We used SMR37 as our primary method to identify SNPs which might mediate association with schizophrenia through effects on gene expression. The significance for SMR is set at the Bonferroni corrected threshold of 0.05/M where M is the number of genes with significant eQTLs tested for a given tissue. Significant SMR associations imply colocalization of the schizophrenia associations with eQTL. We applied the HEIDI test37 to filter out SMR associations (PHEIDI < 0.01) due to linkage disequilibrium between SCZ-associated variants and eQTLs. cis-eQTL summary data were from three studies: fetal brain (N=120)38 , adult brain (n = ~1,500)39 and blood (n = ~32,000)40 . Linkage disequilibrium (LD) data required for the HEIDI test37 were estimated from the Health and Retirement Study (HRS)41 (n = 8,557). We included only genes with at least one cis-eQTL at PeQTL < 5×10−8, excluding those in MHC regions due to the complexity of this region. For blood, we included only genes with eQTLs in brain. This left 7,803 genes in blood, 10,890 genes in prefrontal cortex and 754 genes in fetal brain for analysis (see Supplementary Note for further details). SMR was performed using data from the primary GWAS. The results were then filtered to exclude significant SMR implicated genes where the eQTLs did not map within our definition of an associated locus in the Extended GWAS meta-analysis of our primary GWAS dataset and the dataset provided by deCODE genetics. For genomic regions where there were multiple genes showing significant SMR associations, we attempted to resolve these with conditional analysis using GCTA-COJO42 ,43 . We selected the top-associated cis-eQTL for one gene (or a set of genes sharing the same cis-eQTL) ran a COJO analysis in the schizophrenia GWAS data and the eQTL data for each of the other genes conditioning on the selected top cis-eQTL. We then re-ran the SMR and HEIDI analyses using these conditional GWAS and eQTL results. We used FUSION44 and EpiXcan45 as tests of robustness of the SMR results. Details are supplied in the Supplementary Note as are our approaches to prioritising SMR associated genes.
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Trubetskoy V., Panagiotaropoulou G., Awasthi S., Braun A., Kraft J., Skarabis N., Walter H., Ripke S., Pardiñas A.F., Dennison C.A., Hall L.S., Harwood J.C., Richards A.L., Legge S.E., Lynham A., Williams N.M., Bray N.J., Escott-Price V., Kirov G., Holmans P.A., Pocklington A.J., Owen M.J., Walters J.T., O’Donovan M.C., Qi T., Sidorenko J., Wu Y., Zeng J., Gratten J., Visscher P.M., Yang J., Wray N.R., Qi T., Yang J., Bigdeli T.B., Fanous A.H., Bryois J., Bergen S.E., Kähler A.K., Magnusson P.K., Hultman C.M., Sullivan P.F., Chen C.Y., Atkinson E.G., Goldstein J.I., Howrigan D.P., Martin A.R., Daly M.J., Huang H., Neale B.M., Ripke S., Ge T., Lam M., Ge T., Atkinson E.G., Belliveau R.A., Chambert K.D., Genovese G., Lee P.H., Martin A.R., Pietiläinen O., McCarroll S.A., Moran J.L., Smoller J.W., Brown T.C., Feng G., Hyman S.E., Sheng M., Hyman S.E., Huang H., Neale B.M., Lam M., Chong S.A., Subramaniam M., Lam M., Lencz T., Malhotra A.K., Watanabe K., Frei O., Agartz I., Athanasiu L., Melle I., Andreassen O.A., Frei O., Athanasiu L., Melle I., Steen N.E., Andreassen O.A., Frei O., Ge T., DeLisi L.E., Mesholam-Gately R.I., Seidman L.J., Koopmans F., Magnusson S., Stefánsson H., Stefansson K., Grove J., Agerbo E., Als T.D., Bybjerg-Grauholm J., Demontis D., Hougaard D.M., Mors O., Mortensen P.B., Nordentoft M., Børglum A.D., Grove J., Als T.D., Demontis D., Mattheisen M., Børglum A.D., Grove J., Als T.D., Demontis D., Børglum A.D., Kim M., Gandal M.J., Li Z., Shi Y., Shi Y., Li Z., Zhou W., Qin S., Shi Y., Shi Y., Voloudakis G., Zhang W., Roussos P., Zhang W., Adams M., McIntosh A., Agartz I., Agartz I., Söderman E., Jönsson E.G., McGrath J.J., Al Eissa M., Bass N.J., Fiorentino A., O’Brien N.L., Pimm J., Sharp S.I., McQuillin A., Albus M., Alexander M., Alizadeh B.Z., Bruggeman R., Alizadeh B.Z., Alptekin K., Alptekin K., Amin F., Arolt V., Lencer R., Rothermundt M., Baune B.T., Arrojo M., Azevedo M.H., Bacanu S.A., Webb B.T., Wormley B.K., Riley B.P., Kendler K.S., Begemann M., Mitjans M., Steixner-Kumar A.A., Ehrenreich H., Bene J., Benyamin B., Benyamin B., Benyamin B., Blasi G., Rampino A., Torretta S., Bertolino A., Bobes J., Bobes J., Bobes J., Bonassi S., Bressan R.A., Gadelha A., Noto C., Bressan R.A., Gadelha A., Noto C., Ota V.K., Santoro M.L., Belangero S.I., Bromet E.J., Bruggeman R., Buckley P.F., Buckner R.L., Bybjerg-Grauholm J., Hougaard D.M., Cahn W., Kahn R.S., Cahn W., Cairns M.J., Scott R.J., Tooney P.A., Cairns M.J., Schall U., Scott R.J., Tooney P.A., Cairns M.J., Tooney P.A., Calkins M.E., Gur R.E., Gur R.C., Turetsky B.I., Carr V.J., Carr V.J., Carr V.J., Castle D., Harvey C., Castle D., Catts S.V., Catts S.V., Chan R.C., Chan R.C., Chaumette B., Kebir O., Krebs M.O., Chaumette B., Cheng W., Cheung E.F., Chong S.A., Subramaniam M., Cohen D., Consoli A., Giannitelli M., Laurent-Levinson C., Cohen D., Consoli A., Giannitelli M., Laurent-Levinson C., Cohen D., Cordeiro Q., Costas J., Curtis C., Quattrone D., Breen G., Collier D.A., Di Forti M., Vassos E., Curtis C., Mondelli V., Quattrone D., van Amelsvoort T., Di Forti M., Murray R.M., Vassos E., van Amelsvoort T., Davidson M., Davis K.L., Haroutunian V., Malaspina D., Reichenberg A., Siever L.J., Silverman J.M., Buxbaum J.D., Kahn R.S., de Haan L., de Haan L., de Haan L., de Haan L., Degenhardt F., Forstner A., Nöthen M.M., DeLisi L.E., Dickerson F., Dikeos D., Papadimitriou G.N., Dinan T., Dinan T., Djurovic S., Djurovic S., Duan J., Gejman P.V., Sanders A.R., Duan J., Gejman P.V., Sanders A.R., Ducci G., Dudbridge F., Eriksson J.G., Eriksson J.G., Eriksson J.G., Fañanás L., Fañanás L., Peñas J.G., González-Pinto A., Molto M.D., Moreno C., Parellada M., Sanjuan J., Crepo-Facorro B., Mata I., Arango C., Faraone S.V., Forstner A., Frank J., Streit F., Witt S.H., Rietschel M., Freimer N.B., Ophoff R.A., Freimer N.B., Fromer M., Stahl E.A., Frustaci A., Gershon E.S., Giegling I., Hartmann A.M., Konte B., Rujescu D., Giusti-Rodríguez P., Szatkiewicz J.P., Sullivan P.F., Godard S., González Peñas J., Moreno C., Parellada M., Arango C., González-Pinto A., Gopal S., Savitz A., Li Q.S., Gratten J., Green M.F., Nuechterlein K.H., Sugar C.A., Green M.F., Greenwood T.A., Light G.A., Swerdlow N.R., Braff D., Guillin O., Campion D., Guillin O., Campion D., Guillin O., Gülöksüz S., Luykx J.J., Rutten B.P., van Amelsvoort T., van Winkel R., van Amelsvoort T., van Winkel R., Gülöksüz S., Gutiérrez B., Hahn E., Hakonarson H., Pellegrino R., Haroutunian V., Haroutunian V., Harvey