging, Mental Health, Schizophrenia, Neurosciences, Mental health, Adult, Algorithms, Cerebral Cortex, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Meta-Analysis as Topic, Middle Aged, Neuroimaging, Young Adult, Brain, Cortical thickness, Gray matter, Mega-analysis, Volume, ENIGMA Consortium collaborators, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Published
2020

15. Biological insights from 108 schizophrenia-associated genetic loci

Author

Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Walters, James TR, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A Jr, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, and Joa, Inge

Subjects
Human Genome, Brain Disorders, Serious Mental Illness, Prevention, Schizophrenia, Genetics, Neurosciences, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Mental health, Alleles, Brain, Enhancer Elements, Genetic, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Glutamic Acid, Humans, Immunity, Multifactorial Inheritance, Mutation, Odds Ratio, Polymorphism, Single Nucleotide, Synaptic Transmission, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

Published
2014

16. Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Author

Schijven, Dick, Postema, Merel C, Fukunaga, Masaki, Matsumoto, Junya, Miura, Kenichiro, de Zwarte, Sonja MC, van Haren, Neeltje EM, Cahn, Wiepke, Hulshoff Pol, Hilleke E, Kahn, René S, Ayesa-Arriola, Rosa, Ortiz-García de la Foz, Víctor, Tordesillas-Gutierrez, Diana, Vázquez-Bourgon, Javier, Crespo-Facorro, Benedicto, Alnæs, Dag, Dahl, Andreas, Westlye, Lars T, Agartz, Ingrid, Andreassen, Ole A, Jönsson, Erik G, Kochunov, Peter, Bruggemann, Jason M, Catts, Stanley V, Michie, Patricia T, Mowry, Bryan J, Quidé, Yann, Rasser, Paul E, Schall, Ulrich, Scott, Rodney J, Carr, Vaughan J, Green, Melissa J, Henskens, Frans A, Loughland, Carmel M, Pantelis, Christos, Weickert, Cynthia Shannon, Weickert, Thomas W, de Haan, Lieuwe, Brosch, Katharina, Pfarr, Julia-Katharina, Ringwald, Kai G, Stein, Frederike, Jansen, Andreas, Kircher, Tilo TJ, Nenadić, Igor, Krämer, Bernd, Gruber, Oliver, Satterthwaite, Theodore D, Bustillo, Juan, Mathalon, Daniel H, Preda, Adrian, Calhoun, Vince D, Ford, Judith M, Potkin, Steven G, Chen, Jingxu, Tan, Yunlong, Wang, Zhiren, Xiang, Hong, Fan, Fengmei, Bernardoni, Fabio, Ehrlich, Stefan, Fuentes-Claramonte, Paola, Garcia-Leon, Maria Angeles, Guerrero-Pedraza, Amalia, Salvador, Raymond, Sarró, Salvador, Pomarol-Clotet, Edith, Ciullo, Valentina, Piras, Fabrizio, Vecchio, Daniela, Banaj, Nerisa, Spalletta, Gianfranco, Michielse, Stijn, van Amelsvoort, Therese, Dickie, Erin W, Voineskos, Aristotle N, Sim, Kang, Ciufolini, Simone, Dazzan, Paola, Murray, Robin M, Kim, Woo-Sung, Chung, Young-Chul, Andreou, Christina, Schmidt, André, Borgwardt, Stefan, McIntosh, Andrew M, Whalley, Heather C, Lawrie, Stephen M, du Plessis, Stefan, Luckhoff, Hilmar K, Scheffler, Freda, Emsley, Robin, Grotegerd, Dominik, Lencer, Rebekka, Dannlowski, Udo, Edmond, Jesse T, Rootes-Murdy, Kelly, Stephen, Julia M, Mayer, Andrew R, and Antonucci, Linda A

Subjects
Cerebral Cortex, Male, Neurosciences, Brain, brain imaging, cortical, Magnetic Resonance Imaging, Functional Laterality, Brain Disorders, subcortical, Mental Health, Clinical Research, Case-Control Studies, Schizophrenia, Humans, Female, Mental health, asymmetry
Abstract

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Published
2023

17. Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Author

Constantinides, Constantinos, Han, Laura KM, Alloza, Clara, Antonucci, Linda Antonella, Arango, Celso, Ayesa-Arriola, Rosa, Banaj, Nerisa, Bertolino, Alessandro, Borgwardt, Stefan, Bruggemann, Jason, Bustillo, Juan, Bykhovski, Oleg, Calhoun, Vince, Carr, Vaughan, Catts, Stanley, Chung, Young-Chul, Crespo-Facorro, Benedicto, Díaz-Caneja, Covadonga M, Donohoe, Gary, Plessis, Stefan Du, Edmond, Jesse, Ehrlich, Stefan, Emsley, Robin, Eyler, Lisa T, Fuentes-Claramonte, Paola, Georgiadis, Foivos, Green, Melissa, Guerrero-Pedraza, Amalia, Ha, Minji, Hahn, Tim, Henskens, Frans A, Holleran, Laurena, Homan, Stephanie, Homan, Philipp, Jahanshad, Neda, Janssen, Joost, Ji, Ellen, Kaiser, Stefan, Kaleda, Vasily, Kim, Minah, Kim, Woo-Sung, Kirschner, Matthias, Kochunov, Peter, Kwak, Yoo Bin, Kwon, Jun Soo, Lebedeva, Irina, Liu, Jingyu, Mitchie, Patricia, Michielse, Stijn, Mothersill, David, Mowry, Bryan, de la Foz, Víctor Ortiz-García, Pantelis, Christos, Pergola, Giulio, Piras, Fabrizio, Pomarol-Clotet, Edith, Preda, Adrian, Quidé, Yann, Rasser, Paul E, Rootes-Murdy, Kelly, Salvador, Raymond, Sangiuliano, Marina, Sarró, Salvador, Schall, Ulrich, Schmidt, André, Scott, Rodney J, Selvaggi, Pierluigi, Sim, Kang, Skoch, Antonin, Spalletta, Gianfranco, Spaniel, Filip, Thomopoulos, Sophia I, Tomecek, David, Tomyshev, Alexander S, Tordesillas-Gutiérrez, Diana, van Amelsvoort, Therese, Vázquez-Bourgon, Javier, Vecchio, Daniela, Voineskos, Aristotle, Weickert, Cynthia S, Weickert, Thomas, Thompson, Paul M, Schmaal, Lianne, van Erp, Theo GM, Turner, Jessica, Cole, James H, ENIGMA Schizophrenia Consortium, Dima, Danai, and Walton, Esther

Subjects
Adult, Male, Aging, ENIGMA Schizophrenia Consortium, Adolescent, Medical and Health Sciences, Young Adult, Clinical Research, Behavioral and Social Science, Humans, Prospective Studies, Aged, Psychiatry, Psychology and Cognitive Sciences, Neurosciences, Brain, Middle Aged, Biological Sciences, Serious Mental Illness, Magnetic Resonance Imaging, Brain Disorders, Mental Health, Good Health and Well Being, Neurological, Schizophrenia, Biomedical Imaging, Female, Mental health
Abstract

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Published
2023

18. A polygenic resilience score moderates the genetic risk for schizophrenia

Author

Hess, Jonathan L, Tylee, Daniel S, Mors, Ole, Duan, Jubao, Dudbridge, Frank, Duncanson, Audrey, Durmishi, Naser, Edkins, Sarah, Ehrenreich, Hannelore, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Esko, Tõnu, Nordentoft, Merete, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freeman, Colin, Freimer, Nelson B, Friedl, Marion, Hougaard, David M, Friedman, Joseph I, Fromer, Menachem, Gejman, Pablo V, Genovese, Giulio, Georgieva, Lyudmila, Giannoulatou, Eleni, Giegling, Ina, Gill, Michael, Gillman, Matthew, Giusti-Rodríguez, Paola, Byberg-Grauholm, Jonas, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Gray, Emma, Gurling, Hugh, Gwilliam, Rhian, de Haan, Lieuwe, Hall, Jeremy, Bækvad-Hansen, Marie, Hammer, Christian, Hammond, Naomi, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Hellenthal, Garrett, Henskens, Frans A, Herms, Stefan, Greenwood, Tiffany A, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Huang, Hailiang, Hultman, Christina M, Hunt, Sarah E, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, Tsuang, Ming T, Jablensky, Assen V, Jankowski, Janusz, Jayakumar, Alagurevathi, Joa, Inge, Jönsson, Erik G, Julià, Antonio, Kähler, Anna K, Kahn, René S, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Curtis, David, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kendler, Kenneth S, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Kirov, George, Klovins, Janis, Knight, Jo, Steinberg, Stacy, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Langford, Cordelia, Laurent, Claudine, Lawrie, Stephen, Lee, S Hong, Lee, Phil, Sigurdsson, Engilbert, Lee, Jimmy, Legge, Sophie E, Lencz, Todd, Lerer, Bernard, Levinson, Douglas F, Lewis, Cathryn M, Li, Tao, Li, Qingqin S, Li, Miaoxin, Liang, Kung-Yee, Mattheisen, Manuel, Stefánsson, Hreinn, Liddle, Jennifer, Lieberman, Jeffrey, Limborska, Svetlana, Lin, Kuang, Linszen, Don H, Liu, Jianjun, Lönnqvist, Jouko, Loughland, Carmel M, Lubinski, Jan, Macek, Milan, Stefánsson, Kári, Magnusson, Patrik K E, Maher, Brion S, Maier, Wolfgang, Malhotra, Anil K, Mallet, Jacques, Markus, Hugh S, Marsal, Sara, Mata, Ignacio, Mathew, Christopher G, Mattingsdal, Morten, Edenberg, Howard J, McCann, Owen T, McCarley, Robert W, McCarroll, Steven A, McCarthy, Mark I, McDonald, Colm, McIntosh, Andrew M, McQuillin, Andrew, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Holmans, Peter, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Moran, Jennifer L, Morris, Derek W, Mowry, Bryan J, Faraone, Stephen V, Müller-Myhsok, Bertram, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Neale, Benjamin M, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Glatt, Stephen J, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, Nöthen, Markus M, O'Callaghan, Eadbhard, O'Donovan, Michael C, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Adolfsson, Rolf, Olsen, Line, Ophoff, Roel A, Van Os, Jim, Owen, Michael J, Palmer, Colin N A, Palotie, Aarno, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Agartz, Ingrid, Pato, Michele T, Pato, Carlos N, Paunio, Tiina, Pearson, Richard, Cairns, Murray J, DeLisi, Lynn E, Gershon, Elliot S, Kelly, Brian J, Lam, Max, Norgren, Nina, Agerbo, Esben, Paciga, Sara A, Tooney, Paul A, Wu, Jing Qin, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pers, Tune H, Petryshen, Tracey L, Pietiläinen, Olli, Pimm, Jonathan, Pirinen, Matti, Albus, Margot, Plomin, Robert, Pocklington, Andrew J, Posthuma, Danielle, Potter, Simon C, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Alexander, Madeline, Rautanen, Anna, Ravindrarajah, Radhi, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Ricketts, Michelle, Rietschel, Marcella, Riley, Brien P, Ripke, Stephan, Roffman, Joshua L, Amin, Farooq, Roussos, Panos, Ruderfer, Douglas M, Rujescu, Dan, Salomaa, Veikko, Sanders, Alan R, Sawcer, Stephen J, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Andreassen, Ole A, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Sham, Pak C, Shi, Jianxin, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Sklar, Pamela, Arranz, Maria J, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Söderman, Erik, Spencer, Chris C A, Clair, David St, Stahl, Eli A, Stogmann, Elisabeth, Strange, Amy, Straub, Richard E, Bacanu, Silviu A, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Su, Zhan, Subramaniam, Mythily, Sullivan, Patrick F, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Tashakkori-Ghanbaria, Avazeh, Bakker, Steven, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Trembath, Richard C, Veijola, Juha, Visscher, Peter M, Viswanathan, Ananth C, Vukcevic, Damjan, Waddington, John, Waller, Matthew, Band, Gavin, Walsh, Dermot, Walshe, Muriel, Walters, James T R, Wang, Qiang, Wang, Dai, Webb, Bradley T, Weinberger, Daniel R, Weisbrod, Matthias, Weiser, Mark, Wendland, Jens R, Barroso, Ines, Weston, Paul, Whittaker, Pamela, Widaa, Sara, Wiersma, Durk, Wildenauer, Dieter B, Williams, Stephanie, Williams, Nigel M, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily H M, Begemann, Martin, Wood, Nicholas W, Wormley, Brandon K, Wray, Naomi R, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Bellenguez, Céline, Research, Lundbeck Foundation Initiative for Integrative Psychiatric, Belliveau, Richard A, Bender, Stephan, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Blackburn, Hannah, Blackwell, Jenefer M, Blackwood, Douglas H R, Børglum, Anders D, Bramon, Elvira, Brown, Matthew A, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Bumpstead, Suzannah J, Buxbaum, Joseph D, Byerley, William, Cahn, Wiepke, Als, Thomas D, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Casas, Juan P, Catts, Stanley V, Chambert, Kimberley D, Chan, Ronald Y L, Chan, Raymond C K, Grove, Jakob, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cichon, Sven, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Collier, David A, Cormican, Paul, Werge, Thomas, Corvin, Aiden, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Daly, Mark J, Darvasi, Ariel, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Mortensen, Preben Bo, Deloukas, Panos, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Domenici, Enrico, Donnelly, Peter, Donohoe, Gary, Drapeau, Elodie, Dronov, Serge, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Adult Psychiatry, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Hess, Jonathan L, Tylee, Daniel S, Mattheisen, Manuel, Borglum, Anders D, Glatt, Stephen J, Lee, Sand Hong, Schizophrenia Working Group of thePsychiatric Genomics Consortium, Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, and Myin-Germeys, Inez

Subjects
Multifactorial Inheritance, Schizophrenia/genetics, Genome-wide association study, Disease, Medical and Health Sciences, 0302 clinical medicine, Risk Factors, schizophrenia, genetics, risk, 2.1 Biological and endogenous factors, genetics, polygenic score, Aetiology, genome wide association study, risk, Genetics, Psychiatry, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Genetic Predisposition to Disease/genetics, Single Nucleotide, Genomics, Biological Sciences, Serious Mental Illness, Polymorphism, Single Nucleotide/genetics, Penetrance, 3. Good health, Psychiatry and Mental health, Mental Health, Mendelian disease, Erfðarannsóknir, Life Sciences & Biomedicine, Single Nucleotide/genetics, Biochemistry & Molecular Biology, Schizophrenia (object-oriented programming), high risk, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Geðklofi, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Polymorphism, Resilience (network), Molecular Biology, resilience, Multifactorial Inheritance/genetics, Alleles, 030304 developmental biology, Science & Technology, Prevention, Human Genome, Psychology and Cognitive Sciences, Neurosciences, Brain Disorders, Lundbeck Foundation Initiative for Integrative Psychiatric Research, schizophrenia, Good Health and Well Being, Schizophrenia, Neurosciences & Neurology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Publisher's version (útgefin grein), Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531–538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known “polygenic resilience score” that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder., SJG is supported by grants from the U.S. National Institutes of Health (5R01MH101519, 5R01AG054002), the Sidney R. Baer, Jr. Foundation, and NARSAD: The Brain & Behavior Research Foundation. SVF is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway, the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreement number 667302 and NIMH grants 5R01MH101519 and U01 MH109536-01. HJE is supported by grants from the U.S. National Institutes of Health (U10 AA008401; U01 MH109532). Statistical analyses were conducted on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003) along with a supplement from the Dutch Brain Foundation and VU University. The Danish iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and GEMS2 teams acknowledge funding from The Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no: 294838), the Danish Strategic Research Council and grants from Aarhus University to the iSEQ and CIRRAU centers. The Danish National Biobank resource at Statens Serum Institut was supported by the Novo Nordisk Foundation. Computational resources for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility were provided by the iSEQ center, Aarhus University, Denmark (grant to ADB).

Published
2021

19. Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Author

Pardiñas, Antonio F., Smart, Sophie E., Corvin, Aiden, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S., Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Fanous, Ayman H., Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, Haan, Lieuwe de, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Frank, Josef, Hartmann, Annette M., Henskens, Frans A., Herms, Stefan, Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Kelly, Brian, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C., Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, McQuillin, Andrew, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Keong, Jimmy Lee Chee, Lee, S. Hong, Melle, Ingrid, Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Mortensen, Preben B., Magnusson, Patrik K. E., Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Mowry, Bryan J., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Pato, Carlos N., Morris, Derek W., Mors, Ole, Murphy, Kieran C., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Periyasamy, Sathish, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O’Callaghan, Eadbhard, O’Dushlaine, Colm, O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Os, Jim Van, Willcocks, Isabella R., Rietschel, Marcella, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Rujescu, Dan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Simonsen, Carmen, Roffman, Joshua L., Roussos, Panos, Ruderfer, Douglas M., Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schulze, Thomas G., Schwab, Sibylle G., Scolnick, Edward M., St Clair, David, Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon-Cheong, Tooney, Paul, Spencer, Chris C. A., Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Strohmaier, Jana, Stroup, T. Scott, Subramaniam, Mythily, Wu, Jing Qin, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Andreassen, Ole A., Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Witt, Stephanie H., Wolen, Aaron R., Wong, Emily H. M., Kowalec, Kaarina, Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Blackwood, Douglas H. R., Sullivan, Patrick F., Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Murray, Robin M., Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Holmans, Peter A., Owen, Michael J., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., Moran, Jennifer L., Nöthen, Markus M., Ophoff, Roel A., Palotie, Aarno, Petryshen, Tracey L., MacCabe, James H., Posthuma, Danielle, Riley, Brien P., Sham, Pak C., Sklar, Pamela, Clair, David St, Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., Agbedjro, Deborah, O’Donovan, Michael C., Stahl, Daniel, Kapur, Shitij, Millgate, Edward, Kepinska, Adrianna, Kravariti, Eugenia, Ajnakina, Olesya, Alameda, Luis, Barnes, Thomas R. E., Berardi, Domenico, Bonora, Elena, Walters, James T. R., Camporesi, Sara, Cleusix, Martine, Conus, Philippe, Crespo-Facorro, Benedicto, D’Andrea, Giuseppe, Demjaha, Arsime, Do, Kim Q., Doody, Gillian A., Eap, Chin B., Ferchiou, Aziz, Ripke, Stephan, Di Forti, Marta, Guidi, Lorenzo, Homman, Lina, Jenni, Raoul, Joyce, Eileen M., Kassoumeri, Laura, Khadimallah, Inès, Lastrina, Ornella, Muratori, Roberto, Noyan, Handan, Neale, Benjamin M., O’Neill, Francis A., Pignon, Baptiste, Restellini, Romeo, Richard, Jean-Romain, Schürhoff, Franck, Španiel, Filip, Szöke, Andrei, Tarricone, Ilaria, Tortelli, Andrea, Üçok, Alp, Farh, Kai-How, Vázquez-Bourgon, Javier, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Dennison, Charlotte A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A ., Lynham, Amy J., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Legge, Sophie E., Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberly D., Chan, Raymond C. K., Chen, Ronald Y. L., Chen, Eric Y. H., Cheng, Wei, Baune, Bernhard T., Cheung, Eric F. C., Chong, Siow Ann, Cloninger, C. Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Bigdeli, Tim B., Davis, Kenneth L., Degenhardt, Franziska, Favero, Jurgen Del, DeLisi, Lynn E., Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Cairns, Murray J., Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Farrell, Martilias S., Franke, Lude, Freedman, Robert, Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances (STRATA) Consortium and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC), Ripke, S., Neale, B.M., Farh, K.H., Lee, P., Bulik-Sullivan, B., Collier, D.A., Huang, H., Pers, T.H., Agartz, I., Agerbo, E., Albus, M., Alexander, M., Amin, F., Bacanu, S.A., Begemann, M., Belliveau, R.A., Bene, J., Bergen, S.E., Bevilacqua, E., Black, D.W., Bruggeman, R., Buccola, N.G., Buckner, R.L., Byerley, W., Cahn, W., Cai, G., Campion, D., Cantor, R.M., Carr, V.J., Carrera, N., Catts, S.V., Chambert, K.D., Chan, RCK, Chen, RYL, Chen, EYH, Cheng, W., Cheung, EFC, Chong, S.A., Cloninger, C.R., Cohen, D., Cohen, N., Cormican, P., Craddock, N., Crowley, J.J., Curtis, D., Davidson, M., Davis, K.L., Degenhardt, F., Favero, J.D., DeLisi, L.E., Demontis, D., Dikeos, D., Dinan, T., Djurovic, S., Donohoe, G., Drapeau, E., Duan, J., Dudbridge, F., Durmishi, N., Eichhammer, P., Eriksson, J., Escott-Price, V., Essioux, L., Farrell, M.S., Franke, L., Freedman, R., Freimer, N.B., Friedl, M., Friedman, J.I., Fromer, M., Genovese, G., Georgieva, L., Gershon, E.S., Giegling, I., Giusti-Rodríguez, P., Godard, S., Goldstein, J.I., Golimbet, V., Gopal, S., Gratten, J., Haan, L., Hammer, C., Hamshere, M.L., Hansen, M., Hansen, T., Haroutunian, V., Hartmann, A.M., Henskens, F.A., Herms, S., Hirschhorn, J.N., Hoffmann, P., Hofman, A., Hollegaard, M.V., Hougaard, D.M., Ikeda, M., Joa, I., Julià, A., Kahn, R.S., Kalaydjieva, L., Karachanak-Yankova, S., Karjalainen, J., Kavanagh, D., Keller, M.C., Kennedy, J.L., Khrunin, A., Kim, Y., Klovins, J., Knowles, J.A., Konte, B., Kucinskas, V., Kucinskiene, Z.A., Kuzelova-Ptackova, H., Kähler, A.K., Laurent, C., Keong, JLC, Lee, S.H., Lerer, B., Li, M., Li, T., Liang, K.Y., Lieberman, J., Limborska, S., Loughland, C.M., Lubinski, J., Lönnqvist, J., Macek, M., Magnusson, PKE, Maher, B.S., Maier, W., Mallet, J., Marsal, S., Mattheisen, M., Mattingsdal, M., McCarley, R.W., McDonald, C., McIntosh, A.M., Meier, S., Meijer, C.J., Melegh, B., Melle, I., Mesholam-Gately, R.I., Metspalu, A., Michie, P.T., Milani, L., Milanova, V., Mokrab, Y., Morris, D.W., Mors, O., Murphy, K.C., Myin-Germeys, I., Müller-Myhsok, B., Nelis, M., Nenadic, I., Nertney, D.A., Nestadt, G., Nicodemus, K.K., Nikitina-Zake, L., Nisenbaum, L., Nordin, A., O'Callaghan, E., O'Dushlaine, C., O'Neill, F.A., Oh, S.Y., Olincy, A., Olsen, L., Os, J.V., Pantelis, C., Papadimitriou, G.N., Papiol, S., Parkhomenko, E., Pato, M.T., Paunio, T., Pejovic-Milovancevic, M., Perkins, D.O., Pietiläinen, O., Pimm, J., Pocklington, A.J., Powell, J., Price, A., Pulver, A.E., Purcell, S.M., Quested, D., Rasmussen, H.B., Reichenberg, A., Reimers, M.A., Richards, A.L., Roffman, J.L., Roussos, P., Ruderfer, D.M., Salomaa, V., Sanders, A.R., Schall, U., Schubert, C.R., Schulze, T.G., Schwab, S.G., Scolnick, E.M., Scott, R.J., Seidman, L.J., Shi, J., Sigurdsson, E., Silagadze, T., Silverman, J.M., Sim, K., Slominsky, P., Smoller, J.W., So, H.C., Spencer, CCA, Stahl, E.A., Stefansson, H., Steinberg, S., Stogmann, E., Straub, R.E., Strengman, E., Strohmaier, J., Stroup, T.S., Subramaniam, M., Suvisaari, J., Svrakic, D.M., Szatkiewicz, J.P., Söderman, E., Thirumalai, S., Toncheva, D., Tosato, S., Veijola, J., Waddington, J., Walsh, D., Wang, D., Wang, Q., Webb, B.T., Weiser, M., Wildenauer, D.B., Williams, N.M., Williams, S., Witt, S.H., Wolen, A.R., Wong, EHM, Wormley, B.K., Xi, H.S., Zai, C.C., Zheng, X., Zimprich, F., Wray, N.R., Stefansson, K., Visscher, P.M., Adolfsson, R., Blackwood, DHR, Bramon, E., Buxbaum, J.D., Børglum, A.D., Cichon, S., Darvasi, A., Domenici, E., Ehrenreich, H., Esko, T., Gejman, P.V., Gill, M., Gurling, H., Hultman, C.M., Iwata, N., Jablensky, A.V., Jönsson, E.G., Kendler, K.S., Kirov, G., Knight, J., Lencz, T., Levinson, D.F., Li, Q.S., Liu, J., Malhotra, A.K., McCarroll, S.A., Moran, J.L., Mortensen, P.B., Nöthen, M.M., Ophoff, R.A., Palotie, A., Petryshen, T.L., Posthuma, D., Riley, B.P., Sham, P.C., Sklar, P., Clair, D.S., Weinberger, D.R., Wendland, J.R., Werge, T., Daly, M.J., Agbedjro, D., Stahl, D., Kapur, S., Millgate, E., Kepinska, A., Kravariti, E., Medical Research Council (UK), Cardiff University, Welsh Government, Health and Care Research Wales, European Commission, Academy of Medical Sciences (UK), Research Council of Norway, K. G. Jebsen Centres for Medical Research, National Institute for Health Research (UK), University College London, Government of Canada, University of Manitoba, Swedish Research Council, National Institute of Mental Health (US), Kings College London, Public Health Agency (Northern Ireland), The Psychiatry Research Trust, Maudsley Charity, Swiss National Science Foundation, Fondation Alamaya, Ministry of Health of the Czech Republic, Instituto de Salud Carlos III, Plan Nacional sobre Drogas (España), Fundació Seny, Fundación Marques de Valdecilla, Ministerio de Economía y Competitividad (España), Wellcome Trust, and Universidad de Cantabria

