Genetic studies of bipolar disorder and recurrent major depression in a large Scottish family

Abstract

Bipolar disorder and recurrent major depression are complex psychiatric illnesses with a substantial, yet unknown genetic component. Genetic studies have identified linkage of bipolar disorder and recurrent major depression with markers on chromosome 4p15-p16 in a large Scottish family and three smaller families. To focus the search for genetic factors for susceptibility to illness two approaches were adopted: a chromosome 4p15-p16 candidate gene study and a whole-genome linkage scan. In the first instance, phosphatidylinositol 4-kinase type-II beta (PI4K2B) was selected as a candidate gene. Analysis of haplotypes in the four linked families identified two regions, both of which were shared by three families. PI4K2B lies within one of these regions. PI4K2B is also a worthy functional candidate as it is a member of the phosphatidylinositol pathway, which is targeted by lithium for therapeutic effect in bipolar disorder. Expression studies at the allele-specific mRNA and protein level were performed in lymphoblastoid cell lines from the large Scottish family. There was no evidence for expression differences between affected and non-affected family members. However, a case-control association study showed preliminary evidence for association of schizophrenia but not bipolar disorder, with tagging single nucleotide polymorphisms from the PI4K2B genomic region. Second, the linkage evidence for bipolar disorder and recurrent major depression in the large Scottish family was re-examined. This was important because additional family members had been recruited and advances in technology made it feasible to cover all chromosome regions more densely than had been possible ten years ago. Stringent genotyping and pedigree error checks were performed to ensure an optimised dataset for analysis. Furthermore, the large family was divided in an informative manner for ease of analysis using both parametric and non-parametric methods, supplemented by haplotype analysis. Genome-wide significant evidence for linkage was observed on chromosome 4p15- p16 and genome-wide suggestive evidence was observed on chromosomes 8p21 and 1p36. The analysis clearly supports the evidence for a susceptibility locus of bipolar disorder and recurrent major depression on chromosome 4p15-p16, while identifying other genetic loci that may confer risk to psychiatric illness.