Type

Journal Article

Authors

B Su
M J Wright
N G Martin
B Franke
D P Hibar
A Arias Vasquez
S E Medland
J L Stein
F Bellivier
A Heinz
and 38 others

Subjects

Biochemistry

Topics
case control studies female genetics genetic predisposition to disease genetic association studies pathology male aged polymorphism single nucleotide bipolar disorder neuropsychological tests middle aged neuroimaging creb1 protein human gene frequency phenotype computational biology aged 80 and over european continental ancestry group rna messenger cyclic amp response element binding protein asian continental ancestry group age factors ethnology adult metabolism humans hippocampus gene expression regulation

Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility. (2012)

Abstract Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.
Collections Ireland -> Trinity College Dublin -> PubMed

Full list of authors on original publication

B Su, M J Wright, N G Martin, B Franke, D P Hibar, A Arias Vasquez, S E Medland, J L Stein, F Bellivier, A Heinz and 38 others

Experts in our system

1
Barbara Franke
Trinity College Dublin
Total Publications: 12
 
2
Andreas Heinz
Trinity College Dublin
Total Publications: 55