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

Welcome Trust Case Control Consortium 2

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=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 CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate 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
Pages (from-to)3316-3326
Number of pages11
JournalHuman Molecular Genetics
Volume23
Issue number2
Early online date28 Jan 2014
DOIs
Publication statusPublished - 15 Jun 2014

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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
Mutation

Cite this

Welcome Trust Case Control Consortium 2. / 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. 2. pp. 3316-3326.
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abstract = "Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=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 CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95{\%} CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate 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. / Welcome Trust Case Control Consortium 2.

In: Human Molecular Genetics, Vol. 23, No. 2, 15.06.2014, p. 3316-3326.

Research output: Contribution to journalArticle

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 - Lemieux Perreault, Louis-Philippe

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 - O'Neill, Francis A

AU - Welcome Trust Case Control Consortium 2

PY - 2014/6/15

Y1 - 2014/6/15

N2 - Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=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 CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate 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 mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=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 CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

U2 - 10.1093/hmg/ddu025

DO - 10.1093/hmg/ddu025

M3 - Article

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VL - 23

SP - 3316

EP - 3326

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 2

ER -