Journal
NEUROPSYCHOPHARMACOLOGY
Volume 36, Issue 10, Pages 2076-2085Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2011.98
Keywords
association; bipolar disorder; depression; adult ADHD; NPAS3; CMTM8
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Funding
- DFG [RE1632/5-1, KFO 125, SFB 581, SFB TRR 58 Z02, C02, A1/A5]
- BMBF [IZKF N-27-N]
- EC [NEWMOOD LSHM-CT-2003-503474]
- Astra Zeneca
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Recently, several genome-wide association studies (GWAS) on bipolar disorder (BPD) suggested novel risk genes. However, only few of them were followed up and further, the specificity of these genes is even more elusive. To address these issues, we genotyped SNPs in ANK3, CACNA1C, CMTM8, DGKH, EGFR, and NPAS3, which were significantly associated with BPD in previous GWAS, in a sample of 380 BPD patients. Replicated SNPs were then followed up in patients suffering from unipolar depression (UPD; n = 387) or adult attention-deficit/hyperactivity disorder (aADHD; n = 535). While we could not confirm an association of ANK3, CACNA1C, and EGFR with BPD, 10 SNPs in DGKH, CMTM8, and NPAS3 were nominally associated with disease, with two DGKH markers surviving correction for multiple testing. When these were followed up in UPD and aADHD, seven DGKH SNPs were also associated with UPD, while one SNP each in NPAS3 and CMTM8 and four in DGKH were linked to aADHD. Furthermore, a DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with all disorders tested, while the complementary AGC haplotype was protective. The corresponding haploblock spans a 27-kb region covering exons coding for amino acids 65-243, and thus might include functional variants yet to be identified. We demonstrate an association of DGKH with BPD, UPD, and aADHD by applying a two-stage design. These disorders share the feature of mood instability, so that this phenotype might be associated with genetic variation in DGKH. Neuropsychopharmacology (2011) 36, 2076-2085; doi: 10.1038/npp.2011.98; published online 8 June 2011
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