Subjects
Male, endocrine system, Multifactorial Inheritance, animal structures, Psychiatry and Behavioral Health, Online First, Humans, Genetic Predisposition to Disease, ddc:610, Neurogenetics, Medicinsk genetik, Original Investigation, Research, Schizophrenia Sprectum and Other Psychotic Disorders, Featured, Genetics and genomics, Psychiatry and Mental health, Neurology, Psychotic Disorders, Schizophrenia, Female, Medical Genetics, hormones, hormone substitutes, and hormone antagonists, Comments, Genome-Wide Association Study
Abstract

[Importance] About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts., [Objective] To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples., [Design, Setting, and Participants] Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G])., [Main Outcomes and Measures] GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition., [Results] The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04)., [Conclusions and Relevance] In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance., This work was supported by Medical Research Council Centre grant MR/L010305/1, Medical Research Council Program grant MR/P005748/1, and Medical Research Council Project grants MR/L011794/1 and MC_PC_17212 to Cardiff University and by the National Centre for Mental Health, funded by the Welsh Government through Health and Care Research Wales. This work acknowledges the support of the Supercomputing Wales project, which is partially funded by the European Regional Development Fund via the Welsh Government. Dr Pardiñas was supported by an Academy of Medical Sciences Springboard Award (SBF005\1083). Dr Andreassen was supported by the Research Council of Norway (grants 283798, 262656, 248980, 273291, 248828, 248778, and 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, and the European Union’s Horizon 2020 Research and Innovation Programme (grant 847776). Dr Ajnakina was supported by an National Institute for Health Research postdoctoral fellowship (PDF-2018-11-ST2-020). Dr Joyce was supported by the University College London Hospitals/UCL University College London Biomedical Research Centre. Dr Kowalec received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement (793530) from the government of Canada Banting postdoctoral fellowship programme and the University of Manitoba. Dr Sullivan was supported by the Swedish Research Council (Vetenskapsrådet, D0886501), the European Union’s Horizon 2020 programme (COSYN, 610307) and the US National Institute of Mental Health (U01 MH109528 and R01 MH077139). The Psychiatric Genomics Consortium was partly supported by the National Institute Of Mental Health (grants R01MH124873). The Sweden Schizophrenia Study was supported by the National Institute Of Mental Health (grant R01MH077139). The STRATA consortium was supported by a Stratified Medicine Programme grant to Dr MacCabe from the Medical Research Council (grant MR/L011794/1), which funded the research and supported Drs Pardiñas, Smart, Kassoumeri, Murray, Walters, and MacCabe. Dr Smart was supported by a Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital National Health Service Foundation Trust. The AESOP (US) cohort was funded by the UK Medical Research Council (grant G0500817). The Belfast (UK) cohort was funded by the Research and Development Office of Northern Ireland. The Bologna (Italy) cohort was funded by the European Community’s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Genetics and Psychosis project (London, UK) cohort was funded by the UK National Institute of Health Research Specialist Biomedical Research Centre for Mental Health, South London and the Maudsley National Health Service Mental Health Foundation Trust (SLAM) and the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London; Psychiatry Research Trust; Maudsley Charity Research Fund; and the European Community’s Seventh Framework program (HEALTH-F2-2009-241909, project EU-GEI). The Lausanne (Switzerland) cohort was funded by the Swiss National Science Foundation (grants 320030_135736/1, 320030-120686, 324730-144064, 320030-173211, and 171804); the National Center of Competence in Research Synaptic Bases of Mental Diseases from the Swiss National Science Foundation (grant 51AU40_125759); and Fondation Alamaya. The Oslo (Norway) cohort was funded by the Research Council of Norway (grant 223273/F50, under the Centers of Excellence funding scheme, 300309, 283798) and the South-Eastern Norway Regional Health Authority (grants 2006233, 2006258, 2011085, 2014102, 2015088, and 2017-112). The Paris (France) cohort was funded by European Community’s Seventh Framework program (HEALTH-F2-2010–241909, project EU-GEI). The Prague (Czech Republic) cohort was funded by the Ministry of Health of the Czech Republic (grant NU20-04-00393). The Santander (Spain) cohort was funded by the following grants to Dr Crespo-Facorro: Instituto de Salud Carlos III (grants FIS00/3095, PI020499, PI050427, and PI060507), Plan Nacional de Drogas Research (grant 2005-Orden sco/3246/2004), SENY Fundatio Research (grant 2005-0308007), Fundacion Marques de Valdecilla (grant A/02/07, API07/011) and Ministry of Economy and Competitiveness and the European Fund for Regional Development (grants SAF2016-76046-R and SAF2013-46292-R). The West London (UK) cohort was funded by The Wellcome Trust (grants 042025, 052247, and 064607).

Published
2022

20. Complement genes contribute sex-biased vulnerability in diverse disorders

Author

Kamitaki, Nolan, Sekar, Aswin, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Boehnke, Michael, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Mitjans, Marina, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Kimberly, Robert P, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S, Kaufman, Kenneth M, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kelly, Brian J, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Harley, John B, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K, Laurent, Claudine, Keong, Jimmy Lee Chee, Lee, S Hong, Legge, Sophie E, Langefeld, Carl D, Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M, Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Seidman, Christine E, Magnusson, Patrik K E, Maher, Brion S, Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattheisen, Manuel, Mattingsdal, Morten, McCarley, Robert W, McDonald, Colm, McIntosh, Andrew M, Pato, Michele T, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Pato, Carlos N, Morris, Derek W, Mors, Ole, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Ophoff, Roel A, Nicodemus, Kristin K, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Handsaker, Robert E, Graham, Robert R, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N, Steixner, Agnes A, Parkhomenko, Elena, Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pietiläinen, Olli, Criswell, Lindsey A, Pimm, Jonathan, Pocklington, Andrew J, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Reichenberg, Abraham, Reimers, Mark A, Vyse, Timothy J, Richards, Alexander L, Roffman, Joshua L, Roussos, Panos, Ruderfer, Douglas M, Salomaa, Veikko, Sanders, Alan R, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, McCarroll, Steven A, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Slominsky, Petr, Smoller, Jordan W, Ripke, Stephan, So, Hon-Cheong, Spencer, Chris C A, Stahl, Eli A, Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Neale, Benjamin M, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tooney, Paul A, Tosato, Sarah, Veijola, Juha, Corvin, Aiden, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T, Weiser, Mark, Wildenauer, Dieter B, Williams, Nigel M, Williams, Stephanie, Witt, Stephanie H, Walters, James T R, Wolen, Aaron R, Wong, Emily H M, Wormley, Brandon K, Wu, Jing Qin, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R, Stefansson, Kari, Farh, Kai-How, Visscher, Peter M, Adolfsson, Rolf, Andreassen, Ole A, Blackwood, Douglas H R, Bramon, Elvira, Buxbaum, Joseph D, Børglum, Anders D, Cichon, Sven, Darvasi, Ariel, Domenici, Enrico, Holmans, Peter A, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V, Gill, Michael, Gurling, Hugh, Hultman, Christina M, Iwata, Nakao, Jablensky, Assen V, Jönsson, Erik G, Kendler, Kenneth S, de Rivera, Heather, Lee, Phil, Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F, Li, Qingqin S, Liu, Jianjun, Malhotra, Anil K, McQuillin, Andrew, Moran, Jennifer L, Bulik-Sullivan, Brendan, Mortensen, Preben B, Mowry, Bryan J, Nöthen, Markus M, Owen, Michael J, Palotie, Aarno, Petryshen, Tracey L, Posthuma, Danielle, Rietschel, Marcella, Collier, David A, Riley, Brien P, Rujescu, Dan, Sham, Pak C, Sklar, Pamela, Clair, David St, Weinberger, Daniel R, Wendland, Jens R, Werge, Thomas, Daly, Mark J, Sullivan, Patrick F, Huang, Hailiang, O'Donovan, Michael C, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Tooley, Katherine, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Morris, David L, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Taylor, Kimberly E, Chambert, Kimberly D, Chan, Raymond C K, Chen, Ronald Y L, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Whelan, Christopher W, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Tombleson, Philip, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Loohuis, Loes M Olde, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Adult Psychiatry, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Kamitaki, Nolan, Sekar, Aswin, Handsaker, Robert E, de Rivera, Heather, Lee, S Hong, McCarroll, Steven A, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, HUS Psychiatry, Department of Psychiatry, Center for Population, Health and Society, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Male, SLE, Sjogren's Syndrome/blood, complement cascade, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 0302 clinical medicine, MOLECULAR-BASIS, HLA Antigens, Genotype, 2.1 Biological and endogenous factors, Lupus Erythematosus, Systemic, Medicine, Aetiology, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Complement C3/analysis, SUSCEPTIBILITY VARIANTS, RISK, SJOGRENS-SYNDROME, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Complement component 4, Sex Characteristics, Multidisciplinary, Complement C4, Complement C3, HLA Antigens/genetics, Middle Aged, 3. Good health, Complement cascade, Mental Health, Sjogren's Syndrome, genetic association study, Female, ddc:500, Systemic/blood, Biotechnology, Sex characteristics, Adult, General Science & Technology, Lupus, Human leukocyte antigen, Autoimmune Disease, Lupus Erythematosus, Systemic/blood, 03 medical and health sciences, Young Adult, Systemic lupus erythematosus, C4 DEFICIENCY, SDG 3 - Good Health and Well-being, Genetics, Humans, Genetic Predisposition to Disease, Allele, Alleles, Genetic association study, Differential disease vulnerability, Lupus erythematosus, Lupus Erythematosus, business.industry, Inflammatory and immune system, Systemic, Haplotype, C4A, medicine.disease, Brain Disorders, COPY-NUMBER, 030104 developmental biology, Haplotypes, Sjögren’s syndrome, Immunology, Schizophrenia, Complement C4/analysis, AUTOANTIBODIES, 3111 Biomedicine, MHC, business, DEFICIENCY STATES, 030217 neurology & neurosurgery
Abstract

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Published
2020

21. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Author

Huckins, Laura M, Dobbyn, Amanda, Ruderfer, Douglas M, Hoffman, Gabriel, Wang, Weiqing, Pardinas, Antonio F, Rajagopal, Veera M, Als, Thomas D, Nguyen, Hoang T, Girdhar, Kiran, Boocock, James, Roussos, Panos, Fromer, Menachem, Kramer, Robin, Domenici, Enrico, Gamazon, Eric R, Purcell, Shaun, Demontis, Ditte, Borglum, Anders D, Walters, James TR, O'Donovan, Michael C, Sullivan, Patrick, Owen, Michael J, Devlin, Bernie, Sieberts, Solveig K, Cox, Nancy J, Im, Hae Kyung, Sklar, Pamela, Stahl, Eli A, Johnson, Jessica S, Shah, Hardik R, Klein, Lambertus L, Dang, Kristen K, Logsdon, Benjamin A, Mahajan, Milind C, Mangravite, Lara M, Toyoshiba, Hiroyoshi, Gur, Raquel E, Hahn, Chang-Gyu, Schadt, Eric, Lewis, David A, Haroutunian, Vahram, Peters, Mette A, Lipska, Barbara K, Buxbaum, Joseph D, Hirai, Keisuke, Perumal, Thanneer M, Essioux, Laurent, Rajagopal, Veera Manikandan, Mattheisen, Manuel, Grove, Jakob, Werge, Thomas, Mortensen, Preben Bo, Pedersen, Carsten Bocker, Agerbo, Esben, Pedersen, Marianne Giortz, Mors, Ole, Nordentoft, Merete, Hougaard, David M, Bybjerg-Grauholm, Jonas, Baekvad-Hansen, Marie, Hansen, Christine Soholm, Ripke, Stephan, Neale, Benjamin M, Corvin, Aiden, Farh, Kai-How, Holmans, Peter A, Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Jr, Belliveau Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberly D, Chan, Raymond CK, Chen, Ronald YL, Chen, Eric YH, Cheng, Wei, Cheung, Eric FC, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedl, Marion, Friedman, Joseph I, Genovese, Giulio, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodriguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Ikeda, Masashi, Joa, Inge, Julia, Antonio, Kahn, Rene S, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kahler, Anna K, Laurent, Claudine, Keong, Jimmy Lee Chee, Lee, S Hong, Legge, Sophie E, Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M, Lubinski, Jan, Lonnqvist, Jouko, Jr, Macek Milan, Magnusson, Patrik KE, Maher, Brion S, Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W, McDonald, Colm, McIntosh, Andrew M, Meier, Sandra, Meijer, Carin J, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Muller-Myhsok, Bertram, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T, Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O, Pietilainen, Olli, Pimm, Jonathan, Pocklington, Andrew J, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Roffman, Joshua L, Salomaa, Veikko, Sanders, Alan R, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Scolnick, Edward M, Scott, Rodney J, Seidman, Larry J, Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M, Sim, Kang, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Spencer, Chris CA, Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Soderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T, Weiser, Mark, Wildenauer, Dieter B, Williams, Nigel M, Williams, Stephanie, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily HM, Wormley, Brandon K, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R, Stefansson, Kari, Visscher, Peter M, Adolfsson, Rolf, Andreassen, Ole A, Blackwood, Douglas HR, Bramon, Elvira, Cichon, Sven, Darvasi, Ariel, Ehrenreich, Hannelore, Esko, Tonu, Gejman, Pablo V, Gill, Michael, Gurling, Hugh, Hultman, Christina M, Iwata, Nakao, Jablensky, Assen V, Jonsson, Erik G, Kendler, Kenneth S, Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F, Li, Qingqin S, Liu, Jianjun, Malhotra, Anil K, McCarroll, Steven A, McQuillin, Andrew, Moran, Jennifer L, Mortensen, Preben B, Mowry, Bryan J, Nothen, Markus M, Ophoff, Roel A, Palotie, Aarno, Pato, Carlos N, Petryshen, Tracey L, Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P, Rujescu, Dan, Sham, Pak C, St Clair, David, Weinberger, Daniel R, Wendland, Jens R, Daly, Mark J, Sullivan, Patrick F, Consortium, CommonMind, Consortium, Psychiat Genomics, Working, iPSYCH-GEMS Schizophrenia, Child and Adolescent Psychiatry / Psychology, ANS - Complex Trait Genetics, APH - Mental Health, Adult Psychiatry, Perceptual and Cognitive Neuroscience (PCN), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Stem Cell Aging Leukemia and Lymphoma (SALL), Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, CommonMind Consortium, Psychiat Genomics Consortium, iPSYCH-GEMS Schizophrenia Working, Huckins, LM, Dobbyn, A, Ruderfer, DM, Hoffman, G, Lee, SH, Im, HK, iPSYCH-GEMS Schizophrenia Working Group, The Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics, Amsterdam Reproduction & Development (AR&D), Human genetics, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, and MUMC+: Hersen en Zenuw Centrum (3)

Subjects
DISORDER, Schizophrenia/genetics, iPSYCH-GEMS Schizophrenia Working Group, CHILDHOOD, Gene Expression, Genome-wide association study, VARIANTS, MOUSE, Medical and Health Sciences, ACUTE INTERMITTENT PORPHYRIA, Genome-wide association studies, 0302 clinical medicine, CommonMind Consortium, 2.1 Biological and endogenous factors, Aetiology, Prefrontal cortex, 0303 health sciences, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the PsyUniversity of Copenhagenchiatric Genomics Consortium, Brain, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Schizophrenia, Transcriptome, Single Nucleotide, ASSOCIATION, Transcriptome/genetics, Biological Sciences, Polymorphism, Single Nucleotide/genetics, Mental Health, Genome-Wide Association Study/methods, Medical genetics, TRAITS, Psychosis, medicine.medical_specialty, Computational biology, Quantitative trait locus, Biology, Article, 03 medical and health sciences, PSYCHOSIS, SDG 3 - Good Health and Well-being, medicine, Genetics, Polymorphism, Transcriptomics, Gene, 030304 developmental biology, Brain/physiopathology, Human Genome, medicine.disease, Brain Disorders, Gene Expression/genetics, COGNITIVE DEFICITS, Expression quantitative trait loci, Human medicine, Gene expression, Quantitative Trait Loci/genetics, 030217 neurology & neurosurgery, Imputation (genetics), Developmental Biology
Abstract

