An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis

Derek W. Morris; Richard D. Pearson; Paul Cormican; Elaine M. Kenny; Colm T. O'Dushlaine; Louis Philippe Lemieux Perreault; Eleni Giannoulatou; Daniela Tropea; Brion S. Maher; Brandon Wormley; Eric Kelleher; Ciara Fahey; Ines Molinos; Stefania Bellini; Matti Pirinen; Amy Strange; Colin Freeman; Dawn L. Thiselton; Rachel L. Elves; Regina Regan; Sean Ennis; Timothy G. Dinan; Colm McDonald; Kieran C. Murphy; Eadbhard O'Callaghan; John L. Waddington; Dermot Walsh; Michael O'Donovan; Detelina Grozeva; Nick Craddock; Jennifer Stone; Ed Scolnick; Shaun Purcell; Pamela Sklar; Bradley Coe; Evan E. Eichler; Roel Ophoff; Jacobine Buizer; Jin Szatkiewicz; Christina Hultman; Patrick Sullivan; Hugh Gurling; Andrew Mcquillin; David St Clair; Elliott Rees; George Kirov; James Walters; Douglas Blackwood; Mandy Johnstone; Gary Donohoe; The International Schizophrenia Consortium (ISC); SGENE+ Consortium; Francis A. O'Neill; The Wellcome Trust Case Control Consortium 2 (WTCCC2); Kenneth S. Kendler; Michael Gill; Brien P. Riley; Chris C. A. Spencer; Aiden Corvin

doi:10.1093/hmg/ddu025

An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis

Derek W. Morris, Richard D. Pearson, Paul Cormican, Elaine M. Kenny, Colm T. O'Dushlaine, Louis Philippe Lemieux Perreault, Eleni Giannoulatou, Daniela Tropea, Brion S. Maher, Brandon Wormley, Eric Kelleher, Ciara Fahey, Ines Molinos, Stefania Bellini, Matti Pirinen, Amy Strange, Colin Freeman, Dawn L. Thiselton, Rachel L. Elves, Regina ReganSean Ennis, Timothy G. Dinan, Colm McDonald, Kieran C. Murphy, Eadbhard O'Callaghan, John L. Waddington, Dermot Walsh, Michael O'Donovan, Detelina Grozeva, Nick Craddock, Jennifer Stone, Ed Scolnick, Shaun Purcell, Pamela Sklar, Bradley Coe, Evan E. Eichler, Roel Ophoff, Jacobine Buizer, Jin Szatkiewicz, Christina Hultman, Patrick Sullivan, Hugh Gurling, Andrew Mcquillin, David St Clair, Elliott Rees, George Kirov, James Walters, Douglas Blackwood, Mandy Johnstone, Gary Donohoe, The International Schizophrenia Consortium (ISC), SGENE+ Consortium, Francis A. O'Neill, The Wellcome Trust Case Control Consortium 2 (WTCCC2), Kenneth S. Kendler, Michael Gill, Brien P. Riley, Chris C. A. Spencer, Aiden Corvin^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

Identifying rare, highly penetrant risk mutationsmay be an important step in dissectingthe molecular etiology of schizophrenia.We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium2 (WTCCC2)schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls.Wefound association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P 5 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10^-4; odds ratio (OR) = 11.3, 95% CI 5 3.7,∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10^-21), indicative of a singleancestral duplication event.Weconfirmedthe breakpoints in 8/8carriers testedandfound co-segregation of the duplication with illness in two additional familymembers of one of the affectedprobands.Wedemonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

Original language	English
Pages (from-to)	3316-3326
Number of pages	11
Journal	Human Molecular Genetics
Volume	23
Issue number	12
Early online date	28 Jan 2014
DOIs	https://doi.org/10.1093/hmg/ddu025
Publication status	Published - 15 Jun 2014

Bibliographical note

FUNDING
Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). We acknowledge use of the Trinity Biobank sample from the Irish Blood Transfusion Service; the Trinity Centre for High Performance Computing; British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. Chris Spencer is supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust.

ACKNOWLEDGEMENTS
The authors sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank Akira Sawa and Koko Ishzuki for advice on the PAK7–DISC1 interaction experiment and Jan Korbel for discussions on mechanism of structural variation.

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10.1093/hmg/ddu025Licence: CC BY

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis
© The Author 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Final published version, 863 KBLicence: CC BY

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Morris, D. W., Pearson, R. D., Cormican, P., Kenny, E. M., O'Dushlaine, C. T., Perreault, L. P. L., Giannoulatou, E., Tropea, D., Maher, B. S., Wormley, B., Kelleher, E., Fahey, C., Molinos, I., Bellini, S., Pirinen, M., Strange, A., Freeman, C., Thiselton, D. L., Elves, R. L., ... Corvin, A. (2014). An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis. Human Molecular Genetics, 23(12), 3316-3326. https://doi.org/10.1093/hmg/ddu025

Morris, DW, Pearson, RD, Cormican, P, Kenny, EM, O'Dushlaine, CT, Perreault, LPL, Giannoulatou, E, Tropea, D, Maher, BS, Wormley, B, Kelleher, E, Fahey, C, Molinos, I, Bellini, S, Pirinen, M, Strange, A, Freeman, C, Thiselton, DL, Elves, RL, Regan, R, Ennis, S, Dinan, TG, McDonald, C, Murphy, KC, O'Callaghan, E, Waddington, JL, Walsh, D, O'Donovan, M, Grozeva, D, Craddock, N, Stone, J, Scolnick, E, Purcell, S, Sklar, P, Coe, B, Eichler, EE, Ophoff, R, Buizer, J, Szatkiewicz, J, Hultman, C, Sullivan, P, Gurling, H, Mcquillin, A, St Clair, D, Rees, E, Kirov, G, Walters, J, Blackwood, D, Johnstone, M, Donohoe, G, The International Schizophrenia Consortium (ISC), SGENE+ Consortium, O'Neill, FA, The Wellcome Trust Case Control Consortium 2 (WTCCC2), Kendler, KS, Gill, M, Riley, BP, Spencer, CCA & Corvin, A 2014, 'An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis', Human Molecular Genetics, vol. 23, no. 12, pp. 3316-3326. https://doi.org/10.1093/hmg/ddu025

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title = "An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis",

abstract = "Identifying rare, highly penetrant risk mutationsmay be an important step in dissectingthe molecular etiology of schizophrenia.We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium2 (WTCCC2)schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls.Wefound association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P 5 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10-4; odds ratio (OR) = 11.3, 95% CI 5 3.7,∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10-21), indicative of a singleancestral duplication event.Weconfirmedthe breakpoints in 8/8carriers testedandfound co-segregation of the duplication with illness in two additional familymembers of one of the affectedprobands.Wedemonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.",

author = "Morris, {Derek W.} and Pearson, {Richard D.} and Paul Cormican and Kenny, {Elaine M.} and O'Dushlaine, {Colm T.} and Perreault, {Louis Philippe Lemieux} and Eleni Giannoulatou and Daniela Tropea and Maher, {Brion S.} and Brandon Wormley and Eric Kelleher and Ciara Fahey and Ines Molinos and Stefania Bellini and Matti Pirinen and Amy Strange and Colin Freeman and Thiselton, {Dawn L.} and Elves, {Rachel L.} and Regina Regan and Sean Ennis and Dinan, {Timothy G.} and Colm McDonald and Murphy, {Kieran C.} and Eadbhard O'Callaghan and Waddington, {John L.} and Dermot Walsh and Michael O'Donovan and Detelina Grozeva and Nick Craddock and Jennifer Stone and Ed Scolnick and Shaun Purcell and Pamela Sklar and Bradley Coe and Eichler, {Evan E.} and Roel Ophoff and Jacobine Buizer and Jin Szatkiewicz and Christina Hultman and Patrick Sullivan and Hugh Gurling and Andrew Mcquillin and {St Clair}, David and Elliott Rees and George Kirov and James Walters and Douglas Blackwood and Mandy Johnstone and Gary Donohoe and {The International Schizophrenia Consortium (ISC)} and {SGENE+ Consortium} and O'Neill, {Francis A.} and {The Wellcome Trust Case Control Consortium 2 (WTCCC2)} and Kendler, {Kenneth S.} and Michael Gill and Riley, {Brien P.} and Spencer, {Chris C. A.} and Aiden Corvin",

note = "FUNDING Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). We acknowledge use of the Trinity Biobank sample from the Irish Blood Transfusion Service; the Trinity Centre for High Performance Computing; British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. Chris Spencer is supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. ACKNOWLEDGEMENTS The authors sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank Akira Sawa and Koko Ishzuki for advice on the PAK7–DISC1 interaction experiment and Jan Korbel for discussions on mechanism of structural variation.",

year = "2014",

month = jun,

day = "15",

doi = "10.1093/hmg/ddu025",

language = "English",

volume = "23",

pages = "3316--3326",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

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TY - JOUR

T1 - An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis

AU - Morris, Derek W.

