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Mapping genomic loci implicates genes and synaptic biology in schizophrenia.

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.

SUBMITTER: Trubetskoy V

PROVIDER: S-EPMC9392466 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Mapping genomic loci implicates genes and synaptic biology in schizophrenia.

Trubetskoy Vassily V Pardiñas Antonio F AF Qi Ting T Panagiotaropoulou Georgia G Awasthi Swapnil S Bigdeli Tim B TB Bryois Julien J Chen Chia-Yen CY Dennison Charlotte A CA Hall Lynsey S LS Lam Max M Watanabe Kyoko K Frei Oleksandr O Ge Tian T Harwood Janet C JC Koopmans Frank F Magnusson Sigurdur S Richards Alexander L AL Sidorenko Julia J Wu Yang Y Zeng Jian J Grove Jakob J Kim Minsoo M Li Zhiqiang Z Voloudakis Georgios G Zhang Wen W Adams Mark M Agartz Ingrid I Atkinson Elizabeth G EG Agerbo Esben E Al Eissa Mariam M Albus Margot M Alexander Madeline M Alizadeh Behrooz Z BZ Alptekin Köksal K Als Thomas D TD Amin Farooq F Arolt Volker V Arrojo Manuel M Athanasiu Lavinia L Azevedo Maria Helena MH Bacanu Silviu A SA Bass Nicholas J NJ Begemann Martin M Belliveau Richard A RA Bene Judit J Benyamin Beben B Bergen Sarah E SE Blasi Giuseppe G Bobes Julio J Bonassi Stefano S Braun Alice A Bressan Rodrigo Affonseca RA Bromet Evelyn J EJ Bruggeman Richard R Buckley Peter F PF Buckner Randy L RL Bybjerg-Grauholm Jonas J Cahn Wiepke W Cairns Murray J MJ Calkins Monica E ME Carr Vaughan J VJ Castle David D Catts Stanley V SV Chambert Kimberley D KD Chan Raymond C K RCK Chaumette Boris B Cheng Wei W Cheung Eric F C EFC Chong Siow Ann SA Cohen David D Consoli Angèle A Cordeiro Quirino Q Costas Javier J Curtis Charles C Davidson Michael M Davis Kenneth L KL de Haan Lieuwe L Degenhardt Franziska F DeLisi Lynn E LE Demontis Ditte D Dickerson Faith F Dikeos Dimitris D Dinan Timothy T Djurovic Srdjan S Duan Jubao J Ducci Giuseppe G Dudbridge Frank F Eriksson Johan G JG Fañanás Lourdes L Faraone Stephen V SV Fiorentino Alessia A Forstner Andreas A Frank Josef J Freimer Nelson B NB Fromer Menachem M Frustaci Alessandra A Gadelha Ary A Genovese Giulio G Gershon Elliot S ES Giannitelli Marianna M Giegling Ina I Giusti-Rodríguez Paola P Godard Stephanie S Goldstein Jacqueline I JI González Peñas Javier J González-Pinto Ana A Gopal Srihari S Gratten Jacob J Green Michael F MF Greenwood Tiffany A TA Guillin Olivier O Gülöksüz Sinan S Gur Raquel E RE Gur Ruben C RC Gutiérrez Blanca B Hahn Eric E Hakonarson Hakon H Haroutunian Vahram V Hartmann Annette M AM Harvey Carol C Hayward Caroline C Henskens Frans A FA Herms Stefan S Hoffmann Per P Howrigan Daniel P DP Ikeda Masashi M Iyegbe Conrad C Joa Inge I Julià Antonio A Kähler Anna K AK Kam-Thong Tony T Kamatani Yoichiro Y Karachanak-Yankova Sena S Kebir Oussama O Keller Matthew C MC Kelly Brian J BJ Khrunin Andrey A Kim Sung-Wan SW Klovins Janis J Kondratiev Nikolay N Konte Bettina B Kraft Julia J Kubo Michiaki M Kučinskas Vaidutis V Kučinskiene Zita Ausrele ZA Kusumawardhani Agung A Kuzelova-Ptackova Hana H Landi Stefano S Lazzeroni Laura C LC Lee Phil H PH Legge Sophie E SE Lehrer Douglas S DS Lencer Rebecca R Lerer Bernard B Li Miaoxin M Lieberman Jeffrey J Light Gregory A GA Limborska Svetlana S Liu Chih-Min CM Lönnqvist Jouko J Loughland Carmel M CM