C., Pantelis C., Hayward C., Henskens F.A., Kelly B.J., Herms S., Hoffmann P., Howrigan D.P., Fromer M., Daly M.J., Ikeda M., Iwata N., Iyegbe C., van Os J., Joa I., Julià A., Marsal S., Kam-Thong T., Rautanen A., Kamatani Y., Kamatani Y., Karachanak-Yankova S., Toncheva D., Karachanak-Yankova S., Keller M.C., Khrunin A., Limborska S., Slominsky P., Kim S.W., Klovins J., Nikitina-Zake L., Kondratiev N., Golimbet V., Kraft J., Kubo M., Kučinskas V., Kučinskiene Z.A., Kusumawardhani A., Kuzelova-Ptackova H., Landi S., Lazzeroni L.C., Levinson D.F., Lazzeroni L.C., Lee P.H., Petryshen T.L., Smoller J.W., Lehrer D.S., Lerer B., Li M., Lieberman J., Stroup T.S., Light G.A., Braff D., Liu C.M., Liu C.M., Hwu H.G., Lönnqvist J., Lönnqvist J., Loughland C.M., Lubinski J., Luykx J.J., Bakker S., Kahn R., Luykx J.J., Luykx J.J., Macek M J.r., Mackinnon A., Mackinnon A., Maher B.S., Maier W., Malaspina D., Atbaşoğlu E.C., Mallet J., Marder S.R., Martin A.R., Huang H., Martorell L., Muntané G., Vilella E., Mattheisen M., Meier S., Mattheisen M., Mattheisen M., Schulze T.G., McCarley R.W., McDonald C., Donohoe G., Morris D.W., McGrath J.J., Periyasamy S., Mowry B.J., Wray N.R., McGrath J.J., Medeiros H., Sobell J.L., Medeiros H., Meier S., Melegh B., Mesholam-Gately R.I., Seidman L.J., Metspalu A., Milani L., Esko T., Michie P.T., Milanova V., Molden E., Molden E., Molina E., Molto M.D., Molto M.D., Sanjuan J., Mondelli V., Morley C.P., Muntané G., Murphy K.C., Myin-Germeys I., Nenadić I., Nenadić I., Nestadt G., Pulver A.E., O’Neill F.A., Oh S.Y., Oh S.Y., Olincy A., Freedman R., Ota V.K., Santoro M.L., Belangero S.I., Pantelis C., Pantelis C., Baune B.T., Pantelis C., Baune B.T., Paunio T., Paunio T., Periyasamy S., Mowry B.J., Perkins D.O., Sullivan P.F., Pfuhlmann B., Pietiläinen O., Hyman S.E., Pietiläinen O., Benner C., Pirinen M., Palotie A., Daly M.J., Porteous D., Powell J., Quattrone D., Di Forti M., Quested D., Quested D., Radant A.D., Tsuang D.W., Radant A.D., Tsuang D.W., Rapaport M.H., Roe C., Liu C., Roffman J.L., Moran J.L., Roth J., Gawlik M., Saker-Delye S., Salomaa V., Suvisaari J., Sanjuan J., Schall U., Scott R.J., Shi J., Siever L.J., Silverman J.M., Sigurdsson E., Sigurdsson E., Sim K., Sim K., Sim K., So H.C., So H.C., Stain H.J., Stain H.J., Steen N.E., Jönsson E.G., Stögmann E., Zimprich F., Stone W.S., Stone W.S., Straub R.E., Hyde T., Jaffe A., Weinberger D.R., Strengman E., Sugar C.A., Svrakic D.M., Cloninger C.R., Ta T.M., Ta T.M., Takahashi A., Terao C., Thibaut F., Thibaut F., Toncheva D., Tosato S., Tura G.B., Üçok A., Vaaler A., Vaaler A., van Winkel R., Veijola J., van Winkel R., Veijola J., Waddington J., Waterreus A., Morgan V.A., Waterreus A., Jablensky A.V., Morgan V.A., Weiser M., Wu J.Q., Xu Z., Yolken R., Zai C.C., Kennedy J.L., Zai C.C., Kennedy J.L., Zhu F., Zhu F., Atbaşoğlu E.C., Saka M.C., Ayub M., Black D.W., Buccola N.G., Byerley W.F., Chen W.J., Chen W.J., Crespo-Facorro B., Crespo-Facorro B., Galletly C., Galletly C., Galletly C., Gennarelli M., Gennarelli M., Hwu H.G., Mors O., Müller-Myhsok B., Müller-Myhsok B., Müller-Myhsok B., Neil A.L., Nordentoft M., Pato M.T., Pato C.N., Pato M.T., Pato C.N., Pirinen M., Pirinen M., Schulze T.G., Schulze T.G., Schulze T.G., Stahl E.A., Esko T., Stahl E.A., Wang S.H., Xu S., Xu S., Xu S., Adolfsson R., Bramon E., Cervilla