title: Cross-disorder analysis of bipolar risk genes: further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD.
abstract: 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.
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Psychiatric Neurobiology and Bipolar Disorder Program, University of Würzburg, Würzburg, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Weber
authors.forename: Sarah
authors.initials: S
authors.lastname: Kittel-Schneider
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gessner
authors.forename: Katharina
authors.initials: K
authors.lastname: Domschke
authors.forename: Maria
authors.initials: M
authors.lastname: Neuner
authors.forename: Christian P
authors.initials: CP
authors.lastname: Jacob
authors.forename: Henriette N
authors.initials: HN
authors.lastname: Buttenschon
authors.forename: Andrea
authors.initials: A
authors.lastname: Boreatti-Hümmer
authors.forename: Julia
authors.initials: J
authors.lastname: Volkert
authors.forename: Sabine
authors.initials: S
authors.lastname: Herterich
authors.forename: Bernhard T
authors.initials: BT
authors.lastname: Baune
authors.forename: Silke
authors.initials: S
authors.lastname: Gross-Lesch
authors.forename: Juliane
authors.initials: J
authors.lastname: Kopf
authors.forename: Susanne
authors.initials: S
authors.lastname: Kreiker
authors.forename: Thuy Trang
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Lena
authors.initials: L
authors.lastname: Weissflog
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.forename: Ole
authors.initials: O
authors.lastname: Mors
authors.forename: Jürgen
authors.initials: J
authors.lastname: Deckert
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
mesh_terms: D000328:Adult; D000368:Aged; D001289:Attention Deficit Disorder with Hyperactivity / Q000201:enzymology* / Q000235:genetics* / Q000523:psychology; D001714:Bipolar Disorder / Q000235:genetics* / Q000523:psychology; D003866:Depressive Disorder / Q000235:genetics* / Q000523:psychology; D019852:Diacylglycerol Kinase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
chemical_list: D019852:Diacylglycerol Kinase