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, ColmT T. O'Dushlaine, Louis Philippe Lemieux Perreault, Eleni Giannoulatou, Daniela Tropea, Brion 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, Francis A. OwNeill, Kenneth S. Kendler, Michael Gill, Brien P. Riley, Chris C A Spencer, Aiden Corvin

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)3316-3326
Number of pages11
JournalHuman Molecular Genetics
Volume23
Issue number12
DOIs
StatePublished - 2014
Externally publishedYes

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p21-Activated Kinases
Psychotic Disorders
Protein Kinases
Schizophrenia
Bipolar Disorder
Haplotypes
Proteins
Overlapping Genes
Linkage Disequilibrium
Ireland
Synapses
Genes
Meta-Analysis
Odds Ratio

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Morris, D. W., Pearson, R. D., Cormican, P., Kenny, E. M., O'Dushlaine, C. T., Perreault, L. P. 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

An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis. / Morris, Derek W.; Pearson, Richard D.; Cormican, Paul; Kenny, Elaine M.; O'Dushlaine, ColmT T.; Perreault, Louis Philippe Lemieux; Giannoulatou, Eleni; Tropea, Daniela; Maher, Brion; Wormley, Brandon; Kelleher, Eric; Fahey, Ciara; Molinos, Ines; Bellini, Stefania; Pirinen, Matti; Strange, Amy; Freeman, Colin; Thiselton, Dawn L.; Elves, Rachel L.; Regan, Regina; Ennis, Sean; Dinan, Timothy G.; McDonald, Colm; Murphy, Kieran C.; O'Callaghan, Eadbhard; Waddington, John L.; Walsh, Dermot; O'Donovan, Michael; Grozeva, Detelina; Craddock, Nick; Stone, Jennifer; Scolnick, Ed; Purcell, Shaun; Sklar, Pamela; Coe, Bradley; Eichler, Evan E.; Ophoff, Roel; Buizer, Jacobine; Szatkiewicz, Jin; Hultman, Christina; Sullivan, Patrick; Gurling, Hugh; Mcquillin, Andrew; St Clair, David; Rees, Elliott; Kirov, George; Walters, James; Blackwood, Douglas; Johnstone, Mandy; Donohoe, Gary; OwNeill, Francis A.; Kendler, Kenneth S.; Gill, Michael; Riley, Brien P.; Spencer, Chris C A; Corvin, Aiden.

In: Human Molecular Genetics, Vol. 23, No. 12, 2014, p. 3316-3326.

Research output: Contribution to journalArticle

Morris, DW, Pearson, RD, Cormican, P, Kenny, EM, O'Dushlaine, CT, Perreault, LPL, Giannoulatou, E, Tropea, D, Maher, B, 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, OwNeill, FA, 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
Morris DW, Pearson RD, Cormican P, Kenny EM, O'Dushlaine CT, Perreault LPL et al. An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis. Human Molecular Genetics. 2014;23(12):3316-3326. https://doi.org/10.1093/hmg/ddu025
Morris, Derek W. ; Pearson, Richard D. ; Cormican, Paul ; Kenny, Elaine M. ; O'Dushlaine, ColmT T. ; Perreault, Louis Philippe Lemieux ; Giannoulatou, Eleni ; Tropea, Daniela ; Maher, Brion ; Wormley, Brandon ; Kelleher, Eric ; Fahey, Ciara ; Molinos, Ines ; Bellini, Stefania ; Pirinen, Matti ; Strange, Amy ; Freeman, Colin ; Thiselton, Dawn L. ; Elves, Rachel L. ; Regan, Regina ; Ennis, Sean ; Dinan, Timothy G. ; McDonald, Colm ; Murphy, Kieran C. ; O'Callaghan, Eadbhard ; Waddington, John L. ; Walsh, Dermot ; O'Donovan, Michael ; Grozeva, Detelina ; Craddock, Nick ; Stone, Jennifer ; Scolnick, Ed ; Purcell, Shaun ; Sklar, Pamela ; Coe, Bradley ; Eichler, Evan E. ; Ophoff, Roel ; Buizer, Jacobine ; Szatkiewicz, Jin ; Hultman, Christina ; Sullivan, Patrick ; Gurling, Hugh ; Mcquillin, Andrew ; St Clair, David ; Rees, Elliott ; Kirov, George ; Walters, James ; Blackwood, Douglas ; Johnstone, Mandy ; Donohoe, Gary ; OwNeill, Francis A. ; Kendler, Kenneth S. ; Gill, Michael ; Riley, Brien P. ; Spencer, Chris C A ; Corvin, Aiden. / An inherited duplication at the gene p21 protein-activated Kinase 7 (PAK7) is a risk factor for psychosis. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 12. pp. 3316-3326.
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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.",
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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, ColmT T.

AU - Perreault, Louis Philippe Lemieux

AU - Giannoulatou, Eleni

AU - Tropea, Daniela

AU - Maher, Brion

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 - OwNeill, Francis A.

AU - Kendler, Kenneth S.

AU - Gill, Michael

AU - Riley, Brien P.

AU - Spencer, Chris C A

AU - Corvin, Aiden

PY - 2014

Y1 - 2014

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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