J.A., Cichon S., Cichon S., Cichon S., Collier D.A., Collier D.A., Corvin A., Gill M., Curtis D., Curtis D., Domenici E., Escott-Price V., Fanous A.H., Fanous A.H., Gareeva A., Khusnutdinova E., Gareeva A., Gareeva A., Khusnutdinova E., Gareeva A., Glatt S.J., Hong K.S., Knowles J.A., Knowles J.A., Lee J., Lee J., Lencz T., Malhotra A.K., Lencz T., Malhotra A.K., Liu J., Liu J., Malhotra D., Menezes P.R., Nimgaonkar V., Ophoff R.A., Ophoff R.A., Paciga S.A., Palotie A., Palotie A., Ripke S., Qin S., Rivera M., Rivera M., Schwab S.G., Schwab S.G., Serretti A., Sham P.C., Sham P.C., Sham P.C., Sham P.C., Sham P.C., Sham P.C., Clair D.S., Tsuang M.T., Tsuang M.T., van Os J., Vawter M.P., Werge T., Werge T., Clair D.S., Werge T., Werge T., van Os J., Wildenauer D.B., van Os J., Yu X., Yue W., Yu X., Yue W., Yue W., Roussos P., Vassos E., Verhage M., Koopmans F., Sahasrabudhe D., Toonen R.F., Verhage M., Verhage M., Posthuma D., Yang J., Dai N., Wenwen Q., Wildenauer D.B., Dai N., Wenwen Q., Wildenauer D.B., Agiananda F., Amir N., Antoni R., Arsianti T., Asmarahadi A., Diatri H., Djatmiko P., Irmansyah I., Khalimah S., Kusumadewi I., Kusumaningrum P., Lukman P.R., Nasrun M.W., Safyuni N.S., Prasetyawan P., Semen G., Siste K., Tobing H., Widiasih N., Wiguna T., Wulandari D., Evalina N., Hananto A.J., Ismoyo J.H., Marini T.M., Henuhili S., Reza M., Yusnadewi S., Abyzov A., Akbarian S., van Bakel H., Breen M., Charney A., Dracheva S., Girdhar K., Hoffman G., Jiang Y., Pinto D., Purcell S., Roussos P., Wiseman J., Ashley-Koch A., Crawford G., Reddy T., Brown M., Grennan K., Bryois J., Carlyle B., Emani P., Galeev T., Gerstein M., Gu M., Guerra B., Gursoy G., Kitchen R., Lee D., Li M., Liu S., Navarro F., Pan X., Pochareddy S., Rozowsky J., Sestan N., Sethi A., Shi X., Szekely A., Wang D., Warrell J., Weissman S., Wu F., Xu X., Coetzee G., Farnham P., Lay F., Rhie S., Witt H., Wood S., Yao L., Gandal M., Polioudakis D., Swarup V., Won H., Giase G., Jiang S., Kefi A., Shieh A., Goes F., Zandi P., Kim Y., Knowles J.A., Mattei E., Purcaro M., Pratt H., Peters M.A., Sanders S., Weng Z., White K., Arranz M.J., Bramon E., Iyegbe C., Lewis C., Lin K., Murray R.M., Powell J., Walshe M., Arranz M.J., Bender S., Bender S., Weisbrod M., Bramon E., Crepo-Facorro B., Mata I., Hall J., Lawrie S., McIntosh A., Linszen D.H., Ophoff R.A., van Os J., van Os J., Rujescu D., Rujescu D., Achsel T., Bagni C., Andres-Alonso M., Kreutz M.R., Bayés À., Biederer T., Brose N., Chua J.J., Coba M.P., Cornelisse L.N., van Weering J.R., de Jong A.P., MacGillavry H.D., de Juan-Sanz J., Dieterich D.C., Pielot R., Smalla K.H., Dieterich D.C., Gundelfinger E.D., Pielot R., Smalla K.H., Feng G., Goldschmidt H.L., Huganir R.L., Hoogenraad C., Hyman S.E., Imig C., Jahn R., Jung H., Kim E., Kaeser P.S., Lipstein N., Malenka R., McPherson P.S., O’Connor V., Ryan T.A., Sala C., Verpelli C., Smit A.B., Südhof T.C, & Thomas P.D. (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature, 604(7906), 502-508.