Lubinski Jan J Luykx Jurjen J JJ Lynham Amy A Macek Milan M Mackinnon Andrew A Magnusson Patrik K E PKE Maher Brion S BS Maier Wolfgang W Malaspina Dolores D Mallet Jacques J Marder Stephen R SR Marsal Sara S Martin Alicia R AR Martorell Lourdes L Mattheisen Manuel M McCarley Robert W RW McDonald Colm C McGrath John J JJ Medeiros Helena H Meier Sandra S Melegh Bela B Melle Ingrid I Mesholam-Gately Raquelle I RI Metspalu Andres A Michie Patricia T PT Milani Lili L Milanova Vihra V Mitjans Marina M Molden Espen E Molina Esther E Molto María Dolores MD Mondelli Valeria V Moreno Carmen C Morley Christopher P CP Muntané Gerard G Murphy Kieran C KC Myin-Germeys Inez I Nenadić Igor I Nestadt Gerald G Nikitina-Zake Liene L Noto Cristiano C Nuechterlein Keith H KH O'Brien Niamh Louise NL O'Neill F Anthony FA Oh Sang-Yun SY Olincy Ann A Ota Vanessa Kiyomi VK Pantelis Christos C Papadimitriou George N GN Parellada Mara M Paunio Tiina T Pellegrino Renata R Periyasamy Sathish S Perkins Diana O DO Pfuhlmann Bruno B Pietiläinen Olli O Pimm Jonathan J Porteous David D Powell John J Quattrone Diego D Quested Digby D Radant Allen D AD Rampino Antonio A Rapaport Mark H MH Rautanen Anna A Reichenberg Abraham A Roe Cheryl C Roffman Joshua L JL Roth Julian J Rothermundt Matthias M Rutten Bart P F BPF Saker-Delye Safaa S Salomaa Veikko V Sanjuan Julio J Santoro Marcos Leite ML Savitz Adam A Schall Ulrich U Scott Rodney J RJ Seidman Larry J LJ Sharp Sally Isabel SI Shi Jianxin J Siever Larry J LJ Sigurdsson Engilbert E Sim Kang K Skarabis Nora N Slominsky Petr P So Hon-Cheong HC Sobell Janet L JL Söderman Erik E Stain Helen J HJ Steen Nils Eiel NE Steixner-Kumar Agnes A AA Stögmann Elisabeth E Stone William S WS Straub Richard E RE Streit Fabian F Strengman Eric E Stroup T Scott TS Subramaniam Mythily M Sugar Catherine A CA Suvisaari Jaana J Svrakic Dragan M DM Swerdlow Neal R NR Szatkiewicz Jin P JP Ta Thi Minh Tam TMT Takahashi Atsushi A Terao Chikashi C Thibaut Florence F Toncheva Draga D Tooney Paul A PA Torretta Silvia S Tosato Sarah S Tura Gian Battista GB Turetsky Bruce I BI Üçok Alp A Vaaler Arne A van Amelsvoort Therese T van Winkel Ruud R Veijola Juha J Waddington John J Walter Henrik H Waterreus Anna A Webb Bradley T BT Weiser Mark M Williams Nigel M NM Witt Stephanie H SH Wormley Brandon K BK Wu Jing Qin JQ Xu Zhida Z Yolken Robert R Zai Clement C CC Zhou Wei W Zhu Feng F Zimprich Fritz F Atbaşoğlu Eşref Cem EC Ayub Muhammad M Benner Christian C Bertolino Alessandro A Black Donald W DW Bray Nicholas J NJ Breen Gerome G Buccola Nancy G NG Byerley William F WF Chen Wei J WJ Cloninger C Robert CR Crespo-Facorro Benedicto B Donohoe Gary G Freedman Robert R Galletly Cherrie C Gandal Michael J MJ Gennarelli Massimo M Hougaard David M DM Hwu Hai-Gwo HG Jablensky Assen V AV McCarroll Steven A SA Moran Jennifer L JL Mors Ole O Mortensen Preben B PB Müller-Myhsok Bertram B Neil Amanda L AL Nordentoft Merete M Pato Michele T MT Petryshen Tracey L TL Pirinen Matti M Pulver Ann E AE Schulze Thomas G TG Silverman Jeremy M JM Smoller Jordan W JW Stahl Eli A EA Tsuang Debby W DW Vilella Elisabet E Wang Shi-Heng SH Xu Shuhua S Adolfsson Rolf R Arango Celso C Baune Bernhard T BT Belangero Sintia Iole SI Børglum Anders D AD Braff David D Bramon Elvira E Buxbaum Joseph D