The DISC locus and schizophrenia: evidence from an association study in a central European sample and from a meta-analysis across different European populations.
Association studies, as well as the initial translocation family study, identified the gene Disrupted-In-Schizophrenia-1 (DISC1) as a risk factor for schizophrenia. DISC1 encodes a multifunctional scaffold protein involved in neurodevelopmental processes implicated in the etiology of schizophrenia. The present study explores the contribution of the DISC locus to schizophrenia using three different approaches: (i) systematic association mapping aimed at detecting DISC risk variants in a schizophrenia sample from a central European population (556 SNPs, n = 1621 individuals). In this homogenous sample, a circumscribed DISC1 interval in intron 9 was significantly associated with schizophrenia in females (P = 4 x 10(-5)) and contributed most strongly to early-onset cases (P = 9 x 10(-5)). The odds ratios (ORs) were in the range of 1.46-1.88. (ii) The same sample was used to test for the locus-specific SNP-SNP interaction most recently associated with schizophrenia. Our results confirm the SNP interplay effect between rs1538979 and rs821633 that significantly conferred disease risk in male patients with schizophrenia (P = 0.016, OR 1.57). (iii) In order to detect additional schizophrenia variants, a meta-analysis was performed using nine schizophrenia samples from different European populations (50 SNPs, n = 10 064 individuals maximum, n = 3694 minimum). We found evidence for a common schizophrenia risk interval within DISC1 intron 4-6 (P = 0.002, OR 1.27). The findings point to a complex association between schizophrenia and DISC, including the presence of different risk loci and SNP interplay effects. Furthermore, our phenotype-genotype results--including the consideration of sex-specific effects--highlight the value of homogenous samples in mapping risk genes for schizophrenia in general, and at the DISC locus in particular.
Schumacher
Johannes
J
Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD 20892-3719, USA. schumacherj@mail.nih.gov
Laje
Gonzalo
G
Abou Jamra
Rami
R
Becker
Tim
T
Mühleisen
Thomas W
TW
Vasilescu
Catalina
C
Mattheisen
Manuel
M
Herms
Stefan
S
Hoffmann
Per
P
Hillmer
Axel M
AM
Georgi
Alexander
A
Herold
Christine
C
Schulze
Thomas G
TG
Propping
Peter
P
Rietschel
Marcella
M
McMahon
Francis J
FJ
Nöthen
Markus M
MM
Cichon
Sven
S
D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D012737:Sex Factors; D044465:White People / Q000235:genetics*
C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins