Mapping genomic loci implicates genes and synaptic biology in schizophrenia.

2022-04

Trubetskoy, Vassily

Pardiñas, Antonio F

Qi, Ting

Panagiotaropoulou, Georgia

Awasthi, Swapnil

Bigdeli, Tim B

Bryois, Julien

Chen, Chia-Yen

Dennison, Charlotte A

Hall, Lynsey S

Lam, Max

Watanabe, Kyoko

Frei, Oleksandr

Ge, Tian

Harwood, Janet C

Koopmans, Frank

Magnusson, Sigurdur

Richards, Alexander L

Sidorenko, Julia

Wu, Yang

Zeng, Jian

Grove, Jakob

Kim, Minsoo

Li, Zhiqiang

Voloudakis, Georgios

Zhang, Wen

Adams, Mark

Agartz, Ingrid

Atkinson, Elizabeth G

Agerbo, Esben

Al Eissa, Mariam

Albus, Margot

Alexander, Madeline

Alizadeh, Behrooz Z

Alptekin, Köksal

Als, Thomas D

Amin, Farooq

Arolt, Volker

Arrojo, Manuel

Athanasiu, Lavinia

Azevedo, Maria Helena

Bacanu, Silviu A

Bass, Nicholas J

Begemann, Martin

Belliveau, Richard A

Bene, Judit

Benyamin, Beben

Bergen, Sarah E

Blasi, Giuseppe

Bobes, Julio

Bonassi, Stefano

Braun, Alice

Bressan, Rodrigo Affonseca

Bromet, Evelyn J

Bruggeman, Richard

Buckley, Peter F

Buckner, Randy L

Bybjerg-Grauholm, Jonas

Cahn, Wiepke

Cairns, Murray J

Calkins, Monica E

Carr, Vaughan J

Castle, David

Catts, Stanley V

Chambert, Kimberley D

Chan, Raymond C K

Chaumette, Boris

Cheng, Wei

Cheung, Eric F C

Chong, Siow Ann

Cohen, David

Consoli, Angèle

Cordeiro, Quirino

Costas, Javier

Curtis, Charles

Davidson, Michael

Davis, Kenneth L

de Haan, Lieuwe

Degenhardt, Franziska

DeLisi, Lynn E

Demontis, Ditte

Dickerson, Faith

Dikeos, Dimitris

Dinan, Timothy

Djurovic, Srdjan

Duan, Jubao

Ducci, Giuseppe

Dudbridge, Frank

Eriksson, Johan G

Fañanás, Lourdes

Faraone, Stephen V

Fiorentino, Alessia

Forstner, Andreas

Frank, Josef

Freimer, Nelson B

Fromer, Menachem

Frustaci, Alessandra

Gadelha, Ary

Genovese, Giulio

Gershon, Elliot S

Giannitelli, Marianna

Giegling, Ina

Giusti-Rodríguez, Paola

Godard, Stephanie

Goldstein, Jacqueline I

González Peñas, Javier

González-Pinto, Ana

Gopal, Srihari

Gratten, Jacob

Green, Michael F

Greenwood, Tiffany A

Guillin, Olivier

Gülöksüz, Sinan

Gur, Raquel E

Gur, Ruben C

Gutiérrez, Blanca

Hahn, Eric

Hakonarson, Hakon

Haroutunian, Vahram

Hartmann, Annette M

Harvey, Carol

Hayward, Caroline

Henskens, Frans A

Herms, Stefan

Hoffmann, Per

Howrigan, Daniel P

Ikeda, Masashi

Iyegbe, Conrad

Joa, Inge

Julià, Antonio

Kähler, Anna K

Kam-Thong, Tony

Kamatani, Yoichiro

Karachanak-Yankova, Sena

Kebir, Oussama

Keller, Matthew C

Kelly, Brian J

Khrunin, Andrey

Kim, Sung-Wan

Klovins, Janis

Kondratiev, Nikolay

Konte, Bettina

Kraft, Julia

Kubo, Michiaki

Kučinskas, Vaidutis