JD Campion Dominique D Cervilla Jorge A JA Cichon Sven S Collier David A DA Corvin Aiden A Curtis David D Forti Marta Di MD Domenici Enrico E Ehrenreich Hannelore H Escott-Price Valentina V Esko Tõnu T Fanous Ayman H AH Gareeva Anna A Gawlik Micha M Gejman Pablo V PV Gill Michael M Glatt Stephen J SJ Golimbet Vera V Hong Kyung Sue KS Hultman Christina M CM Hyman Steven E SE Iwata Nakao N Jönsson Erik G EG Kahn René S RS Kennedy James L JL Khusnutdinova Elza E Kirov George G Knowles James A JA Krebs Marie-Odile MO Laurent-Levinson Claudine C Lee Jimmy J Lencz Todd T Levinson Douglas F DF Li Qingqin S QS Liu Jianjun J Malhotra Anil K AK Malhotra Dheeraj D McIntosh Andrew A McQuillin Andrew A Menezes Paulo R PR Morgan Vera A VA Morris Derek W DW Mowry Bryan J BJ Murray Robin M RM Nimgaonkar Vishwajit V Nöthen Markus M MM Ophoff Roel A RA Paciga Sara A SA Palotie Aarno A Pato Carlos N CN Qin Shengying S Rietschel Marcella M Riley Brien P BP Rivera Margarita M Rujescu Dan D Saka Meram C MC Sanders Alan R AR Schwab Sibylle G SG Serretti Alessandro A Sham Pak C PC Shi Yongyong Y St Clair David D Stefánsson Hreinn H Stefansson Kari K Tsuang Ming T MT van Os Jim J Vawter Marquis P MP Weinberger Daniel R DR Werge Thomas T Wildenauer Dieter B DB Yu Xin X Yue Weihua W Holmans Peter A PA Pocklington Andrew J AJ Roussos Panos P Vassos Evangelos E Verhage Matthijs M Visscher Peter M PM Yang Jian J Posthuma Danielle D Andreassen Ole A OA Kendler Kenneth S KS Owen Michael J MJ Wray Naomi R NR Daly Mark J MJ Huang Hailiang H Neale Benjamin M BM Sullivan Patrick F PF Ripke Stephan S Walters James T R JTR O'Donovan Michael C MC

Nature 20220408 7906

Schizophrenia has a heritability of 60-80%<sup>1</sup>, 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 f ...[more]

PMID: 35396580

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Project description:BackgroundAlzheimer's disease (AD) is an incurable neurodegenerative disease currently affecting 1.75% of the US population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION transcriptome-wide association study (TWAS) pipeline to ingest gene expression values from multiple neocortical regions.MethodsA combined dataset of 2003 genotypes clustered to 1000 Genomes individuals from Utah with Northern and Western European ancestry (CEU) was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles from temporal cortex (TCX = 248), prefrontal cortex (FP = 50), inferior frontal gyrus (IFG = 41), superior temporal gyrus (STG = 34), parahippocampal cortex (PHG = 34), and dorsolateral prefrontal cortex (DLPFC = 461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene's surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and support cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues.ResultsCis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05): APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, and KNOP1.ConclusionsWe provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes.

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Mapping genomic loci implicates genes and synaptic biology in schizophrenia.

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Mapping genomic loci implicates genes and synaptic biology in schizophrenia.

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