Linkage disequilibrium mapping of bipolar affective disorder at 12q23‐q24 provides evidence for association at <i>CUX2</i> and <i>FLJ32356</i>

Glaser, Beate; Kirov, George; Green, Elaine; Craddock, Nicholas John

doi:10.1002/ajmg.b.30081

Cited by 25 publications

(17 citation statements)

References 40 publications

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“…This marker, which was not included in our genome scan, is located between D12S78 and D12S2070/79. The same group (Glaser et al, 2005b) also observed association in this region with Cux2, which is a potential regulator of neural cell adhesion molecule expression, and with hypothetical protein FLJ32356; but not with PAH (Green et al, 2003), which we also investigated and for which we found no association.…”

Section: Discussionmentioning

confidence: 49%

Genetic Linkage and Association Analysis for Loneliness in Dutch Twin and Sibling Pairs Points to a Region on Chromosome 12q23–24

et al. 2005

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We obtained evidence from a large study in Dutch twins (N=8387) and siblings (N=2295) that variation in loneliness has a genetic component. The heritability estimate for loneliness, which was assessed as an ordinal trait, was 40% and did not differ between males and females. There were 682 sibling pairs with genotypic (around 400 microsatellite markers) data. We combined phenotypic and genotypic data to carry out a genome scan to localize QTLs for loneliness. One region on chromosome 12q23.3-24.3, showed near suggestive linkage. Genetic association tests within this region revealed significant association ( p-value 0.009) with one of the alleles of marker D12S79 and with one of the alleles of neighbouring marker D12S395 ( p-value 0.043). We review evidence for linkage in this region for psychiatric disorders and discuss our findings within this context.

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Section: Discussionmentioning

confidence: 49%

Genetic Linkage and Association Analysis for Loneliness in Dutch Twin and Sibling Pairs Points to a Region on Chromosome 12q23–24

et al. 2005

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“…16 Another region of 150 kb which is distant from P2RX7, in the12q23-24 region, encompassing the genes CUX2 and FLJ32356 has been studied in a UK case-control sample. 17 Allelic association was identified with one microsatellite marker (P = 0.0016), two single nucleotide polymorphisms (SNPs) (rs3847953, P = 0.002; rs933399, P = 0.004) and an insertion/deletion with putative functional relevance (P = 0.005). 17 Our own group has also published evidence for allelic and haplotypic association in two separate case-control samples with a total of 12 significantly associated microsatellite and SNP markers on 12q24.…”

Section: Introductionmentioning

confidence: 99%

“…17 Allelic association was identified with one microsatellite marker (P = 0.0016), two single nucleotide polymorphisms (SNPs) (rs3847953, P = 0.002; rs933399, P = 0.004) and an insertion/deletion with putative functional relevance (P = 0.005). 17 Our own group has also published evidence for allelic and haplotypic association in two separate case-control samples with a total of 12 significantly associated microsatellite and SNP markers on 12q24. Eleven of these were in a region of 181kb that contains a number of incompletely characterized expressed sequences one of which is called Slynar or AY070435.…”

Section: Introductionmentioning

confidence: 99%

Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders

et al. 2008

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Three linkage studies of bipolar disorder have implicated chromosome 12q24.3 with lod scores of over 3.0 and several other linkage studies have found lods between 2 and 3. Fine mapping within the original chromosomal linkage regions has identified several loci that show association with bipolar disorder. One of these is the P2RX7 gene encoding a central nervous system-expressed purinergic receptor. A non-synonymous single nucleotide polymorphism, rs2230912 (P2RX7-E13A, G allele) and a microsatellite marker NBG6 were both previously found to be associated with bipolar disorder (P = 0.00071 and 0.008, respectively). rs2230912 has also been found to show association with unipolar depression. The effect of the polymorphism is non-conservative and results in a glutamine to arginine change (Gln460Arg), which is likely to affect P2RX7 dimerization and protein-protein interactions. We have confirmed the allelic associations between bipolar disorder and the markers rs2230912 (P2RX7-E13A, G allele, P = 0.043) and NBG6 (P = 0.010) in a London-based sample of 604 bipolar cases and 560 controls. When we combined these data with the published case-control studies of P2RX7 and mood disorder (3586 individuals) the association between rs2230912 (Gln460Arg) and affective disorders became more robust (P = 0.002). The increase in Gln460Arg was confined to heterozygotes rather than homozygotes suggesting a dominant effect (odds ratio 1.302, CI = 1.129-1.503). Although further research is needed to prove that the Gln460Arg change has an aetiological role, it is so far the most convincing mutation to have been found with a role for increasing susceptibility to bipolar and genetically related unipolar disorders.

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“…The results that we have presented are nominal significance levels uncorrected for multiple testing. If we allow for examining nine different two-locus sliding-window haplotypes using a Bonferroni correction, the global significance found in our screening set remains significant (corrected global P ¼ 0.0072) However, we also examined several other candidate genes within the 25 cM wide linkage region of interest on 12q23-24.1 16,31,[36][37][38] and observed one positive LD signal across the Cux2/FLJ32356 region. 37 Clearly, our results have to be interpreted within this context and, as both investigated subsets had approximately the same power (power subset I ¼ 0.89 and power subset II ¼ 0.85; http://calculators.stat.ucla.edu/powercalc/binomial/case-control/), replication of our data in independent samples, preferably from groups with linkage signals in this region, is required.…”

Section: Discussionmentioning

confidence: 99%

Identification of a potential Bipolar risk haplotype in the gene encoding the winged-helix transcription factor RFX4

et al. 2005

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The gene encoding the transcription factor RFX4 represents an excellent neurobiological and positional candidate gene for Bipolar disorder due to the potential involvement of RFX4 proteins in the regulation of circadian rhythms and the proximity of the locus to numerous linkage signals on chromosome 12q23. In this study we have sought to identify common variants within the gene, which might confer risk to the disease in our large UK Caucasian sample of Bipolar patients (676 DSMIV Bipolar I probands, 690 controls). RFX4 was screened for sequence variants and the LD block structure across the genomic region determined using 22 biallelic polymorphisms (minor allele frequency Z0.1). Through analysis of 10 haplotypetagging markers and using a two-stage approach (subset I: 347 cases, 374 controls; subset II: 329 cases, 316 controls), we identified a haplotype at rs10778502 and ss24735177, which showed nominally significant disease association in our full sample (haplotype-specific P ¼ 0.002, global P ¼ 0.017; subset I: haplotype-specific P ¼ 0.0002, global P ¼ 0.0008; subset II: haplotype-specific P ¼ 0.572, global P ¼ 0.109). Evidence for potential disease association with mutations across the RFX4 region came also from the analysis of the nearby microsatellite D12S2072 (empirical P ¼ 0.009 in our full sample). Investigation of RFX4 brain cDNA tagged by rs10778502 provided evidence for significant allelic differences in expression (Po0.001), where some of the variance was accounted for by the genotype at ss24735177. Our findings thus indicate the potential functional relevance of the associated haplotype and now require replication in independent samples. Molecular Psychiatry (2005) 10, 920-927.

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Linkage disequilibrium mapping of bipolar affective disorder at 12q23‐q24 provides evidence for association at CUX2 and FLJ32356

Cited by 25 publications

References 40 publications

Genetic Linkage and Association Analysis for Loneliness in Dutch Twin and Sibling Pairs Points to a Region on Chromosome 12q23–24

Genetic Linkage and Association Analysis for Loneliness in Dutch Twin and Sibling Pairs Points to a Region on Chromosome 12q23–24

Case–control studies show that a non-conservative amino-acid change from a glutamine to arginine in the P2RX7 purinergic receptor protein is associated with both bipolar- and unipolar-affective disorders

Identification of a potential Bipolar risk haplotype in the gene encoding the winged-helix transcription factor RFX4

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