Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.
Glucocorticoids, in conjunction with their cognate receptors, exert negative-feedback effects on the hypothalamus-pituitary-adrenal axis, suppressing adrenal steroid secretions. Two types of corticosteroid receptor, distinguishable by their ability to bind corticosterone, have been identified as classical mineralocorticoid (type I) and glucocorticoid (type II) receptors by cloning their complementary DNAs. The type I receptor controls the basal circadian rhythm of corticosteroid secretion. Both receptor types are involved in negative feedback, but the type II receptor may be more important for terminating the stress response as it is the only one to be increased in animals rendered more sensitive to corticosteroid negative-feedback effects. Here we create a transgenic mouse with impaired corticosteroid-receptor function by partially knocking out gene expression with type II glucocorticoid receptor antisense RNA. We use this animal to study the glucocorticoid feedback effect on the hypothalamus-pituitary-adrenal axis.
The P2RX7 gene is located within a region on chromosome 12q24.31 that has been identified as a susceptibility locus for affective disorders by linkage and association studies. P2RX7 is a purinergic ATP-binding calcium channel expressed in neurons as well as in microglial cells in various brain regions. We investigated 29 single nucleotide polymorphisms (SNPs) within the P2RX7 gene and adjacent genes in a sample of 1000 German Caucasian patients suffering from recurrent major depressive disorder (MDD). These were contrasted with diagnosed healthy Caucasian controls from the same population (n=1029). A non-synonymous coding SNP in the P2RX7 gene (rs2230912), previously found to be associated with bipolar disorder, was significantly associated (P=0.0019) with MDD. This polymorphism results in an amino acid exchange in the C-terminal cytosolic domain of the P2RX7 channel protein, suggesting that the observed P2RX7 polymorphism might play a causal role in the development of depression.
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