title: A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B.
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.
authors.affiliation: Medical Genetics Section, Molecular Medicine Centre, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. lorna.houlihan@ed.ac.uk
authors.forename: Lorna M
authors.initials: LM
authors.lastname: Houlihan
authors.forename: Andrea
authors.initials: A
authors.lastname: Christoforou
authors.forename: Margaret I
authors.initials: MI
authors.lastname: Arbuckle
authors.forename: Helen S
authors.initials: HS
authors.lastname: Torrance
authors.forename: Susan M
authors.initials: SM
authors.lastname: Anderson
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Muir
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Blackwood
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Evans
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics
chemical_list: D015778:Minor Histocompatibility Antigens; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase