Common variants conferring risk of schizophrenia.
Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
Stefansson
Hreinn
H
deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
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Roel A
RA
Steinberg
Stacy
S
Andreassen
Ole A
OA
Cichon
Sven
S
Rujescu
Dan
D
Werge
Thomas
T
Pietiläinen
Olli P H
OP
Mors
Ole
O
Mortensen
Preben B
PB
Sigurdsson
Engilbert
E
Gustafsson
Omar
O
Nyegaard
Mette
M
Tuulio-Henriksson
Annamari
A
Ingason
Andres
A
Hansen
Thomas
T
Suvisaari
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Lonnqvist
Jouko
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Paunio
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Børglum
Anders D
AD
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Annette
A
Fink-Jensen
Anders
A
Nordentoft
Merete
M
Hougaard
David
D
Norgaard-Pedersen
Bent
B
Böttcher
Yvonne
Y
Olesen
Jes
J
Breuer
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R
Möller
Hans-Jürgen
HJ
Giegling
Ina
I
Rasmussen
Henrik B
HB
Timm
Sally
S
Mattheisen
Manuel
M
Bitter
István
I
Réthelyi
János M
JM
Magnusdottir
Brynja B
BB
Sigmundsson
Thordur
T
Olason
Pall
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Masson
Gisli
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Gulcher
Jeffrey R
JR
Haraldsson
Magnus
M
Fossdal
Ragnheidur
R
Thorgeirsson
Thorgeir E
TE
Thorsteinsdottir
Unnur
U
Ruggeri
Mirella
M
Tosato
Sarah
S
Franke
Barbara
B
Strengman
Eric
E
Kiemeney
Lambertus A
LA
Melle
Ingrid
I
Djurovic
Srdjan
S
Abramova
Lilia
L
Kaleda
Vasily
V
Sanjuan
Julio
J
de Frutos
Rosa
R
Bramon
Elvira
E
Vassos
Evangelos
E
Fraser
Gillian
G
Ettinger
Ulrich
U
Picchioni
Marco
M
Walker
Nicholas
N
Toulopoulou
Timi
T
Need
Anna C
AC
Ge
Dongliang
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Yoon
Joeng Lim
JL
Shianna
Kevin V
KV
Freimer
Nelson B
NB
Cantor
Rita M
RM
Murray
Robin
R
Kong
Augustine
A
Golimbet
Vera
V
Carracedo
Angel
A
Arango
Celso
C
Costas
Javier
J
Jönsson
Erik G
EG
Terenius
Lars
L
Agartz
Ingrid
I
Petursson
Hannes
H
Nöthen
Markus M
MM
Rietschel
Marcella
M
Matthews
Paul M
PM
Muglia
Pierandrea
P
Peltonen
Leena
L
St Clair
David
D
Goldstein
David B
DB
Stefansson
Kari
K
Collier
David A
DA
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D051579:Neurogranin / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000276:immunology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D005819:Genetic Markers; C496649:NRGN protein, human; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051579:Neurogranin