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Charité - Universitätsmedizin Berlin, Cardiff University, University of Queensland, SUNY Downstate Health Sciences University, Karolinska Institutet, Biogen (United States), Broad Institute, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, University of Oslo, Massachusetts General Hospital, deCODE Genetics (Iceland), Lundbeck Foundation, University of California, Los Angeles, Affiliated Hospital of Qingdao University, Qingdao University, Allen Institute for Brain Science, Icahn School of Medicine at Mount Sinai, Royal Edinburgh Hospital, University of Edinburgh, University College London, McLean Hospital, University Medical Center Groningen, University of Groningen, Dokuz Eylül University, Emory University, University of Münster, Complejo Hospitalario Universitario de Santiago, Servicio Gallego de Salud, Complexo Hospitalario Universitario A Coruña, University of Coimbra, Virginia Commonwealth University, Max Planck Institute of Experimental Medicine, University of Pecs, University of South Australia, University of Bari Aldo Moro, Central University Hospital of Asturias, Universidad de Oviedo, San Raffaele University of Rome, Istituti di Ricovero e Cura a Carattere Scientifico, Universidade Federal de São Paulo, Stony Brook University, University of Tennessee Health Science Center, Harvard University, University Medical Center Utrecht, University of Newcastle Australia, University of Pennsylvania, UNSW Sydney, University of Melbourne, University of Sydney, Institute of Psychology, Chinese Academy of Sciences, Institut de Psychiatrie et Neurosciences de Paris, Université Paris Cité, Inserm, University of North Carolina at Chapel Hill, Castle Peak Hospital, Institute of Mental Health, Pitié-Salpêtrière Hospital, Sorbonne Université, Troubles psychiatriques et développement, Irmandade da Santa Casa de Misericórdia de São Paulo, Instituto de Investigación Sanitaria de Santiago, King's College London, University of Nicosia, University of Amsterdam, University of Bonn, Sheppard Pratt Health System, Eginition Hospital, National and Kapodistrian University of Athens, University College Cork, University of Bergen, NorthShore University HealthSystem, Azienda Sanitaria Locale Roma 3, University of Leicester, University of Helsinki, Helsinki University Hospital, Institut de Biologia Evolutiva, Universitat de Barcelona, SUNY Upstate Medical University, Central Institute of Mental Health, Heidelberg University, University Hospital Heidelberg, Barnet Enfield and Haringey Mental Health Trust, St Ann’s Hospital, University of Chicago, Medical University of Vienna, Institut de Myologie, Centro de Investigación Biomédica en Red de Salud Mental, Janssen (United States), University of California, San Diego, Maastricht University Medical Centre, Universidad de Granada, Children's Hospital of Philadelphia, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, University of Basel, Fujita Health University, Stavanger University Hospital, Vall d'Hebron Institut de Recerca, Roche (Switzerland), The University of Tokyo, Medical University of Sofia, University of Colorado Boulder, Kurchatov Institute, Institute of Molecular Genetics, Chonnam National University, Latvian Biomedical Research and Study Centre, Mental Health Research Center of Russian Academy of Medical Sciences, RIKEN Center for Integrative Medical Sciences, Vilnius University, Rumah Sakit Umum Pusat Nasional Dr. Cipto Mangunkusumo, University of Indonesia, General University Hospital in Prague, University of Pisa, Stanford University, Wright State University, Hadassah Medical Center, Sun Yat-sen University, Columbia University, National