An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.
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 (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 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 Cochran-Mantel-Haenszel P-value = 2 × 10(-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 9.68 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 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.
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Derek W
DW
Morris
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Richard D
RD
Pearson
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Paul
P
Cormican
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Elaine M
EM
Kenny
Broad Institute and Center for Human Genetics Research of Massachusetts General Hospital, Boston, MA 02142, USA.
Colm T
CT
O'Dushlaine
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK Montreal Heart Institute, Université de Montréal, Montréal, Québec H1T 1C8, Canada.
Louis-Philippe Lemieux
LP
Perreault
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Eleni
E
Giannoulatou
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Daniela
D
Tropea
Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
Brion S
BS
Maher
Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
Brandon
B
Wormley
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Eric
E
Kelleher
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Ciara
C
Fahey
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Ines
I
Molinos
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Stefania
S
Bellini
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Matti
M
Pirinen
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Amy
A
Strange
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Colin
C
Freeman
Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
Dawn L
DL
Thiselton
Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
Rachel L
RL
Elves
School of Medicine and Medical Science, University College Dublin, Ireland.
Regina
R
Regan
School of Medicine and Medical Science, University College Dublin, Ireland.
Sean
S
Ennis
Department of Psychiatry, University College Cork, Cork, Ireland.
Timothy G
TG
Dinan
Department of Psychiatry, National University of Ireland, Galway, University Road, Galway, Ireland.
Colm
C
McDonald
Department of Psychiatry, RCSI Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
Kieran C
KC
Murphy
DETECT Early Intervention in Psychosis Services, Dun Laoghaire, Co. Dublin, Ireland.
Eadbhard
E
O'Callaghan
Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
John L
JL
Waddington
Health Research Board, 73 Lower Baggot St, Dublin 2, Ireland.
Dermot
D
Walsh
MRC Centre for Neuropsychiatric Genetics and Genomics, and Neuroscience and Mental Health Research Institute, Cardiff University, Heath Park, Cardiff CF4 4XN, UK.
Michael
M
O'Donovan
MRC Centre for Neuropsychiatric Genetics and Genomics, and Neuroscience and Mental Health Research Institute, Cardiff University, Heath Park, Cardiff CF4 4XN, UK.
Detelina
D
Grozeva
MRC Centre for Neuropsychiatric Genetics and Genomics, and Neuroscience and Mental Health Research Institute, Cardiff University, Heath Park, Cardiff CF4 4XN, UK.
Nick
N
Craddock
Broad Institute and Center for Human Genetics Research of Massachusetts General Hospital, Boston, MA 02142, USA.
Jennifer
J
Stone
Broad Institute and Center for Human Genetics Research of Massachusetts General Hospital, Boston, MA 02142, USA.
Ed
E
Scolnick
Broad Institute and Center for Human Genetics Research of Massachusetts General Hospital, Boston, MA 02142, USA The Mount Sinai Hospital, New York, NY 10029, USA.
Shaun
S
Purcell
Broad Institute and Center for Human Genetics Research of Massachusetts General Hospital, Boston, MA 02142, USA The Mount Sinai Hospital, New York, NY 10029, USA.
Pamela
P
Sklar
University of Washington School of Medicine, Howard Hughes Medical Institute, Seattle, WA 98195, USA.
Bradley
B
Coe
University of Washington School of Medicine, Howard Hughes Medical Institute, Seattle, WA 98195, USA.
Evan E
EE
Eichler
Department of Human Genetics, UCLA School of Medicine, Los Angeles, CA 90095, USA.
Roel
R
Ophoff
Rudolf Magnus Institute, University of Utrecht, 3584 CG Utrecht, Netherlands.
Jacobine
J
Buizer
University of North Carolina, Chapel Hill, NC 27599-7264, USA.
Jin
J
Szatkiewicz
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Christina
C
Hultman
University of North Carolina, Chapel Hill, NC 27599-7264, USA.
Patrick
P
Sullivan
Molecular Psychiatry Laboratory, Mental Health Sciences Unit, University College London, London WC1E 6BT, UK.
Hugh
H
Gurling
Molecular Psychiatry Laboratory, Mental Health Sciences Unit, University College London, London WC1E 6BT, UK.
Andrew
A
Mcquillin
Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
David
D
St Clair
MRC Centre for Neuropsychiatric Genetics and Genomics, and Neuroscience and Mental Health Research Institute, Cardiff University, Heath Park, Cardiff CF4 4XN, UK.
Elliott
E
Rees
MRC Centre for Neuropsychiatric Genetics and Genomics, and Neuroscience and Mental Health Research Institute, Cardiff University, Heath Park, Cardiff CF4 4XN, UK.
George
G
Kirov
MRC Centre for Neuropsychiatric Genetics and Genomics, and Neuroscience and Mental Health Research Institute, Cardiff University, Heath Park, Cardiff CF4 4XN, UK.
James
J
Walters
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK and.
Douglas
D
Blackwood
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK and.
Mandy
M
Johnstone
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Gary
G
Donohoe
Department of Psychiatry, Queen's University, Belfast BT7 1NN, Northern Ireland.
Francis A
FA
O'Neill
Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
Kenneth S
KS
Kendler
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland.
Michael
M
Gill
Departments of Psychiatry and Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23284, USA.
Brien P
BP
Riley
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Chris C A
CC
Spencer
Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland acorvin@tcd.ie.
Aiden
A
Corvin
D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D056905:Chromosome Breakpoints; D058674:Chromosome Duplication; D056915:DNA Copy Number Variations; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity; D011618:Psychotic Disorders / Q000235:genetics* / Q000473:pathology; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000235:genetics; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism*
C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; C443802:PAK5 protein, human; D054462:p21-Activated Kinases