Large recurrent microdeletions associated with schizophrenia.
Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.
Stefansson
Hreinn
H
CNS Division, deCODE genetics, Sturlugata 8, IS-101 Reykjavík, Iceland.
Rujescu
Dan
D
Cichon
Sven
S
Pietiläinen
Olli P H
OP
Ingason
Andres
A
Steinberg
Stacy
S
Fossdal
Ragnheidur
R
Sigurdsson
Engilbert
E
Sigmundsson
Thordur
T
Buizer-Voskamp
Jacobine E
JE
Hansen
Thomas
T
Jakobsen
Klaus D
KD
Muglia
Pierandrea
P
Francks
Clyde
C
Matthews
Paul M
PM
Gylfason
Arnaldur
A
Halldorsson
Bjarni V
BV
Gudbjartsson
Daniel
D
Thorgeirsson
Thorgeir E
TE
Sigurdsson
Asgeir
A
Jonasdottir
Adalbjorg
A
Jonasdottir
Aslaug
A
Bjornsson
Asgeir
A
Mattiasdottir
Sigurborg
S
Blondal
Thorarinn
T
Haraldsson
Magnus
M
Magnusdottir
Brynja B
BB
Giegling
Ina
I
Möller
Hans-Jürgen
HJ
Hartmann
Annette
A
Shianna
Kevin V
KV
Ge
Dongliang
D
Need
Anna C
AC
Crombie
Caroline
C
Fraser
Gillian
G
Walker
Nicholas
N
Lonnqvist
Jouko
J
Suvisaari
Jaana
J
Tuulio-Henriksson
Annamarie
A
Paunio
Tiina
T
Toulopoulou
Timi
T
Bramon
Elvira
E
Di Forti
Marta
M
Murray
Robin
R
Ruggeri
Mirella
M
Vassos
Evangelos
E
Tosato
Sarah
S
Walshe
Muriel
M
Li
Tao
T
Vasilescu
Catalina
C
Mühleisen
Thomas W
TW
Wang
August G
AG
Ullum
Henrik
H
Djurovic
Srdjan
S
Melle
Ingrid
I
Olesen
Jes
J
Kiemeney
Lambertus A
LA
Franke
Barbara
B
Sabatti
Chiara
C
Freimer
Nelson B
NB
Gulcher
Jeffrey R
JR
Thorsteinsdottir
Unnur
U
Kong
Augustine
A
Andreassen
Ole A
OA
Ophoff
Roel A
RA
Georgi
Alexander
A
Rietschel
Marcella
M
Werge
Thomas
T
Petursson
Hannes
H
Goldstein
David B
DB
Nöthen
Markus M
MM
Peltonen
Leena
L
Collier
David A
DA
St Clair
David
D
Stefansson
Kari
K
D002681:China; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D005060:Europe; D018628:Gene Dosage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*