Linkage of bipolar affective disorder on chromosome 8q24: follow-up and parametric analysis

Avramopoulos, Dimitri; Willour, Virginia L.; Zandi, Peter; Huo, Yuqing; MacKinnon, D. F.; Potash, JB; DePaulo, J. Raymond; McInnis, M. G.

doi:10.1038/sj.mp.4001388

Cited by 38 publications

(40 citation statements)

References 43 publications

(51 reference statements)

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“…However, some of the most significant results in the NIMH sample did not replicate in the German sample, and by design, we did not pursue association signals present only in the German sample. Association signals that did not replicate under our criteria were observed in several genes that have been implicated by previous studies, [50][51][52][53] including NPAS3, GRIK2, GRM3, GRM4, KCNQ3 and GRIN2B (data not shown). Since others may wish to pursue these findings, we will make our genome-wide set of results available at http://mapgenetics.nimh.nih.gov/bp_pooling.…”

Section: Ae Baum Et Almentioning

confidence: 51%

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

et al. 2007

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The genetic basis of bipolar disorder has long been thought to be complex, with the potential involvement of multiple genes, but methods to analyze populations with respect to this complexity have only recently become available. We have carried out a genome-wide association study of bipolar disorder by genotyping over 550 000 single-nucleotide polymorphisms (SNPs) in two independent case-control samples of European origin. The initial association screen was performed using pooled DNA, and selected SNPs were confirmed by individual genotyping. While DNA pooling reduces power to detect genetic associations, there is a substantial cost saving and gain in efficiency. A total of 88 SNPs, representing 80 different genes, met the prior criteria for replication in both samples. Effect sizes were modest: no single SNP of large effect was detected. Of 37 SNPs selected for individual genotyping, the strongest association signal was detected at a marker within the first intron of diacylglycerol kinase eta (DGKH; P = 1.5 Â 10 À8 , experiment-wide P < 0.01, OR = 1.59). This gene encodes DGKH, a key protein in the lithium-sensitive phosphatidyl inositol pathway. This first genome-wide association study of bipolar disorder shows that several genes, each of modest effect, reproducibly influence disease risk. Bipolar disorder may be a polygenic disease.

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Section: Ae Baum Et Almentioning

confidence: 51%

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

et al. 2007

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“…27 Interestingly, a susceptibility locus for BD was recently identified on chromosome 8q24, a region that contains the KCNQ3 gene. 39 We tested the effects of Q2-3H2 or Q2-3H9 on KCNQ3 channel activity and we found that currents generated by the channel are unchanged in the presence of either of the splice variants (Supplementary information, Figure 7). These data indicate that these proteins probably do not interact.…”

Section: Pp2a-bc and Kcnq2 In Bipolar Diseasementioning

confidence: 99%

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

Borsotto

Cavarec²,

Bouillot³

et al. 2006

Pharmacogenomics J

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Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bg-regulatory subunit of the protein phosphatase 2A (PP2A-Bg). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bg subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K þ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bg subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3b) is considered as an interesting target of lithium, the classical drug used in BD. GSK3b phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li þ .

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“…[5][6][7] Increased OPG serum levels have been reported to be significantly related to cardiovascular disease (CVD) phenotypes, 8 and in apparently healthy individuals, with an increased future risk of coronary events. 9 Genetic variation at the human OPG gene locus has been associated with colorectal 10 /prostate cancer risk 11 and bipolar disorders 12 in whole genome approaches; in single variant analyses, OPG T-159C has been associated with elevated OPG serum levels, 13 CVD, 13,14 intima media thickness, and reduced maximal forearm blood flow in healthy subjects. 15 The human OPG gene (8q24) consists of 5 exons and 4 introns, and is transcribed into 4 transcripts (2.4 kb, 3.0 kb, 4.2 kb, and 6.5 kb in lengths).…”

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confidence: 99%

Identification and Functional Analyses of Molecular Haplotypes of the Human Osteoprotegerin Gene Promoter

Hagedorn

Telgmann

Dördelmann

et al. 2009

ATVB

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Objective— Osteoprotegerin (OPG) has been reported to be involved in the development of atherosclerotic disease, and OPG gene variation has been associated with plasma OPG levels and different cardiovascular disease phenotypes. However, the genetic architecture of the OPG promoter and its transcriptional regulation are poorly characterized. Methods and Results— We identified 1008 bp of the OPG 5′-flanking region to be sufficiently transcriptionally active in osteosarcoma cell lines and generated serial promoter deletion constructs. Individual subcloning revealed the existence of 3 molecular haplotypes (MolHaps): [T −960 -A −946 -G −900 -T −864 ; MolHap1, wild type], [T −960 -G −946 -G −900 -T −864 ; MolHap2], [C −960 -G −946 -A −900 -G −864 ; MolHap4]. Compared to MolHap1, transcriptional activities of MolHaps 2 and 4 were significantly reduced ( P =0.0018). Whereas introduction of the −159C allele reduced transcriptional activities of the full-length constructs ( P =0.0014), it significantly increased activities of the deletion constructs ( P =0.0005). Electrophoretic mobility shift, competition, and chromatin immunoprecipitation assays revealed specific DNA:protein interactions for the MolHaps with Sp1 and NF-1, and identified Egr1 interacting exclusively with the −159T allele. Conclusions— We propose new structural and transcriptional features within the OPG promoter region and identified MolHaps being differentially transcriptionally active and allele-dependently interacting with a proximal polymorphic site.

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Linkage of bipolar affective disorder on chromosome 8q24: follow-up and parametric analysis

Cited by 38 publications

References 43 publications

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

PP2A-Bγ subunit and KCNQ2 K+ channels in bipolar disorder

Identification and Functional Analyses of Molecular Haplotypes of the Human Osteoprotegerin Gene Promoter

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