Taiwan University Hospital, Finnish Institute for Health and Welfare, Hunter New England Local Health District, International Hereditary Cancer Center, Pomeranian Medical University, University Hospital in Motol, Black Dog Institute, Johns Hopkins University, German Center for Neurodegenerative Diseases, University 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Jersey, Ludwig-Maximilians-Universität München, China Medical University, Fudan University, Harry Perkins Institute of Medical Research, Mayo Clinic in Arizona, Mount Sinai Medical Center, Duke University, University of Illinois Chicago, Yale University, University of Massachusetts Amherst, Sage Bionetworks, University of Massachusetts Chan Medical School, Utrecht University, TU Dresden, Mental Health Research UK, Eli Lilly (United Kingdom), Academic Medical Center, University of Lausanne, Leibniz Institute for Neurobiology, Synapse (Spain), Centre National de la Recherche Scientifique, Assistance Publique – Hôpitaux de Paris, Institut du Cerveau, Otto-von-Guericke University Magdeburg, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Discovery Institute, University of Copenhagen, Max Planck Institute for Biophysical Chemistry, Korea Advanced Institute of Science and Technology, Institute for Basic Science, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Montreal Neurological Institute and Hospital, McGill University, University of Southampton, Cornell University, Neuroscience Institute, Howard Hughes Medical Institute, Umeå University, Hospital General Universitario Gregorio Marañón, VA San Diego Healthcare System, VA Desert Pacific Healthcare Network, Mental Illness Research, Education and Clinical Centers, Centre Hospitalier du Rouvray, University Hospital of Basel, Trinity College Dublin, Mental Health Foundation, University of Trento, UK Dementia Research Institute, Phoenix VA Health Care System, Russian Academy of Sciences, Samsung Medical Center, Sungkyunkwan University, Feinstein Institute for Medical Research, Genome Institute of Singapore, Agency for Science, Technology and Research, Universidade de São Paulo, Queensland Centre for Mental Health Research, University of Pittsburgh, Pfizer (United States), Shanghai Mental Health Center, Ankara University, University of Wollongong, University of Bologna, University of Hong Kong, University of Aberdeen, University of California, Irvine, Copenhagen University Hospital, Mental Health Services, Peking University, Peking University Sixth Hospital, James J. Peters VA Medical Center, Westlake University, Reinier van Arkel, Arkin
Significance for SMR set at Bonferroni corrected threshold of 0.05/M
HEIDI test to filter out SMR associations (P_HEIDI < 0.01) due to linkage disequilibrium
Conditional analysis using GCTA-COJO to resolve regions with multiple significant SMR associations
Use of FUSION and EpiXcan as tests of robustness of the SMR results
dependent variables
Identification of SNPs that might mediate association with schizophrenia through effects on gene expression
control variables
Exclusion of genes in MHC regions due to the complexity of this region
Inclusion of only genes with at least one cis-eQTL at P_eQTL < 5×10^-8
For blood, inclusion of only genes with eQTLs in brain
Annotations
Based on most similar protocols
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