Abstract
Bipolar disorder, schizophrenia and recurrent major depression are complex psychiatric illnesses with a substantial, yet unknown genetic component. Linkage of bipolar disorder and recurrent major depression with markers on chromosome 4p15–p16 has been identified in a large Scottish family and three smaller families. Analysis of haplotypes in the four chromosome 4p-linked families, identified two regions, each shared by three of the four families, which are also supported by a case-control association study. The candidate gene phosphatidylinositol 4-kinase type-II beta (PI4K2B) lies within one of these regions. PI4K2B is a strong functional candidate as it is a member of the phosphatidylinositol pathway, which is targeted by lithium for therapeutic effect in bipolar disorder. Two approaches were undertaken to test the PI4K2B candidate gene as a susceptibility factor for psychiatric illness. First, a case-control association study, using tagging SNPs from the PI4K2B genomic region, in bipolar disorder (n=368), schizophrenia (n=386) and controls (n=458) showed association with a two-marker haplotype in schizophrenia but not bipolar disorder (rs10939038 and rs17408391, global P=0.005, permuted global P=0.039). Second, expression studies at the allele-specific mRNA and protein level using lymphoblastoid cell lines from members of the large Scottish family, which showed linkage to 4p15–p16 in bipolar disorder and recurrent major depression, showed no difference in expression differences between affected and non-affected family members. There is no evidence to suggest that PI4K2B is contributing to bipolar disorder in this family but a role for this gene in schizophrenia has not been excluded.
Highlights
ObjectivesGenetic evidence for psychiatric illness, including bipolar disorder, schizophrenia and related phenotypes to chromosome 4p15– p16, has been established in linkage, population and affected individual studies as detailed previously (Le Hellard et al, 2007)
Positional evidence from linkage and association analyses have implicated this genomic region on chromosome 4p15–p16
Genetic evidence has suggested other members of the phosphoinositide signalling pathway as susceptibility factors for bipolar disorder, schizophrenia and recurrent major depression (Kato, 2007) and components of the phosphoinositide pathway are inhibited by lithium, a therapeutic agent in bipolar disorder (Berridge et al, 1989)
Summary
Genetic evidence for psychiatric illness, including bipolar disorder, schizophrenia and related phenotypes to chromosome 4p15– p16, has been established in linkage, population and affected individual studies as detailed previously (Le Hellard et al, 2007). Haplotype analysis of chromosome 4p15–p16 using four families with linkage to that region, highlighted two areas in the 20 Mb linked region, where three of the four linkage regions overlap, namely region B and region D (Le Hellard et al, 2007). These regions have been supported by association analysis in the Scottish population (Christoforou et al, 2007). PI4K2B is a phosphatidylinositol 4-kinase and a member of the phosphoinositide (PI) signal transduction pathway. The PI signalling pathway is a target for the mood stabilising drugs, lithium and sodium valproate (Berridge et al, 1989; Farmer et al, 2007; Kato, 2007)
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