Kučinskiene, Zita Ausrele

Kusumawardhani, Agung

Kuzelova-Ptackova, Hana

Landi, Stefano

Lazzeroni, Laura C

Lee, Phil H

Legge, Sophie E

Lehrer, Douglas S

Lencer, Rebecca

Lerer, Bernard

Li, Miaoxin

Lieberman, Jeffrey

Light, Gregory A

Limborska, Svetlana

Liu, Chih-Min

Lönnqvist, Jouko

Loughland, Carmel M

Lubinski, Jan

Luykx, Jurjen J

Lynham, Amy

Macek, Milan

Mackinnon, Andrew

Magnusson, Patrik K E

Maher, Brion S

Maier, Wolfgang

Malaspina, Dolores

Mallet, Jacques

Marder, Stephen R

Marsal, Sara

Martin, Alicia R

Martorell, Lourdes

Mattheisen, Manuel

McCarley, Robert W

McDonald, Colm

McGrath, John J

Medeiros, Helena

Meier, Sandra

Melegh, Bela

Melle, Ingrid

Mesholam-Gately, Raquelle I

Metspalu, Andres

Michie, Patricia T

Milani, Lili

Milanova, Vihra

Mitjans, Marina

Molden, Espen

Molina, Esther

Molto, María Dolores

Mondelli, Valeria

Moreno, Carmen

Morley, Christopher P

Muntané, Gerard

Murphy, Kieran C

Myin-Germeys, Inez

Nenadić, Igor

Nestadt, Gerald

Nikitina-Zake, Liene

Noto, Cristiano

Nuechterlein, Keith H

O'Brien, Niamh Louise

O'Neill, F Anthony

Oh, Sang-Yun

Olincy, Ann

Ota, Vanessa Kiyomi

Pantelis, Christos

Papadimitriou, George N

Parellada, Mara

Paunio, Tiina

Pellegrino, Renata

Periyasamy, Sathish

Perkins, Diana O

Pfuhlmann, Bruno

Pietiläinen, Olli

Pimm, Jonathan

Porteous, David

Powell, John

Quattrone, Diego

Quested, Digby

Radant, Allen D

Rampino, Antonio

Rapaport, Mark H

Rautanen, Anna

Reichenberg, Abraham

Roe, Cheryl

Roffman, Joshua L

Roth, Julian

Rothermundt, Matthias

Rutten, Bart P F

Saker-Delye, Safaa

Salomaa, Veikko

Sanjuan, Julio

Santoro, Marcos Leite

Savitz, Adam

Schall, Ulrich

Scott, Rodney J

Seidman, Larry J

Sharp, Sally Isabel

Shi, Jianxin

Siever, Larry J

Sigurdsson, Engilbert

Sim, Kang

Skarabis, Nora

Slominsky, Petr

So, Hon-Cheong

Sobell, Janet L

Söderman, Erik

Stain, Helen J

Steen, Nils Eiel

Steixner-Kumar, Agnes A

Stögmann, Elisabeth

Stone, William S

Straub, Richard E

Streit, Fabian

Strengman, Eric

Stroup, T Scott

Subramaniam, Mythily

Sugar, Catherine A

Suvisaari, Jaana

Svrakic, Dragan M

Swerdlow, Neal R

Szatkiewicz, Jin P

Ta, Thi Minh Tam

Takahashi, Atsushi

Terao, Chikashi

Thibaut, Florence

Toncheva, Draga

Tooney, Paul A

Torretta, Silvia

Tosato, Sarah

Tura, Gian Battista

Turetsky, Bruce I

Üçok, Alp

Vaaler, Arne

van Amelsvoort, Therese

van Winkel, Ruud

Veijola, Juha

Waddington, John

Walter, Henrik

Waterreus, Anna

Webb, Bradley T

Weiser, Mark

Williams, Nigel M

Witt, Stephanie H

Wormley, Brandon K

Wu, Jing Qin

Xu, Zhida

Yolken, Robert

Zai, Clement C

Zhou, Wei