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression. Working Group The Schizophrenia Working Group of the Psychiatric Genomics Consortium Stephan Ripke37,38 Benjamin M. Neale37,38,39,40 Aiden Corvin41 James T. R. Walters6 Kai-How Farh37 Peter A. Holmans6,42 Phil Lee37,38,40 Brendan Bulik-Sullivan37,38 David A. Collier43,44 Hailiang Huang37,39 Tune H. Pers39,45,46 Ingrid Agartz47,48,49 Esben Agerbo8,32,33 Margot Albus50 Madeline Alexander51 Farooq Amin52,53 Silviu A. Bacanu54 Martin Begemann55 Richard A. Belliveau Jr38 Judit Bene56,57 Sarah E. Bergen38,58 Elizabeth Bevilacqua38 Tim B. Bigdeli54 Donald W. Black59 Richard Bruggeman60 Nancy G. Buccola61 Randy L. Buckner62,63,64 William Byerley65 Wiepke Cahn66 Guiqing Cai2,3 Dominique Campion67 Rita M. Cantor10 Vaughan J. Carr68,69 Noa Carrera6 Stanley V. Catts68,70 Kimberly D. Chambert38 Raymond C. K. Chan71 Ronald Y. L. Chen72 Eric Y. H. Chen72,73 Wei Cheng15 Eric F. C. Cheung74 Siow Ann Chong75 C. Robert Cloninger76 David Cohen77 Nadine Cohen78 Paul Cormican41 Nick Craddock6,42 James J. Crowley79 David Curtis80,81 Michael Davidson82 Kenneth L. Davis3 Franziska Degenhardt83,84 Jurgen Del Favero85 Ditte Demontis7,8,9 Dimitris Dikeos86 Timothy Dinan87 Srdjan Djurovic49,88 Gary Donohoe41,89 Elodie Drapeau3 Jubao Duan90,91 Frank Dudbridge92 Naser Durmishi93 Peter Eichhammer94 Johan Eriksson95,96,97 Valentina Escott-Price6 Laurent Essioux98 Ayman H. Fanous99,100,101,102 Martilias S. Farrell79 Josef Frank103 Lude Franke104 Robert Freedman105 Nelson B. Freimer106 Marion Friedl107 Joseph I. Friedman3 Menachem Fromer1,37,38,40 Giulio Genovese38 Lyudmila Georgieva6 Ina Giegling107,108 Paola Giusti-Rodríguez79 Stephanie Godard109 Jacqueline I. Goldstein37,39 Vera Golimbet110 Srihari Gopal111 Jacob Gratten112 Lieuwe de Haan113 Christian Hammer55 Marian L. Hamshere6 Mark Hansen114 Thomas Hansen8,30 Vahram Haroutunian3,25,23 Annette M. Hartmann107 Frans A. Henskens68,115,116 Stefan Herms83,84,117 Joel N. Hirschhorn39,46,118 Per Hoffmann83,84,117 Andrea Hofman83,84 Mads V. Hollegaard36 David M. Hougaard36 Masashi Ikeda119 Inge Joa120 Antonio Julia121 Rene S. Kahn66 Luba Kalaydjieva122,123 Sena Karachanak-Yankova124 Juha Karjalainen104 David Kavanagh6 Matthew C. Keller125 James L. Kennedy126,127,128 Andrey Khrunin129 Yunjung Kim79 Janis Klovins130 James A. Knowles131 Bettina Konte107 Vaidutis Kucinskas132 Zita Ausrele Kucinskiene132 Hana Kuzelova-Ptackova133 Anna K. Kahler58 Claudine Laurent51,134 Jimmy Lee Chee Keong75,135 S. Hong Lee112 Sophie E. Legge6 Bernard Lerer136 Miaoxin Li72,73,137 Tao Li138 Kung-Yee Liang139 Jeffrey Lieberman140 Svetlana Limborska129 Carmel M. Loughland68,141 Jan Lubinski142 Jouko Lonnqvist143 Milan Macek Jr133 Patrik K. E. Magnusson58 Brion S. Maher144 Wolfgang Maier145 Jacques Mallet146 Sara Marsal121 Manuel Mattheisen7,8,9,147 Morten Mattingsdal49,148 Robert W. McCarley149,150 Colm McDonald151 Andrew M. McIntosh152,153 Sandra Meier103 Carin J. Meijer113 Bela Melegh56,57 Ingrid Melle49,154 Raquelle I. Mesholam-Gately149,155 Andres Metspalu156 Patricia T. Michie68,157 Lili Milani156 Vihra Milanova158 Younes Mokrab43 Derek W. Morris41,89 Ole Mors8,9,159 Kieran C. Murphy160 Robin M. Murray161 Inez Myin-Germeys162 Bertram Muller-Myhsok163,164,165 Mari Nelis156 Igor Nenadic166 Deborah A. Nertney167 Gerald Nestadt168 Kristin K. Nicodemus169 Liene Nikitina-Zake130 Laura Nisenbaum170 Annelie Nordin171 Eadbhard O’Callaghan172 Colm O’Dushlaine38 F. Anthony O’Neill173 Sang-Yun Oh174 Ann Olincy126 Line Olsen8,64 Jim Van Os162,175 Christos Pantelis68,176 George N. Papadimitriou86 Sergi Papiol55 Elena Parkhomenko3 Michele T. Pato131 Tiina Paunio177,178 Milica Pejovic-Milovancevic179 Diana O. Perkins180 Olli Pietiläinen178,181 Jonathan Pimm81 Andrew J. Pocklington6 John Powell161 Alkes Price39,182 Ann E. Pulver168 Shaun M. Purcell1 Digby Quested183 Henrik B. Rasmussen30,43 Abraham Reichenberg3 Mark A. Reimers184 Alexander L. Richards6 Joshua L. Roffman62,64 Panos Roussos1,4 Douglas M. Ruderfer1,5,6 Veikko Salomaa97 Alan R. Sanders90,91 Ulrich Schall68,141 Christian R. Schubert185 Thomas G. Schulze103,186 Sibylle G. Schwab187 Edward M. Scolnick38 Rodney J. Scott68,188,189 Larry J. Seidman144,155 Jianxin Shi190 Engilbert Sigurdsson191 Teimuraz Silagadze192 Jeremy M. Silverman3,193 Kang Sim75 Petr Slominsky129 Jordan W. Smoller38,40 Hon-Cheong So72 Chris C. A. Spencer194 Eli A. Stahl1,2,3,4 Hreinn Stefansson195 Stacy Steinberg195 Elisabeth Stogmann196 Richard E. Straub197 Eric Strengman66,198 Jana Strohmaier103 T. Scott Stroup140 Mythily Subramaniam75 Jaana Suvisaari143 Dragan M. Svrakic76 Jin P. Szatkiewicz79 Erik Soderman47 Srinivas Thirumalai199 Draga Toncheva124 Sarah Tosato200 Juha Veijola201,202 John Waddington203 Dermot Walsh204 Dai Wang111 Qiang Wang138 Bradley T. Webb54 Mark Weiser82 Dieter B. Wildenauer205 Nigel M. Williams6 Stephanie Williams79 Stephanie H. Witt103 Aaron R. Wolen184 Emily H. M. Wong72 Brandon K. Wormley54 Hualin Simon Xi206 Clement C. Zai126,127 Xuebin Zheng207 Fritz Zimprich196 Naomi R. Wray112 Kari Stefansson195 Peter M. Visscher112 Rolf Adolfsson171 Ole A. Andreassen49,154 Douglas H. R. Blackwood153 Elvira Bramon208 Joseph D. Buxbaum2,3,24,25 Anders D. Børglum7,8,9,159 Sven Cichon83,84,117,209 Ariel Darvasi210 Enrico Domenici211 Hannelore Ehrenreich55 Tonu Esko39,46,118,156 Pablo V. Gejman90,91 Michael Gill41 Hugh Gurling81 Christina M. Hultman58 Nakao Iwata119 Assen V. Jablensky68,123,205,212 Erik G. Jonsson47,49 Kenneth S. Kendler213 George Kirov6 Jo Knight125,127,128 Todd Lencz214,215,216 Douglas F. Levinson51 Qingqin S. Li111 Jianjun Liu207,217 Anil K. Malhotra214,215,216 Steven A. McCarroll38,118 Andrew McQuillin81 Jennifer L. Moran38 Preben B. Mortensen8,32,33 Bryan J. Mowry112,218 Markus M. Nothen83,84 Roel A. Ophoff10,66,105 Michael J. Owen6,42 Aarno Palotie38,40,181 Carlos N. Pato131 Tracey L. Petryshen38,149,219 Danielle Posthuma220,221,222 Marcella Rietschel103 Brien P. Riley213 Dan Rujescu107,108 Pak C. Sham72,73,137 Pamela Sklar1,2,3,4,25 David St Clair223 Daniel R. Weinberger197,224 Jens R. Wendland185 Thomas Werge8,30,225 Mark J. Daly37,38,39 Patrick F. Sullivan58,79,180 Michael C. O’Donovan6,42 20Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. 21Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 22Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 23Psychiatry, JJ Peters Virginia Medical Center, Bronx, NY, USA. 24Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA. 25Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 26Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 27CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan. 28F. Hoffman-La Roche Ltd, Basel, Switzerland. 29Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark. 30Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. 31Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 32National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark. 33Centre for Integrated Registerbased Research, Aarhus University, Aarhus, Denmark. 34Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. 35Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark. 36Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. 37Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 38Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 39Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. 40Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. 41Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 42NationalCentre for Mental Health, Cardiff University, Cardiff, UK. 43Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, UK. 44Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK. 45Center for BiologicalSequence Analysis, Department of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark. 46Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA. 47Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden. 48Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway. 49NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 50State Mental Hospital, Haar, Germany. 51Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA. 52Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA. 53Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA. 54Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA. 55Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Gottingen, Germany. 56Department of Medical Genetics, University of Pécs, Pécs, Hungary. 57Szentagothai Research Center, University of Pécs, Pécs, Hungary. 58Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 59Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA. 60University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, the Netherlands. 61School of Nursing, Louisiana State University Health Sciences Center, New Orleans, LA, USA. 62Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, MA, USA. 63Center for Brain Science, Harvard University, Cambridge, MA, USA. 64Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. 65Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA. 66University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, the Netherlands. 67Centre Hospitalier du Rouvray and INSERM U1079 Faculty of Medicine, Rouen, France. 68Schizophrenia Research Institute, Sydney, New South Wales, Australia. 69School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia. 70Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Queensland, Australia. 71Institute of Psychology, Chinese Academy of Science, Beijing, China. 72Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 73State Key Laboratory for Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 74Castle Peak Hospital, Hong Kong, China. 75Institute of Mental Health, Singapore, Singapore. 76Department of Psychiatry, Washington University, St. Louis, MO, USA. 77Department of Child and Adolescent Psychiatry, Assistance Publique Hopitaux de Paris, Pierre and Marie Curie Faculty of Medicine and Institute for Intelligent Systems and Robotics, Paris, France. 78Blue Note Biosciences, Princeton, NJ, USA. 79Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. 80Department of Psychological Medicine, Queen Mary University of London, London, UK. 81Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK. 82Sheba Medical Center, Tel Hashomer, Israel. 83Department of Genomics, Life and Brain Center, Bonn, Germany. 84Institute of Human Genetics, University of Bonn, Bonn, Germany. 85AppliedMolecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. 86First Department of Psychiatry, University of Athens Medical School, Athens, Greece. 87Department of Psychiatry, University College Cork, Co, Cork, Ireland. 88Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. 89Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Co, Galway, Ireland. 90Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA. 91Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, IL, USA. 92Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. 93Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Republic of Macedonia. 94Department of Psychiatry, University of Regensburg, Regensburg, Germany. 95Department of General Practice, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland. 96Folkhälsan Research Center, Helsinki, Finland, Biomedicum Helsinki, Helsinki, Finland. 97National Institute for Health and Welfare, Helsinki, Finland. 98Translational Technologies and Bioinformatics, Pharma Research and Early Development, F. Hoffman-La Roche, Basel, Switzerland. 99Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA. 100Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA. 101Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. 102Mental Health Service Line, Washington VA Medical Center, Washington, DC, USA. 103Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany. 104Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands. 105Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA. 106Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA. 107Department of Psychiatry, University of Halle, Halle, Germany. 108Department of Psychiatry, University of Munich, Munich, Germany. 109Departments of Psychiatry and Human and Molecular Genetics, INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris, France. 110Mental Health Research Centre, Russian Academy of Medical Sciences, Moscow, Russia. 111Neuroscience Therapeutic Area, Janssen Research and Development, Raritan, NJ, USA. 112Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia. 113Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands. 114Illumina, La Jolla, CA, USA. 115Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, New South Wales, Australia. 116School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, New South Wales, Australia. 117Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland. 118Department of Genetics, Harvard Medical School, Boston, MA, USA. 119Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan. 120Regional Centre for Clinical Researchin Psychosis, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway. 121Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain. 122Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. 123The Perkins Institute for Medical Research, The University of Western Australia, Perth, Western Australia, Australia. 124Department of Medical Genetics, Medical University, Sofia, Bulgaria. 125Department of Psychology, University of Colorado Boulder, Boulder, CO, USA. 126Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 127Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. 128Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. 129Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia. 130Latvian Biomedical Research and Study Centre, Riga, Latvia. 131Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, CA, USA. 132Faculty of Medicine, Vilnius University, Vilnius, Lithuania. 133Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic. 134Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France. 135Duke-NUS Graduate Medical School, Singapore, Singapore. 136Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 137Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China. 138Mental Health Centre and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China. 139Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA. 140Department of Psychiatry, Columbia University, New York, New York, NY, USA. 141Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, New South Wales, Australia. 142Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland. 143Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland. 144Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. 145Department of Psychiatry, University of Bonn, Bonn, Germany. 146Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodénégératifs, Hôpital de la Pitiè-Salpêtrière, Paris, France. 147Department of Genomics Mathematics, University of Bonn, Bonn, Germany. 148Research Unit, Sørlandet Hospital, Kristiansand, Norway. 149Department of Psychiatry, Harvard Medical School, Boston, MA, USA. 150VA Boston Health Care System, Brockton, MA, USA. 151Department of Psychiatry, National University of Ireland Galway, Co, Galway, Ireland. 152Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. 153Division of Psychiatry, University of Edinburgh, Edinburgh, UK. 154Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 155Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, USA. 156Estonian Genome Center, University of Tartu, Tartu, Estonia. 157School of Psychology, University of Newcastle, Newcastle, New South Wales, Australia. 158First Psychiatric Clinic, Medical University, Sofia, Bulgaria. 159Department P, Aarhus University Hospital, Risskov, Denmark. 160Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland. 161King’s College London, London, UK. 162Maastricht University Medical Centre, South Limburg Mental Health Research and TeachingNetwork, EURON, Maastricht, the Netherlands. 163Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 164Max Planck Institute of Psychiatry, Munich, Germany. 165Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 166Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany. 167Department of Psychiatry, Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia. 168Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 169Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 170Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA. 171Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden. 172DETECT Early Intervention Service for Psychosis, Blackrock, Co, Dublin, Ireland. 173Centre for Public Health, Institute of Clinical Sciences, Queen’s University Belfast, Belfast, UK. 174Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, CA, USA. 175Institute of Psychiatry, King’s College London, London, UK. 176Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Victoria, Australia. 177Department of Psychiatry, University of Helsinki, Helsinki, Finland. 178Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland. 179Medical Faculty, University of Belgrade, Belgrade, Serbia. 180Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA. 181Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland. 182Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. 183Department of Psychiatry, University of Oxford, Oxford, UK. 184Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA. 185Pharma Therapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA. 186Department of Psychiatry and Psychotherapy, University of Gottingen, Göttingen, Germany. 187Psychiatry and Psychotherapy Clinic, University of Erlangen, Erlangen, Germany. 188Hunter New England Health Service, Newcastle, New South Wales, Australia. 189School of Biomedical Sciences, University of Newcastle, Newcastle, New South Wales, Australia. 190Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 191University of Iceland, Landspitali, National University Hospital, Reykjavik, Iceland. 192Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia. 193Research and Development, Bronx Veterans Affairs Medical Center, New York, NY, USA. 194WellcomeTrust Centre for Human Genetics, Oxford, UK. 195deCODE Genetics, Reykjavik, Iceland. 196Department of Clinical Neurology, Medical University of Vienna, Wien, Austria. 197Lieber Institute for Brain Development, Baltimore, MD, USA. 198Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands. 199Berkshire Healthcare NHS Foundation Trust, Bracknell, UK. 200Section of Psychiatry, University of Verona, Verona, Italy. 201Department of Psychiatry, University of Oulu, Oulu, Finland. 202University Hospital of Oulu, Oulu, Finland. 203Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland. 204Health Research Board, Dublin, Ireland. 205School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Western Australia, Australia. 206Computational Sciences CoE, Pfizer Worldwide Research and Development, Cambridge, MA, USA. 207Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore. 208University College London, London, UK. 209Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany. 210Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel. 211NeuroscienceDiscovery and Translational Area, Pharma Research and Early Development, F. Hoffman-La Roche, Basel, Switzerland. 212Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Medical Research Foundation Building, Perth, Western Australia, Australia. 213Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA. 214The Feinstein Institute for Medical Research, Manhasset, NY, USA. 215The Hofstra NS-LIJ School of Medicine, Hempstead, NY, USA. 216The Zucker Hillside Hospital, Glen Oaks, NY, USA. 217Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. 218Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia. 219Center for HumanGenetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. 220Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, the Netherlands. 221Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam, the Netherlands. 222Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands. 223University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK. 224Departments of Psychiatry, Neurology, Neuroscience and Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA. 225Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Published
2019

22. Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

Author

Franke, Barbara, Stein, Jason L, McIntosh, Andrew M, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Lee, Phil, Friedman, Joseph I, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Gopal, Srihari, McMahon, Francis J, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan L, Meyer-Lindenberg, Andreas, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V, Hougaard, David M, Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kähler, Anna K, Kahn, René S, Mattheisen, Manuel, Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Keller, Matthew C, Kelly, Brian J, Kennedy, James L, Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Andreassen, Ole A, Knowles, James A, Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Laurent, Claudine, Lee, S Hong, Keong, Jimmy Lee Chee, Legge, Sophie E, Lerer, Bernard, Gruber, Oliver, Li, Miaoxin, Li, Tao, Liang, Kung-Yee, Lieberman, Jeffrey, Limborska, Svetlana, Lönnqvist, Jouko, Loughland, Carmel M, Lubinski, Jan, Macek, Milan, Magnusson, Patrik K E, Sachdev, Perminder S, Maher, Brion S, Maier, Wolfgang, Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W, McDonald, Colm, Meier, Sandra, Roiz-Santiañez, Roberto, Meijer, Carin J, Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I, Metspalu, Andres, Michie, Patricia T, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W, Saykin, Andrew J, Mors, Ole, Müller-Myhsok, Bertram, Murphy, Kieran C, Murray, Robin M, Myin-Germeys, Inez, Nelis, Mari, Nenadic, Igor, Nertney, Deborah A, Nestadt, Gerald, Nicodemus, Kristin K, Ripke, Stephan, Ehrlich, Stefan, Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, O'Neill, F Anthony, Oh, Sang-Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Mather, Karen A, Pantelis, Christos, Papadimitriou, George N, Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T, Paunio, Tiina, Perkins, Diana O, Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J, Turner, Jessica A, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Quested, Digby, Rasmussen, Henrik B, Reichenberg, Abraham, Reimers, Mark A, Richards, Alexander L, Roffman, Joshua L, Schwarz, Emanuel, Roussos, Panos, Ruderfer, Douglas M, Salomaa, Veikko, Sanders, Alan R, Schall, Ulrich, Schubert, Christian R, Schulze, Thomas G, Schwab, Sibylle G, Scolnick, Edward M, Scott, Rodney J, Thalamuthu, Anbupalam, Seidman, Larry J, Shi, Jianxin, Silverman, Jeremy M, Sim, Kang, Slominsky, Petr, Smoller, Jordan W, So, Hon-Cheong, Söderman, Erik, Spencer, Chris C A, Stahl, Eli A, Shugart, Yin Yao, Stogmann, Elisabeth, Straub, Richard E, Strengman, Eric, Strohmaier, Jana, Stroup, T Scott, Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Thirumalai, Srinivas, Ho, Yvonne Yw, Toncheva, Draga, Tooney, Paul A, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T, Weiser, Mark, Wildenauer, Dieter B, Martin, Nicholas G, Williams, Nigel M, Williams, Stephanie, Witt, Stephanie H, Wolen, Aaron R, Wong, Emily H M, Wormley, Brandon K, Wu, Jing Qin, Xi, Hualin Simon, Zai, Clement C, Zheng, Xuebin, Wright, Margaret J, Zimprich, Fritz, Wray, Naomi R, Visscher, Peter M, Adolfsson, Rolf, Blackwood, Douglas H R, Børglum, Anders D, Bramon, Elvira, Buxbaum, Joseph D, Cichon, Sven, Consortium, Schizophrenia Working Group of the Psychiatric Genomics, Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V, Gill, Michael, Gurling, Hugh, Hultman, Christina M, Iwata, Nakao, Jablensky, Assen V, Anttila, Verneri, Consortium, ENIGMA, Jönsson, Erik G, Kendler, Kenneth S, Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F, Li, Qingqin S, Liu, Jianjun, Malhotra, Anil K, McCarroll, Steven A, O'Donovan, Michael C, McQuillin, Andrew, Moran, Jennifer L, Mortensen, Preben B, Mowry, Bryan J, Nöthen, Markus M, Ophoff, Roel A, Owen, Michael J, Palotie, Aarno, Pato, Carlos N, Petryshen, Tracey L, Thompson, Paul M, Posthuma, Danielle, Rietschel, Marcella, Riley, Brien P, Rujescu, Dan, Sham, Pak C, Sklar, Pamela, Clair, David St, Weinberger, Daniel R, Wendland, Jens R, Werge, Thomas, Neale, Benjamin M, Daly, Mark J, Sullivan, Patrick F, Hibar, Derrek P, Renteria, Miguel E, Arias-Vasquez, Alejandro, Desrivières, Sylvane, Jahanshad, Neda, Toro, Roberto, Medland, Sarah E, Wittfeld, Katharina, Abramovic, Lucija, Andersson, Micael, Aribisala, Benjamin S, Armstrong, Nicola J, Bernard, Manon, Bohlken, Marc M, Boks, Marco P, Bralten, Janita, Brown, Andrew A, Chakravarty, M Mallar, Chen, Qiang, Ching, Christopher R K, Cuellar-Partida, Gabriel, den Braber, Anouk, Giddaluru, Sudheer, Goldman, Aaron L, Grimm, Oliver, Guadalupe, Tulio, Hass, Johanna, Woldehawariat, Girma, Holmes, Avram J, Hoogman, Martine, Janowitz, Deborah, Jia, Tianye, Kim, Sungeun, Klein, Marieke, Kraemer, Bernd, Loohuis, Loes M Olde, Luciano, Michelle, Macare, Christine, Milaneschi, Yuri, Nho, Kwangsik, Papmeyer, Martina, Ramasamy, Adaikalavan, Risacher, Shannon L, Corvin, Aiden, Rose, Emma J, Salami, Alireza, Sämann, Philipp G, Schmaal, Lianne, Schork, Andrew J, Shin, Jean, Strike, Lachlan T, Teumer, Alexander, van Donkelaar, Marjolein M J, van Eijk, Kristel R, Walters, James T R, Walters, Raymond K, Westlye, Lars T, Whelan, Christopher D, Winkler, Anderson M, Zwiers, Marcel P, Alhusaini, Saud, Athanasiu, Lavinia, Hakobjan, Marina M H, Hartberg, Cecilie B, Farh, Kai-How, Haukvik, Unn, Heister, Angelien J G A M, Höhn, David, Kasperaviciute, Dalia, Liewald, David C M, Lopez, Lorna M, Makkinje, Remco R R, Matarin, Mar, Naber, Marlies A M, McKay, David R, Holmans, Peter A, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Royle, Natalie A, Shen, Li, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia S L, van Hulzen, Kimm J E, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Bulik-Sullivan, Brendan, Curran, Joanne E, Czisch, Michael, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Collier, David A, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Gibbs, Raphael, Göring, Harald H H, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Huang, Hailiang, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Jack, Clifford R, Jenkinson, Mark, Pers, Tune H, Johnson, Robert, Kanai, Ryota, Keil, Maria, Kent, Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Agartz, Ingrid, Meisenzahl, Eva, Mohnke, Sebastian, Montgomery, Grant W, Mostert, Jeanette C, Mühleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Agerbo, Esben, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Albus, Margot, Schnell, Knut, Schofield, Peter R, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Toga, Arthur W, Traynor, Bryan, Troncoso, Juan, Alexander, Madeline, Hernández, Maria C Valdés, van 't Ent, Dennis, van der Brug, Marcel, van der Wee, Nic J A, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Amin, Farooq, Zonderman, Alan, Ashbrook, David G, Hager, Reinmar, Lu, Lu, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Bacanu, Silviu A, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Begemann, Martin, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Hoffmann, Wolfgang, Hosten, Norbert, LeHellard, Stephanie, Nauck, Matthias, Belliveau, Richard A, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda W J H, Sisodiya, Sanjay M, van Bokhoven, Hans, van Haren, Neeltje E M, Völzke, Henry, Walter, Henrik, Bene, Judit, Weiner, Michael W, Wen, Wei, White, Tonya, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, Bergen, Sarah E, de Geus, Eco J C, Deary, Ian J, Donohoe, Gary, Fernández, Guillén, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Hardy, John, Bevilacqua, Elizabeth, Hashimoto, Ryota, Hulshoff Pol, Hilleke E, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, Bigdeli, Tim B, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Simmons, Andy, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Black, Donald W, Adams, Hieab H H, Launer, Lenore J, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa, van der Lee, Sven J, Bruggeman, Richard, Ebling, Maritza, Fischl, Bruce, Longstreth, W. T., Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Luting, Xue, Mazoyer, Bernard, Buccola, Nancy G, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Ikram, M Arfan, Schumann, Gunter, Byerley, William F, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Chan, Raymond C K, Chen, Eric Y H, Chen, Ronald Y L, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Cloninger, C Robert, Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Neale, Michael C, Del Favero, Jurgen, DeLisi, Lynn E, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Franke, Barbara, Stein, Jason L, Ripke, Stephan, Anttila, Verneri, Hong Lee, S, Ikram, M Arfan, Schizophrenia Working Group of the Psychiatric Genomics Consortium, ENIGMA Consortium, Radboud University Medical Center [Nijmegen], University of Southern California (USC), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], University of Warwick [Coventry], University of Oxford [Oxford], Virginia Commonwealth University (VCU), University of Edinburgh, National Institutes of Health [Bethesda] (NIH), Chinese PLA General Hospital, University of Missouri [Columbia], University of Missouri System, Cardiff University, Aarhus University [Aarhus], Stanford University [Stanford], Max-Planck-Institut, University of Iowa [Iowa City], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Schizophrenia Research Institute [Sydney], Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Mathematics [CUHK], The Chinese University of Hong Kong [Hong Kong], The University of Hong Kong (HKU), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Castle Peak Hospital [Hong Kong], Institute of Mental Health [Singapore], Service de psychiatrie des enfants et adultes [CHU Pitié-Salpêtrière ], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Queen Mary University of London (QMUL), Open University of Israël, University of Antwerp (UA), Harvard Medical School [Boston] (HMS), University of Athens Medical School [Athens], University College Cork (UCC), University of Oslo (UiO), London School of Hygiene and Tropical Medicine (LSHTM), Universität Regensburg (UR), Biomedicum Helsinki, Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], Universität Heidelberg [Heidelberg], University Medical Center Groningen [Groningen] (UMCG), Haverford College, Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Limoges, University of Queensland [Brisbane], James J. Peters VA Medical Center [New York], Martin-Luther-University Halle-Wittenberg, University of Newcastle [Australia] (UoN), University of Basel (Unibas), Division of Medical Genetics [Seattle], University of Washington [Seattle], Statens Serum Institut [Copenhagen], Tohoku University [Sendai], University of Stavanger, Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), University of Sofia, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), Universität Stuttgart [Stuttgart], Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], University Hospital Motol [Prague], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hadassah Hebrew University Medical Center [Jerusalem], Karolinska Institutet [Stockholm], University of Bonn, Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Vall d'Hebron University Hospital [Barcelona], Department of Life Sciences, Imperial College London, Deutscher Wetterdienst [Offenbach] (DWD), Eli Lilly and Company Limited [Windlesham], Trinity College Dublin, Royal College of Surgeons in Ireland (RCSI), Université de Lausanne (UNIL), University of Tartu, Johns Hopkins University School of Medicine [Baltimore], Stockholm University, Queen's University [Belfast] (QUB), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Universidade de São Paulo (USP), Department of Mathematics [Nanticoke], Luzerne County Community College, National Institute for Health and Welfare [Helsinki], King‘s College London, University of Chicago, Fraunhofer Heinrich Hertz Institute [Berlin] (HHI), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), National Cancer Institute [Bethesda] (NCI-NIH), The Wellcome Trust Centre for Human Genetics [Oxford], Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, The Natural History Museum [London] (NHM), University of Calgary, Department of Medical Epidemiology and Biostatistics (MEB), The University of Western Australia (UWA), Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Montreal Neurological Institute and Hospital, McGill University, Universidade do Algarve (UAlg), Beijing Normal University, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Dpt of Psychiatry [New Haven], Yale University School of Medicine, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Bijvoet Center of Biomolecular Research, Utrecht University [Utrecht], School of Psychology, University of Queensland, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Mathematics, University of Colorado, University of Colorado [Boulder], VU University Amsterdam, Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Health and Human Services, McConnell Brain Imaging Centre (MNI), McGill University-McGill University, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Computer Science and Artificial Intelligence Laboratory [Cambridge] (CSAIL), Massachusetts Institute of Technology (MIT), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Del-Favero, Jurgen, Enigma Consortium, School of Medicine / Clinical Medicine, University of Oxford, University of Missouri [Columbia] (Mizzou), Stanford University, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Heidelberg [Heidelberg] = Heidelberg University, University of Newcastle [Callaghan, Australia] (UoN), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Софийски университет = Sofia University, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universität Bonn = University of Bonn, Université de Lausanne = University of Lausanne (UNIL), Universidade de São Paulo = University of São Paulo (USP), Fraunhofer Institute for Telecommunications - Heinrich Hertz Institute (Fraunhofer HHI), Fraunhofer (Fraunhofer-Gesellschaft), Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Beijing Normal University (BNU), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), Centre épigénétique et destin cellulaire (EDC), Bijvoet Center of Biomolecular Research [Utrecht], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Vrije Universiteit Amsterdam [Amsterdam] (VU), McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Biological Psychology, EMGO+ - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Other departments, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Adult Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Psychiatrie (3), and MUMC+: Hersen en Zenuw Centrum (3)

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), genetic association, Genome-wide association study, brain imaging, VARIANTS, Genome-wide association studies, Linkage Disequilibrium, 0302 clinical medicine, pathology [Brain], 2.1 Biological and endogenous factors, Psychology, GWAS, genetics [Schizophrenia], genetics, genetics [Genetic Predisposition to Disease], Aetiology, Non-U.S. Gov't, PERSPECTIVE, humans, Schizophrenia Working Group of the Psychiatric Genomics Consortium, neuroimaging, General Neuroscience, Research Support, Non-U.S. Gov't, Brain, Single Nucleotide, Organ Size, Endophenotypes, Genetic Predisposition to Disease, Humans, Magnetic Resonance Imaging, Neuroimaging, Polymorphism, Single Nucleotide, Schizophrenia, Genome-Wide Association Study, Neuroscience (all), Serious Mental Illness, ENIGMA Consortium, 3. Good health, endophenotype, Mental Health, Meta-analysis, Neurological, genetics [Polymorphism, Single Nucleotide], Cognitive Sciences, MRI, Neuroinformatics, DISORDERS, heredity, Schizophrenia (object-oriented programming), brain, Non-P.H.S, Brain Structure and Function, RELATIVES, PHENOTYPES, Research Support, N.I.H, 03 medical and health sciences, Magnetic resonance imaging, ENDOPHENOTYPE, Research Support, N.I.H., Extramural, ddc:570, Journal Article, Polymorphism, GENOME-WIDE ASSOCIATION, pathology [Schizophrenia], METAANALYSIS, genetic predisposition to disease, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, genome-wide association study, [SCCO.NEUR]Cognitive science/Neuroscience, Human Genome, Neurosciences, Extramural, Genetic architecture, Brain Disorders, meta-analysis, schizophrenia, INDIVIDUALS, 030104 developmental biology, Genetic marker, Endophenotype, DISCOVERY, Genetic markers, U.S. Gov't, Human medicine, Neuroscience, genetic predisposition, 030217 neurology & neurosurgery, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract

Article, Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders., final draft, peerReviewed

Published
2016

23. Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium

Author

van Erp, Theo GM, Walton, Esther, Hibar, Derrek P, Schmaal, Lianne, Jiang, Wenhao, Glahn, David C, Pearlson, Godfrey D, Yao, Nailin, Fukunaga, Masaki, Hashimoto, Ryota, Okada, Naohiro, Yamamori, Hidenaga, Bustillo, Juan R, Clark, Vincent P, Agartz, Ingrid, Mueller, Bryon A, Cahn, Wiepke, de Zwarte, Sonja MC, Hulshoff Pol, Hilleke E, Kahn, René S, Ophoff, Roel A, van Haren, Neeltje EM, Andreassen, Ole A, Dale, Anders M, Doan, Nhat Trung, Gurholt, Tiril P, Hartberg, Cecilie B, Haukvik, Unn K, Jørgensen, Kjetil N, Lagerberg, Trine V, Melle, Ingrid, Westlye, Lars T, Gruber, Oliver, Kraemer, Bernd, Richter, Anja, Zilles, David, Calhoun, Vince D, Crespo-Facorro, Benedicto, Roiz-Santiañez, Roberto, Tordesillas-Gutiérrez, Diana, Loughland, Carmel, Carr, Vaughan J, Catts, Stanley, Cropley, Vanessa L, Fullerton, Janice M, Green, Melissa J, Henskens, Frans A, Jablensky, Assen, Lenroot, Rhoshel K, Mowry, Bryan J, Michie, Patricia T, Pantelis, Christos, Quidé, Yann, Schall, Ulrich, Scott, Rodney J, Cairns, Murray J, Seal, Marc, Tooney, Paul A, Rasser, Paul E, Cooper, Gavin, Shannon Weickert, Cynthia, Weickert, Thomas W, Morris, Derek W, Hong, Elliot, Kochunov, Peter, Beard, Lauren M, Gur, Raquel E, Gur, Ruben C, Satterthwaite, Theodore D, Wolf, Daniel H, Belger, Aysenil, Brown, Gregory G, Ford, Judith M, Macciardi, Fabio, Mathalon, Daniel H, O'Leary, Daniel S, Potkin, Steven G, Preda, Adrian, Voyvodic, James, Lim, Kelvin O, McEwen, Sarah, Yang, Fude, Tan, Yunlong, Tan, Shuping, Wang, Zhiren, Fan, Fengmei, Chen, Jingxu, Xiang, Hong, Tang, Shiyou, Guo, Hua, Wan, Ping, Wei, Dong, Bockholt, Henry J, Ehrlich, Stefan, Wolthusen, Rick PF, King, Margaret D, Shoemaker, Jody M, Sponheim, Scott R, De Haan, Lieuwe, and Koenders, Laura

Subjects
Adult, Male, Adolescent, Surface area, Prefrontal Cortex, Neuroimaging, Severity of Illness Index, Medical and Health Sciences, Imaging, Young Adult, Cortical, Clinical Research, Humans, Age of Onset, Child, Karolinska Schizophrenia Project, Aged, Psychiatry, Psychology and Cognitive Sciences, Neurosciences, Brain, Middle Aged, Biological Sciences, Serious Mental Illness, Magnetic Resonance Imaging, Temporal Lobe, Frontal Lobe, Brain Disorders, Meta-analysis, Mental Health, Case-Control Studies, Linear Models, Schizophrenia, Biomedical Imaging, Female, Thickness
Abstract

BackgroundThe profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.MethodsThe study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide.ResultsCompared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d=-0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d=-0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset.ConclusionsThe findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

Published
2018

24. Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 controls via the ENIGMA consortium

Author

van Erp, Theo GM., Walton, Esther, Hibar, Derrek P., Schmaal, Lianne, Jiang, Wenhao, Glahn, David C., Pearlson, Godfrey D., Yao, Nailin, Fukunaga, Masaki, Hashimoto, Ryota, Okada, Naohiro, Yamamori, Hidenaga, Bustillo, Juan R., Clark, Vincent P., Agartz, Ingrid, Mueller, Bryon A., Cahn, Wiepke, de Zwarte, Sonja MC., Hulshoff Pol, Hilleke E., Kahn, René S., Ophoff, Roel A., van Haren, Neeltje EM., Andreassen, Ole A., Dale, Anders M., Doan, Nhat Trung, Gurholt, Tiril P., Hartberg, Cecilie B., Haukvik, Unn K., Jørgensen, Kjetil N., Lagerberg, Trine V., Melle, Ingrid, Westlye, Lars T., Gruber, Oliver, Kraemer, Bernd, Richter, Anja, Zilles, David, Calhoun, Vince D., Crespo-Facorro, Benedicto, Roiz-Santiañez, Roberto, Tordesillas-Gutiérrez, Diana, Loughland, Carmel, Carr, Vaughan J., Catts, Stanley, Cropley, Vanessa L., Fullerton, Janice M., Green, Melissa J., Henskens, Frans, Jablensky, Assen, Lenroot, Rhoshel K., Mowry, Bryan J., Michie, Patricia T., Pantelis, Christos, Quidé, Yann, Schall, Ulrich, Scott, Rodney J., Cairns, Murray J., Seal, Marc, Tooney, Paul A., Rasser, Paul E., Cooper, Gavin, Weickert, Cynthia Shannon, Weickert, Thomas W., Morris, Derek W., Hong, Elliot, Kochunov, Peter, Beard, Lauren M., Gur, Raquel E., Gur, Ruben C., Satterthwaite, Theodore D., Wolf, Daniel H., Belger, Aysenil, Brown, Gregory G., Ford, Judith M., Macciardi, Fabio, Mathalon, Daniel H., O’Leary, Daniel S., Potkin, Steven G., Preda, Adrian, Voyvodic, James, Lim, Kelvin O., McEwen, Sarah, Yang, Fude, Tan, Yunlong, Tan, Shuping, Wang, Zhiren, Fan, Fengmei, Chen, Jingxu, Xiang, Hong, Tang, Shiyou, Guo, Hua, Wan, Ping, Wei, Dong, Bockholt, Henry J., Ehrlich, Stefan, Wolthusen, Rick PF., King, Margaret D., Shoemaker, Jody M., Sponheim, Scott R., De Haan, Lieuwe, Koenders, Laura, Machielsen, Marise W., van Amelsvoort, Therese, Veltman, Dick J., Assogna, Francesca, Banaj, Nerisa, de Rossi, Pietro, Iorio, Mariangela, Piras, Fabrizio, Spalletta, Gianfranco, McKenna, Peter J., Pomarol-Clotet, Edith, Salvador, Raymond, Corvin, Aiden, Donohoe, Gary, Kelly, Sinead, Whelan, Christopher D., Dickie, Erin W., Rotenberg, David, Voineskos, Aristotle, Ciufolini, Simone, Radua, Joaquim, Dazzan, Paola, Murray, Robin, Marques, Tiago Reis, Simmons, Andrew, Borgwardt, Stefan, Egloff, Laura, Harrisberger, Fabienne, Riecher-Rössler, Anita, Smieskova, Renata, Alpert, Kathryn I., Wang, Lei, Jönsson, Erik G., Koops, Sanne, Sommer, Iris EC., Bertolino, Alessandro, Bonvino, Aurora, Di Giorgio, Annabella, Neilson, Emma, Mayer, Andrew R., Stephen, Julia M., Kwon, Jun Soo, Yun, Je-Yeon, Cannon, Dara M., McDonald, Colm, Lebedeva, Irina, Tomyshev, Alexander S., Akhadov, Tolibjohn, Kaleda, Vasily, Fatouros-Bergman, Helena, Flyckt, Lena, Busatto, Geraldo F., Rosa, Pedro GP., Serpa, Mauricio H., Zanetti, Marcus V., Hoschl, Cyril, Skoch, Antonin, Spaniel, Filip, Tomecek, David, Hagenaars, Saskia P., McIntosh, Andrew M., Whalley, Heather C., Lawrie, Stephen M., Knöchel, Christian, Oertel-Knöchel, Viola, Stäblein, Michael, Howells, Fleur M., Stein, Dan J., Temmingh, Henk, Uhlmann, Anne, Lopez-Jaramillo, Carlos, Dima, Danai, McMahon, Agnes, Faskowitz, Joshua I., Gutman, Boris A., Jahanshad, Neda, Thompson, Paul M., and Turner, Jessica A.

Subjects
Data Aggregation, Schizophrenia, Brain, Humans, Cooperative Behavior, Social Behavior, Article
Abstract

BACKGROUND. The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta Analysis) Schizophrenia Working Group. METHOD. The study included data from 4474 individuals with schizophrenia (mean age=32.3, range: 11–78; 66% male) and 5098 healthy volunteers (mean age=32.8, range: 10–87; 53% male), assessed with standardized methods, at 39 centers worldwide. RESULTS. Compared to healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen’s d=−0.530/−0.516) and smaller surface area (left/right hemisphere: d=−0.251/−0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, the effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were 2 to 3 times larger in antipsychotic medicated relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness, and positive correlations with age at onset. CONCLUSIONS. The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

Published
2018

25. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Author

Marshall, Christian R, Howrigan, Daniel P, Merico, Daniele, Thiruvahindrapuram, Bhooma, Wu, Wenting, Greer, Douglas S, Antaki, Danny, Shetty, Aniket, Holmans, Peter A, Pinto, Dalila, Gujral, Madhusudan, Brandler, William M, Malhotra, Dheeraj, Wang, Zhouzhi, Fajarado, Karin V Fuentes, Maile, Michelle S, Ripke, Stephan, Agartz, Ingrid, Albus, Margot, Alexander, Madeline, Amin, Farooq, Atkins, Joshua, Bacanu, Silviu A, Belliveau, Richard A, Bergen, Sarah E, Bertalan, Marcelo, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Bulik-Sullivan, Brendan, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Cairns, Murray J, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Cheng, Wei, Cloninger, C Robert, Cohen, David, Cormican, Paul, Craddock, Nick, Crespo-Facorro, Benedicto, Crowley, James J, Curtis, David, Davidson, Michael, Davis, Kenneth L, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H, Farh, Kai-How, Farrell, Martilias S, Frank, Josef, Franke, Lude, Freedman, Robert, Freimer, Nelson B, Friedman, Joseph I, Forstner, Andreas J, Fromer, Menachem, Genovese, Giulio, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I, Gratten, Jacob, de Haan, Lieuwe, Hamshere, Marian L, Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M, Henskens, Frans A, Herms, Stefan, Hirschhorn, Joel N, Hoffmann, Per, Hofman, Andrea, Huang, Hailiang, Ikeda, Masashi, and Joa, Inge

Subjects
Genetic Markers, Male, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, Genotype, DNA Copy Number Variations, Medical and Health Sciences, Clinical Research, Risk Factors, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Aetiology, Psychosis Endophenotypes International Consortium, Prevention, Human Genome, Biological Sciences, Serious Mental Illness, Brain Disorders, Mental Health, Genetic Loci, Case-Control Studies, Schizophrenia, Female, Genome-Wide Association Study, Biotechnology, Developmental Biology
Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Published
2017

26. No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

Author

Johnson, Emma C., Bjelland, Douglas W., Howrigan, Daniel P., Abdellaoui, Abdel, Breen, Gerome, Borglum, Anders, Cichon, Sven, Degenhardt, Franziska, Forstner, Andreas J., Frank, Josef, Genovese, Giulio, Heilmann-Heimbach, Stefanie, Herms, Stefan, Hoffman, Per, Maier, Wolfgang, Mattheisen, Manuel, Morris, Derek, Mowry, Bryan, Müller-Mhysok, Betram, Neale, Benjamin, Nenadic, Igor, Nöthen, Markus M., O’Dushlaine, Colm, Rietschel, Marcella, Ruderfer, Douglas M., Rujescu, Dan, Schulze, Thomas G., Simonson, Matthew A., Stahl, Eli, Strohmaier, Jana, Witt, Stephanie H., Ripke, Stephan, Neale, Benjamin M., Corvin, Aiden, Walters, James T R, Farh, Kai How, Holmans, Peter A., Lee, Phil, Bulik-Sullivan, Brendan, Collier, David A., Huang, Hailiang, Pers, Tune H., Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A., Begemann, Martin, Belliveau, Richard A., Bene, Judit, Bergen, Sarah E., Bevilacqua, Elizabeth, Bigdeli, Tim B., Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M., Carr, Vaughan J., Carrera, Noa, Catts, Stanley V., Chambert, Kimberly D., Chan, Raymond C K, Chen, Ronald Y L, Chen, Eric Y H, Cheng, Wei, Cheung, Eric F C, Chong, Siow Ann, Robert Cloninger, C., Cohen, David, Cohen, Nadine, Cormican, Paul, Craddock, Nick, Crowley, James J., Curtis, David, Davidson, Michael, Davis, Kenneth L., Del Favero, Jurgen, Demontis, Ditte, Dikeos, Dimitris, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Dudbridge, Frank, Durmishi, Naser, Eichhammer, Peter, Eriksson, Johan, Escott-Price, Valentina, Essioux, Laurent, Fanous, Ayman H., Farrell, Martilias S., Franke, Lude, Freedman, Robert, Freimer, Nelson B., Friedl, Marion, Friedman, Joseph I., Fromer, Menachem, Georgieva, Lyudmila, Giegling, Ina, Giusti-Rodríguez, Paola, Godard, Stephanie, Goldstein, Jacqueline I., Golimbet, Vera, Gopal, Srihari, Gratten, Jacob, de Haan, Lieuwe, Hammer, Christian, Hamshere, Marian L., Hansen, Mark, Hansen, Thomas, Haroutunian, Vahram, Hartmann, Annette M., Henskens, Frans A., Hirschhorn, Joel N., Hoffmann, Per, Hofman, Andrea, Hollegaard, Mads V., Hougaard, David M., Ikeda, Masashi, Joa, Inge, Julià, Antonio, Kahn, René S., Kalaydjieva, Luba, Karachanak-Yankova, Sena, Karjalainen, Juha, Kavanagh, David, Kennedy, James L., Khrunin, Andrey, Kim, Yunjung, Klovins, Janis, Knowles, James A., Konte, Bettina, Kucinskas, Vaidutis, Kucinskiene, Zita Ausrele, Kuzelova-Ptackova, Hana, Kähler, Anna K., Laurent, Claudine, Chee Keong, Jimmy Lee, Hong Lee, S., Legge, Sophie E., Lerer, Bernard, Li, Miaoxin, Li, Tao, Liang, Kung Yee, Lieberman, Jeffrey, Limborska, Svetlana, Loughland, Carmel M., Lubinski, Jan, Lönnqvist, Jouko, Macek, Milan, Magnusson, Patrik K E, Maher, Brion S., Mallet, Jacques, Marsal, Sara, Mattingsdal, Morten, McCarley, Robert W., McDonald, Colm, McIntosh, Andrew M., Meier, Sandra, Meijer, Carin J., Melegh, Bela, Melle, Ingrid, Mesholam-Gately, Raquelle I., Metspalu, Andres, Michie, Patricia T., Milani, Lili, Milanova, Vihra, Mokrab, Younes, Morris, Derek W., Mors, Ole, Murphy, Kieran C., Murray, Robin M., Myin-Germeys, Inez, Müller-Myhsok, Bertram, Nelis, Mari, Nertney, Deborah A., Nestadt, Gerald, Nicodemus, Kristin K., Nikitina-Zake, Liene, Nisenbaum, Laura, Nordin, Annelie, O'Callaghan, Eadbhard, O'Dushlaine, Colm, Anthony O'Neill, F., Oh, Sang Yun, Olincy, Ann, Olsen, Line, Van Os, Jim, Pantelis, Christos, Papadimitriou, George N., Papiol, Sergi, Parkhomenko, Elena, Pato, Michele T., Paunio, Tiina, Pejovic-Milovancevic, Milica, Perkins, Diana O., Pietiläinen, Olli, Pimm, Jonathan, Pocklington, Andrew J., Powell, John, Price, Alkes, Pulver, Ann E., Purcell, Shaun M., Quested, Digby, Rasmussen, Henrik B., Reichenberg, Abraham, Reimers, Mark A., Richards, Alexander L., Roffman, Joshua L., Roussos, Panos, Salomaa, Veikko, Sanders, Alan R., Schall, Ulrich, Schubert, Christian R., Schwab, Sibylle G., Scolnick, Edward M., Scott, Rodney J., Seidman, Larry J., Shi, Jianxin, Sigurdsson, Engilbert, Silagadze, Teimuraz, Silverman, Jeremy M., Sim, Kang, Slominsky, Petr, Smoller, Jordan W., So, Hon Cheong, Spencer, Chris C A, Stahl, Eli A., Stefansson, Hreinn, Steinberg, Stacy, Stogmann, Elisabeth, Straub, Richard E., Strengman, Eric, Scott Stroup, T., Subramaniam, Mythily, Suvisaari, Jaana, Svrakic, Dragan M., Szatkiewicz, Jin P., Söderman, Erik, Thirumalai, Srinivas, Toncheva, Draga, Tosato, Sarah, Veijola, Juha, Waddington, John, Walsh, Dermot, Wang, Dai, Wang, Qiang, Webb, Bradley T., Weiser, Mark, Wildenauer, Dieter B., Williams, Nigel M., Williams, Stephanie, Wolen, Aaron R., Wong, Emily H M, Wormley, Brandon K., Xi, Hualin Simon, Zai, Clement C., Zheng, Xuebin, Zimprich, Fritz, Wray, Naomi R., Stefansson, Kari, Visscher, Peter M., Adolfsson, Rolf, Andreassen, Ole A., Blackwood, Douglas H R, Bramon, Elvira, Buxbaum, Joseph D., Børglum, Anders D., Darvasi, Ariel, Domenici, Enrico, Ehrenreich, Hannelore, Esko, Tõnu, Gejman, Pablo V., Gill, Michael, Gurling, Hugh, Hultman, Christina M., Iwata, Nakao, Jablensky, Assen V., Jönsson, Erik G., Kendler, Kenneth S., Kirov, George, Knight, Jo, Lencz, Todd, Levinson, Douglas F., Li, Qingqin S., Liu, Jianjun, Malhotra, Anil K., McCarroll, Steven A., McQuillin, Andrew, Moran, Jennifer L., Mortensen, Preben B., Mowry, Bryan J., Ophoff, Roel A., Owen, Michael J., Palotie, Aarno, Pato, Carlos N., Petryshen, Tracey L., Posthuma, Danielle, Riley, Brien P., Sham, Pak C., Sklar, Pamela, Clair, David S., Weinberger, Daniel R., Wendland, Jens R., Werge, Thomas, Daly, Mark J., O'Donovan, Michael C., Sullivan, Patrick F., Keller, Matthew C., Biological Psychology, Johnson, Emma C, Bjelland, Douglas W, Howrigan, Daniel P, Abdellaoui, Abdel, Lee, S Hong, Keller, Matthew C, and Schizophrenia Working Group of the Psychiatric Genomics Consortium

Subjects
0301 basic medicine, Male, Cancer Research, Heredity, Ecology, Evolution, Behavior and Systematics, Molecular Biology, Genetics, Genetics (clinical), Social Sciences, Genome-wide association study, Disease, 030105 genetics & heredity, Runs of Homozygosity, Homozygosity, Consanguinity, Sociology, Polymorphism (computer science), Consortia, Medicine and Health Sciences, Genetics(clinical), Inbreeding, Ecology, Depression, Homozygote, Genomics, 3. Good health, Schizophrenia, Research Design, Physical Sciences, Female, Statistics (Mathematics), Research Article, lcsh:QH426-470, Evolution, Replication Studies, inbreeding, Single-nucleotide polymorphism, Biology, Genome Complexity, Research and Analysis Methods, Polymorphism, Single Nucleotide, 03 medical and health sciences, SDG 17 - Partnerships for the Goals, Behavior and Systematics, SDG 3 - Good Health and Well-being, Mental Health and Psychiatry, medicine, Confidence Intervals, Humans, replication study, Mood Disorders, Genome, Human, Biology and Life Sciences, Computational Biology, medicine.disease, schizophrenia, lcsh:Genetics, 030104 developmental biology, homozygosity, Mathematics, Genome-Wide Association Study
Abstract

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest., Author Summary It is well known that mating between relatives increases the risk that a child will have a rare recessive genetic disease, but there has also been increasing interest and inconsistent findings on whether inbreeding is a risk factor for common, complex psychiatric disorders such as schizophrenia. The best powered study to date investigating this theory predicted that the odds of developing schizophrenia increase by approximately 17% for every additional percent of the genome that shows evidence of inbreeding. In this replication, we used genome-wide single nucleotide polymorphism data from 18,562 schizophrenia cases and 21,268 controls to quantify the degree to which they were inbred and to test the hypothesis that schizophrenia cases show higher mean levels of inbreeding. Contrary to the original study, we did not find evidence for distant inbreeding to play a role in schizophrenia risk. There are various confounding factors that could explain the discrepancy in results from the original study and our replication, and this should serve as a cautionary note–careful attention should be paid to issues like ascertainment when using the data from genome-wide case-control association studies for secondary analyses for which the data may not have originally been intended.

Published
2016

27. Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Author

Mehta, Divya, Tropf, Felix C, Gratten, Jacob, Bakshi, Andrew, Zhu, Zhihong, Bacanu, Silviu-Alin, Hemani, Gibran, Magnusson, Patrik KE, Barban, Nicola, Esko, Tõnu, Metspalu, Andres, Snieder, Harold, Mowry, Bryan J, Kendler, Kenneth S, Yang, Jian, Visscher, Peter M, McGrath, John J, Mills, Melinda C, Wray, Naomi R, Lee, S Hong, Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUK, Andreassen, Ole A, Bramon, Elvira, Bruggeman, Richard, Buxbaum, Joseph D, Cairns, Murray J, Cantor, Rita M, Cloninger, C Robert, Cohen, David, Crespo-Facorro, Benedicto, Darvasi, Ariel, DeLisi, Lynn E, Dinan, Timothy, Djurovic, Srdjan, Donohoe, Gary, Drapeau, Elodie, Escott-Price, Valentina, Freimer, Nelson B, Georgieva, Lyudmila, de Haan, Lieuwe, Henskens, Frans A, Joa, Inge, Julià, Antonio, Khrunin, Andrey, Lerer, Bernard, Limborska, Svetlana, Loughland, Carmel M, Macek, Milan, Marsal, Sara, McCarley, Robert W, McIntosh, Andrew M, McQuillin, Andrew, Melegh, Bela, Michie, Patricia T, Morris, Derek W, Murphy, Kieran C, Myin-Germeys, Inez, Olincy, Ann, Van Os, Jim, Pantelis, Christos, Posthuma, Danielle, Quested, Digby, Schall, Ulrich, Scott, Rodney J, Seidman, Larry J, Toncheva, Draga, Tooney, Paul A, Waddington, John, Weinberger, Daniel R, Weiser, Mark, and Wu, Jing Qin

Subjects
Risk, Adult, Denmark, Cohort Studies, Pregnancy, Clinical Research, Genetics, Humans, Psychology, Genetic Predisposition to Disease, Alleles, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Other Medical and Health Sciences, Prevention, Human Genome, and TwinsUK, Serious Mental Illness, Brain Disorders, Phenotype, Mental Health, Schizophrenia, Female, Cognitive Sciences, Birth Order, LifeLines Cohort Study, Maternal Age, Genome-Wide Association Study
Abstract

ImportanceA recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.ObjectiveTo determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.Design, setting, and participantsThis investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.Main outcomes and measuresWe tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age.ResultsWe observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.Conclusions and relevanceThis study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Published
2016

28. Increased power by harmonizing structural MRI site differences with the ComBat batch method in ENIGMA

Author

Radua, Joaquim, Vieta, Eduard, Shinohara, Russell, Kochunov, Peter, Quide, Yann, Green, Melissa J., Weickert, Cynthia S., Weickert, Thomas, Bruggemann, Jason, Kircher, Tilo, Nenadic, Igor, Cairns, Murray J., Seal, Marc, Schall, Ulrich, Henskens, Frans, Fullerton, Janice M., Mowry, Bryan, Pantelis, Christos, Lenroot, Rhoshel, Cropley, Vanessa, Loughland, Carmel, Scott, Rodney, Wolf, Daniel, Satterthwaite, Theodore D., Tan, Yunlong, Sim, Kang, Piras, Fabrizio, Spalletta, Gianfranco, Banaj, Nerisa, Pomarol-Clotet, Edith, Solanes, Aleix, Albajes-Eizagirre, Anton, Canales-Rodriguez, Erick J., Sarro, Salvador, Di Giorgio, Annabella, Bertolino, Alessandro, Staeblein, Michael, Oertel, Viola, Knoechel, Christian, Borgwardt, Stefan, du Plessis, Stefan, Yun, Je-Yeon, Kwon, Jun Soo, Dannlowski, Udo, Hahn, Tim, Grotegerd, Dominik, Alloza, Clara, Arango, Celso, Janssen, Joost, Diaz-Caneja, Covadonga, Jiang, Wenhao, Calhoun, Vince, Ehrlich, Stefan, Yang, Kun, Cascella, Nicola G., Takayanagi, Yoichiro, Sawa, Akira, Tomyshev, Alexander, Lebedeva, Irina, Kaleda, Vasily, Kirschner, Matthias, Hoschl, Cyril, Tomecek, David, Skoch, Antonin, van Amelsvoort, Therese, Bakker, Geor, James, Anthony, Preda, Adrian, Weideman, Andrea, Stein, Dan J., Howells, Fleur, Uhlmann, Anne, Temmingh, Henk, Lopez-Jaramillo, Carlos, Diaz-Zuluaga, Ana, Fortea, Lydia, Martinez-Heras, Eloy, Solana, Elisabeth, Llufriu, Sara, Jahanshad, Neda, Thompson, Paul, Turner, Jessica, and van Erp, Theo

Subjects
mega-analysis, schizophrenia, volume, neuroimaging, brain, gray matter, cortical thickness, surface-based analysis
Abstract

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega -analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related het-erogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega -analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random - effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

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