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Rare coding variants in ten genes confer substantial risk for schizophrenia. / Singh, Tarjinder; Poterba, Timothy; Curtis, David; Akil, Huda; Al Eissa, Mariam; Barchas, Jack D.; Bass, Nicholas; Bigdeli, Tim B.; Breen, Gerome; Bromet, Evelyn J.; Buckley, Peter F.; Bunney, William E.; Bybjerg-Grauholm, Jonas; Byerley, William F.; Chapman, Sinéad B.; Chen, Wei J.; Churchhouse, Claire; Craddock, Nicholas; Cusick, Caroline M.; DeLisi, Lynn; Dodge, Sheila; Escamilla, Michael A.; Eskelinen, Saana; Fanous, Ayman H.; Faraone, Stephen V.; Fiorentino, Alessia; Francioli, Laurent; Gabriel, Stacey B.; Gage, Diane; Gagliano Taliun, Sarah A.; Ganna, Andrea; Genovese, Giulio; Glahn, David C.; Grove, Jakob; Hall, Mei Hua; Hämäläinen, Eija; Heyne, Henrike O.; Holi, Matti; Hougaard, David M.; Howrigan, Daniel P.; Huang, Hailiang; Hwu, Hai Gwo; Kahn, René S.; Kang, Hyun Min; Karczewski, Konrad J.; Kirov, George; Knowles, James A.; Lee, Francis S.; Lehrer, Douglas S.; Lescai, Francesco; Malaspina, Dolores; Marder, Stephen R.; McCarroll, Steven A.; McIntosh, Andrew M.; Medeiros, Helena; Milani, Lili; Morley, Christopher P.; Morris, Derek W.; Mortensen, Preben Bo; Myers, Richard M.; Nordentoft, Merete; O’Brien, Niamh L.; Olivares, Ana Maria; Ongur, Dost; Ouwehand, Willem H.; Palmer, Duncan S.; Paunio, Tiina; Quested, Digby; Rapaport, Mark H.; Rees, Elliott; Rollins, Brandi; Satterstrom, F. Kyle; Schatzberg, Alan; Scolnick, Edward; Scott, Laura J.; Sharp, Sally I.; Sklar, Pamela; Smoller, Jordan W.; Sobell, Janet L.; Solomonson, Matthew; Stahl, Eli A.; Stevens, Christine R.; Suvisaari, Jaana; Tiao, Grace; Watson, Stanley J.; Watts, Nicholas A.; Blackwood, Douglas H.; Børglum, Anders D.; Cohen, Bruce M.; Corvin, Aiden P.; Esko, Tõnu; Freimer, Nelson B.; Glatt, Stephen J.; Hultman, Christina M.; McQuillin, Andrew; Palotie, Aarno; Pato, Carlos N.; Pato, Michele T.; Pulver, Ann E.; St. Clair, David; Tsuang, Ming T.; Vawter, Marquis P.; Walters, James T.; Werge, Thomas M.; Ophoff, Roel A.; Sullivan, Patrick F.; Owen, Michael J.; Boehnke, Michael; O’Donovan, Michael C.; Neale, Benjamin M.; Daly, Mark J.
I:
Nature, Bind 604, Nr. 7906, 2022, s. 509-516.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
Singh, T, Poterba, T, Curtis, D, Akil, H, Al Eissa, M, Barchas, JD, Bass, N, Bigdeli, TB, Breen, G, Bromet, EJ, Buckley, PF, Bunney, WE, Bybjerg-Grauholm, J, Byerley, WF, Chapman, SB, Chen, WJ, Churchhouse, C, Craddock, N, Cusick, CM, DeLisi, L, Dodge, S, Escamilla, MA, Eskelinen, S, Fanous, AH, Faraone, SV, Fiorentino, A, Francioli, L, Gabriel, SB, Gage, D, Gagliano Taliun, SA, Ganna, A, Genovese, G, Glahn, DC, Grove, J, Hall, MH, Hämäläinen, E, Heyne, HO, Holi, M, Hougaard, DM, Howrigan, DP, Huang, H, Hwu, HG, Kahn, RS, Kang, HM, Karczewski, KJ, Kirov, G, Knowles, JA, Lee, FS, Lehrer, DS, Lescai, F, Malaspina, D, Marder, SR, McCarroll, SA, McIntosh, AM, Medeiros, H, Milani, L, Morley, CP, Morris, DW, Mortensen, PB, Myers, RM
, Nordentoft, M, O’Brien, NL, Olivares, AM, Ongur, D, Ouwehand, WH, Palmer, DS, Paunio, T, Quested, D, Rapaport, MH, Rees, E, Rollins, B, Satterstrom, FK, Schatzberg, A, Scolnick, E, Scott, LJ, Sharp, SI, Sklar, P, Smoller, JW, Sobell, JL, Solomonson, M, Stahl, EA, Stevens, CR, Suvisaari, J, Tiao, G, Watson, SJ, Watts, NA, Blackwood, DH, Børglum, AD, Cohen, BM, Corvin, AP, Esko, T, Freimer, NB, Glatt, SJ, Hultman, CM, McQuillin, A, Palotie, A, Pato, CN, Pato, MT, Pulver, AE, St. Clair, D, Tsuang, MT, Vawter, MP, Walters, JT
, Werge, TM, Ophoff, RA, Sullivan, PF, Owen, MJ, Boehnke, M, O’Donovan, MC, Neale, BM & Daly, MJ 2022, '
Rare coding variants in ten genes confer substantial risk for schizophrenia',
Nature, bind 604, nr. 7906, s. 509-516.
https://doi.org/10.1038/s41586-022-04556-wAPA
Singh, T., Poterba, T., Curtis, D., Akil, H., Al Eissa, M., Barchas, J. D., Bass, N., Bigdeli, T. B., Breen, G., Bromet, E. J., Buckley, P. F., Bunney, W. E., Bybjerg-Grauholm, J., Byerley, W. F., Chapman, S. B., Chen, W. J., Churchhouse, C., Craddock, N., Cusick, C. M., ... Daly, M. J. (2022).
Rare coding variants in ten genes confer substantial risk for schizophrenia.
Nature,
604(7906), 509-516.
https://doi.org/10.1038/s41586-022-04556-wVancouver
Singh T, Poterba T, Curtis D, Akil H, Al Eissa M, Barchas JD o.a.
Rare coding variants in ten genes confer substantial risk for schizophrenia.
Nature. 2022;604(7906):509-516.
https://doi.org/10.1038/s41586-022-04556-wAuthor
Singh, Tarjinder ; Poterba, Timothy ; Curtis, David ; Akil, Huda ; Al Eissa, Mariam ; Barchas, Jack D. ; Bass, Nicholas ; Bigdeli, Tim B. ; Breen, Gerome ; Bromet, Evelyn J. ; Buckley, Peter F. ; Bunney, William E. ; Bybjerg-Grauholm, Jonas ; Byerley, William F. ; Chapman, Sinéad B. ; Chen, Wei J. ; Churchhouse, Claire ; Craddock, Nicholas ; Cusick, Caroline M. ; DeLisi, Lynn ; Dodge, Sheila ; Escamilla, Michael A. ; Eskelinen, Saana ; Fanous, Ayman H. ; Faraone, Stephen V. ; Fiorentino, Alessia ; Francioli, Laurent ; Gabriel, Stacey B. ; Gage, Diane ; Gagliano Taliun, Sarah A. ; Ganna, Andrea ; Genovese, Giulio ; Glahn, David C. ; Grove, Jakob ; Hall, Mei Hua ; Hämäläinen, Eija ; Heyne, Henrike O. ; Holi, Matti ; Hougaard, David M. ; Howrigan, Daniel P. ; Huang, Hailiang ; Hwu, Hai Gwo ; Kahn, René S. ; Kang, Hyun Min ; Karczewski, Konrad J. ; Kirov, George ; Knowles, James A. ; Lee, Francis S. ; Lehrer, Douglas S. ; Lescai, Francesco ; Malaspina, Dolores ; Marder, Stephen R. ; McCarroll, Steven A. ; McIntosh, Andrew M. ; Medeiros, Helena ; Milani, Lili ; Morley, Christopher P. ; Morris, Derek W. ; Mortensen, Preben Bo ; Myers, Richard M. ; Nordentoft, Merete ; O’Brien, Niamh L. ; Olivares, Ana Maria ; Ongur, Dost ; Ouwehand, Willem H. ; Palmer, Duncan S. ; Paunio, Tiina ; Quested, Digby ; Rapaport, Mark H. ; Rees, Elliott ; Rollins, Brandi ; Satterstrom, F. Kyle ; Schatzberg, Alan ; Scolnick, Edward ; Scott, Laura J. ; Sharp, Sally I. ; Sklar, Pamela ; Smoller, Jordan W. ; Sobell, Janet L. ; Solomonson, Matthew ; Stahl, Eli A. ; Stevens, Christine R. ; Suvisaari, Jaana ; Tiao, Grace ; Watson, Stanley J. ; Watts, Nicholas A. ; Blackwood, Douglas H. ; Børglum, Anders D. ; Cohen, Bruce M. ; Corvin, Aiden P. ; Esko, Tõnu ; Freimer, Nelson B. ; Glatt, Stephen J. ; Hultman, Christina M. ; McQuillin, Andrew ; Palotie, Aarno ; Pato, Carlos N. ; Pato, Michele T. ; Pulver, Ann E. ; St. Clair, David ; Tsuang, Ming T. ; Vawter, Marquis P. ; Walters, James T. ; Werge, Thomas M. ; Ophoff, Roel A. ; Sullivan, Patrick F. ; Owen, Michael J. ; Boehnke, Michael ; O’Donovan, Michael C. ; Neale, Benjamin M. ; Daly, Mark J. / Rare coding variants in ten genes confer substantial risk for schizophrenia. I: Nature. 2022 ; Bind 604, Nr. 7906. s. 509-516.