Zhu, Feng

Zimprich, Fritz

Atbaşoğlu, Eşref Cem

Ayub, Muhammad

Benner, Christian

Bertolino, Alessandro

Black, Donald W

Bray, Nicholas J

Breen, Gerome

Buccola, Nancy G

Byerley, William F

Chen, Wei J

Cloninger, C Robert

Crespo-Facorro, Benedicto

Donohoe, Gary

Freedman, Robert

Galletly, Cherrie

Gandal, Michael J

Gennarelli, Massimo

Hougaard, David M

Hwu, Hai-Gwo

Jablensky, Assen V

McCarroll, Steven A

Moran, Jennifer L

Mors, Ole

Mortensen, Preben B

Müller-Myhsok, Bertram

Neil, Amanda L

Nordentoft, Merete

Pato, Michele T

Petryshen, Tracey L

Pirinen, Matti

Pulver, Ann E

Schulze, Thomas G

Silverman, Jeremy M

Smoller, Jordan W

Stahl, Eli A

Tsuang, Debby W

Vilella, Elisabet

Wang, Shi-Heng

Xu, Shuhua

Adolfsson, Rolf

Arango, Celso

Baune, Bernhard T

Belangero, Sintia Iole

Børglum, Anders D

Braff, David

Bramon, Elvira

Buxbaum, Joseph D

Campion, Dominique

Cervilla, Jorge A

Cichon, Sven

Collier, David A

Corvin, Aiden

Curtis, David

Forti, Marta Di

Domenici, Enrico

Ehrenreich, Hannelore

Escott-Price, Valentina

Esko, Tõnu

Fanous, Ayman H

Gareeva, Anna

Gawlik, Micha

Gejman, Pablo V

Gill, Michael

Glatt, Stephen J

Golimbet, Vera

Hong, Kyung Sue

Hultman, Christina M

Hyman, Steven E

Iwata, Nakao

Jönsson, Erik G

Kahn, René S

Kennedy, James L

Khusnutdinova, Elza

Kirov, George

Knowles, James A

Krebs, Marie-Odile

Laurent-Levinson, Claudine

Lee, Jimmy

Lencz, Todd

Levinson, Douglas F

Li, Qingqin S

Liu, Jianjun

Malhotra, Anil K

Malhotra, Dheeraj

McIntosh, Andrew

McQuillin, Andrew

Menezes, Paulo R

Morgan, Vera A

Morris, Derek W

Mowry, Bryan J

Murray, Robin M

Nimgaonkar, Vishwajit

Nöthen, Markus M

Ophoff, Roel A

Paciga, Sara A

Palotie, Aarno

Pato, Carlos N

Qin, Shengying

Rietschel, Marcella

Riley, Brien P

Rivera, Margarita

Rujescu, Dan

Saka, Meram C

Sanders, Alan R

Schwab, Sibylle G

Serretti, Alessandro

Sham, Pak C

Shi, Yongyong

St Clair, David

Stefánsson, Hreinn

Stefansson, Kari

Tsuang, Ming T

van Os, Jim

Vawter, Marquis P

Weinberger, Daniel R

Werge, Thomas

Wildenauer, Dieter B

Yu, Xin

Yue, Weihua

Holmans, Peter A

Pocklington, Andrew J

Roussos, Panos

Vassos, Evangelos

Verhage, Matthijs

Visscher, Peter M

Yang, Jian

Posthuma, Danielle

Andreassen, Ole A

Kendler, Kenneth S

Owen, Michael J

Wray, Naomi R

Daly, Mark J

Huang, Hailiang

Neale, Benjamin M

Sullivan, Patrick F

Ripke, Stephan

Walters, James T R

O'Donovan, Michael C

Journal Article

0000-0002-9565-0238

0000-0001-6548-426X

10.1038/s41586-022-04434-5

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.

link

Nature 2022; 604(7906): 502-508

Nature