Copy number variation in schizophrenia in Sweden.
Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare copy number variations (CNVs) in SCZ cases and identified multiple rare recurrent CNVs that increase risk of SCZ although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for SCZ CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with SCZ using a Swedish national sample (4719 cases and 5917 controls). High-confidence CNV calls were generated using genotyping array intensity data, and their effect on risk of SCZ was measured. Our data confirm increased burden of large, rare CNVs in SCZ cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not SCZ. Intriguingly, gene set association analyses implicate biological pathways previously associated with SCZ through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500 kb) in genes present in the postsynaptic density, in genomic regions implicated via SCZ genome-wide association studies and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry--genome-wide screens for CNVs, common variation and exonic variation--are converging on similar sets of pathways and/or genes.
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
J P
JP
Szatkiewicz
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
C
C
O'Dushlaine
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
G
G
Chen
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
K
K
Chambert
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
J L
JL
Moran
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
B M
BM
Neale
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.
M
M
Fromer
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.
D
D
Ruderfer
Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
S
S
Akterin
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
S E
SE
Bergen
Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
A
A
Kähler
Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
P K E
PK
Magnusson
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
Y
Y
Kim
Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
J J
JJ
Crowley
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
E
E
Rees
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
G
G
Kirov
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
M C
MC
O'Donovan
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
M J
MJ
Owen
MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
J
J
Walters
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
E
E
Scolnick
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.
P
P
Sklar
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA.
S
S
Purcell
Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
C M
CM
Hultman
1] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Department of Genetics, Harvard Medical School, Boston, MA, USA.
S A
SA
McCarroll
1] Department of Genetics, University of North Carolina, Chapel Hill, NC, USA [2] Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
P F
PF
Sullivan
D000328:Adult; D016022:Case-Control Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D013548:Sweden; D044465:White People / Q000235:genetics*