TY - JOUR
T1 - The DISC locus and schizophrenia
T2 - Evidence from an association study in a central European sample and from a meta-analysis across different European populations
AU - Schumacher, Johannes
AU - Laje, Gonzalo
AU - Jamra, Rami Abou
AU - Becker, Tim
AU - Mühleisen, Thomas W.
AU - Vasilescu, Catalina
AU - Mattheisen, Manuel
AU - Herms, Stefan
AU - Hoffmann, Per
AU - Hillmer, Axel M.
AU - Georgi, Alexander
AU - Herold, Christine
AU - Schulze, Thomas G.
AU - Propping, Peter
AU - Rietschel, Marcella
AU - McMahon, Francis J.
AU - Nöthen, Markus M.
AU - Cichon, Sven
PY - 2009
Y1 - 2009
N2 - 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 × 10-5) and contributed most strongly to early-onset cases (P = 9 × 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.
AB - 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 × 10-5) and contributed most strongly to early-onset cases (P = 9 × 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.
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U2 - 10.1093/hmg/ddp204
DO - 10.1093/hmg/ddp204
M3 - Article
C2 - 19414483
AN - SCOPUS:67649832375
SN - 0964-6906
VL - 18
SP - 2719
EP - 2727
JO - Human molecular genetics
JF - Human molecular genetics
IS - 14
ER -