Bibtex
@article{bec8d3dbb00c4a2f9c8dfa3f02766179,
title = "Rare coding variants in ten genes confer substantial risk for schizophrenia",
abstract = "Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.",
author = "Tarjinder Singh and Timothy Poterba and David Curtis and Huda Akil and {Al Eissa}, Mariam and Barchas, {Jack D.} and Nicholas Bass and Bigdeli, {Tim B.} and Gerome Breen and Bromet, {Evelyn J.} and Buckley, {Peter F.} and Bunney, {William E.} and Jonas Bybjerg-Grauholm and Byerley, {William F.} and Chapman, {Sin{\'e}ad B.} and Chen, {Wei J.} and Claire Churchhouse and Nicholas Craddock and Cusick, {Caroline M.} and Lynn DeLisi and Sheila Dodge and Escamilla, {Michael A.} and Saana Eskelinen and Fanous, {Ayman H.} and Faraone, {Stephen V.} and Alessia Fiorentino and Laurent Francioli and Gabriel, {Stacey B.} and Diane Gage and {Gagliano Taliun}, {Sarah A.} and Andrea Ganna and Giulio Genovese and Glahn, {David C.} and Jakob Grove and Hall, {Mei Hua} and Eija H{\"a}m{\"a}l{\"a}inen and Heyne, {Henrike O.} and Matti Holi and Hougaard, {David M.} and Howrigan, {Daniel P.} and Hailiang Huang and Hwu, {Hai Gwo} and Kahn, {Ren{\'e} S.} and Kang, {Hyun Min} and Karczewski, {Konrad J.} and George Kirov and Knowles, {James A.} and Lee, {Francis S.} and Lehrer, {Douglas S.} and Francesco Lescai and Dolores Malaspina and Marder, {Stephen R.} and McCarroll, {Steven A.} and McIntosh, {Andrew M.} and Helena Medeiros and Lili Milani and Morley, {Christopher P.} and Morris, {Derek W.} and Mortensen, {Preben Bo} and Myers, {Richard M.} and Merete Nordentoft and O{\textquoteright}Brien, {Niamh L.} and Olivares, {Ana Maria} and Dost Ongur and Ouwehand, {Willem H.} and Palmer, {Duncan S.} and Tiina Paunio and Digby Quested and Rapaport, {Mark H.} and Elliott Rees and Brandi Rollins and Satterstrom, {F. Kyle} and Alan Schatzberg and Edward Scolnick and Scott, {Laura J.} and Sharp, {Sally I.} and Pamela Sklar and Smoller, {Jordan W.} and Sobell, {Janet L.} and Matthew Solomonson and Stahl, {Eli A.} and Stevens, {Christine R.} and Jaana Suvisaari and Grace Tiao and Watson, {Stanley J.} and Watts, {Nicholas A.} and Blackwood, {Douglas H.} and B{\o}rglum, {Anders D.} and Cohen, {Bruce M.} and Corvin, {Aiden P.} and T{\~o}nu Esko and Freimer, {Nelson B.} and Glatt, {Stephen J.} and Hultman, {Christina M.} and Andrew McQuillin and Aarno Palotie and Pato, {Carlos N.} and Pato, {Michele T.} and Pulver, {Ann E.} and {St. Clair}, David and Tsuang, {Ming T.} and Vawter, {Marquis P.} and Walters, {James T.} and Werge, {Thomas M.} and Ophoff, {Roel A.} and Sullivan, {Patrick F.} and Owen, {Michael J.} and Michael Boehnke and O{\textquoteright}Donovan, {Michael C.} and Neale, {Benjamin M.} and Daly, {Mark J.}",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
doi = "10.1038/s41586-022-04556-w",
language = "English",
volume = "604",
pages = "509--516",
journal = "Nature",
issn = "0028-0836",
publisher = "nature publishing group",
number = "7906",
}
RIS
TY - JOUR
T1 - Rare coding variants in ten genes confer substantial risk for schizophrenia
AU - Singh, Tarjinder
AU - Poterba, Timothy
AU - Curtis, David
AU - Akil, Huda
AU - Al Eissa, Mariam
AU - Barchas, Jack D.
AU - Bass, Nicholas
AU - Bigdeli, Tim B.
AU - Breen, Gerome
AU - Bromet, Evelyn J.
AU - Buckley, Peter F.
AU - Bunney, William E.
AU - Bybjerg-Grauholm, Jonas
AU - Byerley, William F.
AU - Chapman, Sinéad B.
AU - Chen, Wei J.
AU - Churchhouse, Claire
AU - Craddock, Nicholas
AU - Cusick, Caroline M.
AU - DeLisi, Lynn
AU - Dodge, Sheila
AU - Escamilla, Michael A.
AU - Eskelinen, Saana
AU - Fanous, Ayman H.
AU - Faraone, Stephen V.
AU - Fiorentino, Alessia
AU - Francioli, Laurent
AU - Gabriel, Stacey B.
AU - Gage, Diane
AU - Gagliano Taliun, Sarah A.
AU - Ganna, Andrea
AU - Genovese, Giulio
AU - Glahn, David C.
AU - Grove, Jakob
AU - Hall, Mei Hua
AU - Hämäläinen, Eija
AU - Heyne, Henrike O.
AU - Holi, Matti
AU - Hougaard, David M.
AU - Howrigan, Daniel P.
AU - Huang, Hailiang
AU - Hwu, Hai Gwo
AU - Kahn, René S.
AU - Kang, Hyun Min
AU - Karczewski, Konrad J.
AU - Kirov, George
AU - Knowles, James A.
AU - Lee, Francis S.
AU - Lehrer, Douglas S.
AU - Lescai, Francesco
AU - Malaspina, Dolores
AU - Marder, Stephen R.
AU - McCarroll, Steven A.
AU - McIntosh, Andrew M.
AU - Medeiros, Helena
AU - Milani, Lili
AU - Morley, Christopher P.
AU - Morris, Derek W.
AU - Mortensen, Preben Bo
AU - Myers, Richard M.
AU - Nordentoft, Merete
AU - O’Brien, Niamh L.
AU - Olivares, Ana Maria
AU - Ongur, Dost
AU - Ouwehand, Willem H.
AU - Palmer, Duncan S.
AU - Paunio, Tiina
AU - Quested, Digby
AU - Rapaport, Mark H.
AU - Rees, Elliott
AU - Rollins, Brandi
AU - Satterstrom, F. Kyle
AU - Schatzberg, Alan
AU - Scolnick, Edward
AU - Scott, Laura J.
AU - Sharp, Sally I.
AU - Sklar, Pamela
AU - Smoller, Jordan W.
AU - Sobell, Janet L.
AU - Solomonson, Matthew
AU - Stahl, Eli A.
AU - Stevens, Christine R.
AU - Suvisaari, Jaana
AU - Tiao, Grace
AU - Watson, Stanley J.
AU - Watts, Nicholas A.
AU - Blackwood, Douglas H.
AU - Børglum, Anders D.
AU - Cohen, Bruce M.
AU - Corvin, Aiden P.
AU - Esko, Tõnu
AU - Freimer, Nelson B.
AU - Glatt, Stephen J.
AU - Hultman, Christina M.
AU - McQuillin, Andrew
AU - Palotie, Aarno
AU - Pato, Carlos N.
AU - Pato, Michele T.
AU - Pulver, Ann E.
AU - St. Clair, David
AU - Tsuang, Ming T.
AU - Vawter, Marquis P.
AU - Walters, James T.
AU - Werge, Thomas M.
AU - Ophoff, Roel A.
AU - Sullivan, Patrick F.
AU - Owen, Michael J.
AU - Boehnke, Michael
AU - O’Donovan, Michael C.
AU - Neale, Benjamin M.
AU - Daly, Mark J.
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022
Y1 - 2022
N2 - Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.
AB - Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-d-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.
U2 - 10.1038/s41586-022-04556-w
DO - 10.1038/s41586-022-04556-w
M3 - Journal article
C2 - 35396579
AN - SCOPUS:85127630161
VL - 604
SP - 509
EP - 516
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7906
ER -