AU - Pearson, Richard D.

AU - Cormican, Paul

AU - Kenny, Elaine M.

AU - O'Dushlaine, Colm T.

AU - Perreault, Louis Philippe Lemieux

AU - Giannoulatou, Eleni

AU - Tropea, Daniela

AU - Maher, Brion S.

AU - Wormley, Brandon

AU - Kelleher, Eric

AU - Fahey, Ciara

AU - Molinos, Ines

AU - Bellini, Stefania

AU - Pirinen, Matti

AU - Strange, Amy

AU - Freeman, Colin

AU - Thiselton, Dawn L.

AU - Elves, Rachel L.

AU - Regan, Regina

AU - Ennis, Sean

AU - Dinan, Timothy G.

AU - McDonald, Colm

AU - Murphy, Kieran C.

AU - O'Callaghan, Eadbhard

AU - Waddington, John L.

AU - Walsh, Dermot

AU - O'Donovan, Michael

AU - Grozeva, Detelina

AU - Craddock, Nick

AU - Stone, Jennifer

AU - Scolnick, Ed

AU - Purcell, Shaun

AU - Sklar, Pamela

AU - Coe, Bradley

AU - Eichler, Evan E.

AU - Ophoff, Roel

AU - Buizer, Jacobine

AU - Szatkiewicz, Jin

AU - Hultman, Christina

AU - Sullivan, Patrick

AU - Gurling, Hugh

AU - Mcquillin, Andrew

AU - St Clair, David

AU - Rees, Elliott

AU - Kirov, George

AU - Walters, James

AU - Blackwood, Douglas

AU - Johnstone, Mandy

AU - Donohoe, Gary

AU - The International Schizophrenia Consortium (ISC)

AU - SGENE+ Consortium

AU - O'Neill, Francis A.

AU - The Wellcome Trust Case Control Consortium 2 (WTCCC2)

AU - Kendler, Kenneth S.

AU - Gill, Michael

AU - Riley, Brien P.

AU - Spencer, Chris C. A.

AU - Corvin, Aiden

N1 - FUNDING Funding for this study was provided by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), NIMH grants (MH 41953 and MH083094) and Science Foundation Ireland (08/IN.1/B1916). We acknowledge use of the Trinity Biobank sample from the Irish Blood Transfusion Service; the Trinity Centre for High Performance Computing; British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02) and of the UK National Blood Service controls funded by the Wellcome Trust. Chris Spencer is supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. ACKNOWLEDGEMENTS The authors sincerely thank all patients who contributed to this study and all staff who facilitated their involvement. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We thank Akira Sawa and Koko Ishzuki for advice on the PAK7–DISC1 interaction experiment and Jan Korbel for discussions on mechanism of structural variation.

PY - 2014/6/15

Y1 - 2014/6/15

N2 - Identifying rare, highly penetrant risk mutationsmay be an important step in dissectingthe molecular etiology of schizophrenia.We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium2 (WTCCC2)schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls.Wefound association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P 5 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10-4; odds ratio (OR) = 11.3, 95% CI 5 3.7,∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10-21), indicative of a singleancestral duplication event.Weconfirmedthe breakpoints in 8/8carriers testedandfound co-segregation of the duplication with illness in two additional familymembers of one of the affectedprobands.Wedemonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

AB - Identifying rare, highly penetrant risk mutationsmay be an important step in dissectingthe molecular etiology of schizophrenia.We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium2 (WTCCC2)schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls.Wefound association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P 5 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10-4; odds ratio (OR) = 11.3, 95% CI 5 3.7,∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10-21), indicative of a singleancestral duplication event.Weconfirmedthe breakpoints in 8/8carriers testedandfound co-segregation of the duplication with illness in two additional familymembers of one of the affectedprobands.Wedemonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

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An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis

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