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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.

SUBMITTER: Houlihan LM

PROVIDER: S-EPMC2789249 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B.

Houlihan Lorna M LM Christoforou Andrea A Arbuckle Margaret I MI Torrance Helen S HS Anderson Susan M SM Muir Walter J WJ Porteous David J DJ Blackwood Douglas H DH Evans Kathryn L KL

Journal of psychiatric research 20090617 16

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 associ ...[more]

PMID: 19539307

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Project description:The TPH2 gene encodes the enzyme responsible for serotonin (5-HT) synthesis in the Central Nervous System (CNS). Stereotypic and repetitive behaviors are influenced by 5-HT, and initial studies report an association of TPH2 alleles with childhood-onset obsessive-compulsive disorder (OCD) and with autism. GLO1 encodes glyoxalase I, the enzyme which detoxifies alpha-oxoaldehydes such as methylglyoxal in all living cells. The A111E GLO1 protein variant, encoded by SNP C419A, was identified in autopsied autistic brains and proposed to act as an autism susceptibility factor. Hyperserotoninemia, macrocephaly, and peptiduria represent some of the best-characterized endophenotypes in autism research.Family-based and case-control association studies were performed on clinical samples drawn from 312 simplex and 29 multiplex families including 371 non-syndromic autistic patients and 156 unaffected siblings, as well as on 171 controls. TPH2 SNPs rs4570625 and rs4565946 were genotyped using the TaqMan assay; GLO1 SNP C419A was genotyped by PCR and allele-specific restriction digest. Family-based association analyses were performed by TDT and FBAT, case-control by chi2, endophenotypic analyses for 5-HT blood levels, cranial circumference and urinary peptide excretion rates by ANOVA and FBAT.TPH2 alleles and haplotypes are not significantly associated in our sample with autism (rs4570625: TDT P = 0.27, and FBAT P = 0.35; rs4565946: TDT P = 0.45, and FBAT P = 0.55; haplotype P = 0.84), with any endophenotype, or with the presence/absence of prominent repetitive and stereotyped behaviors (motor stereotypies: P = 0.81 and 0.84, verbal stereotypies: P = 0.38 and 0.73 for rs4570625 and rs4565946, respectively). Also GLO1 alleles display no association with autism (191 patients vs 171 controls, P = 0.36; TDT P = 0.79, and FBAT P = 0.37), but unaffected siblings seemingly carry a protective gene variant marked by the A419 allele (TDT P < 0.05; patients vs unaffected siblings TDT and FBAT P < 0.00001).TPH2 gene variants are unlikely to contribute to autism or to the presence/absence of prominent repetitive behaviors in our sample, although an influence on the intensity of these behaviors in autism cannot be excluded. GLO1 gene variants do not confer autism vulnerability in this sample, but allele A419 apparently carries a protective effect, spurring interest into functional correlates of the C419A SNP.

Dataset Information

A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B.

Publications

A case-control association study and family-based expression analysis of the bipolar disorder candidate gene PI4K2B.

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