Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder
Recessive mutations of the potassium chloride co-transporter 3 gene (SLC12A6, KCC3) cause severe peripheral neuropathy frequently associated with agenesis of the corpus callosum and psychoses (ACCPN). SLC12A6 is localized on chromosome 15q14, a region where linkage to schizophrenia and bipolar disorder has previously been shown. Mutation analysis of SLC12A6 was carried out by direct sequencing of PCR-generated DNA fragments in two affected members of a multiplex family, and three non-affected individuals. A case-control study was performed to assess association of variants with bipolar disorder and schizophrenia in a large sample. Several variants including two rare single nucleotide polymorphisms (G/A, G/A) in the promoter and 5′-UTR, and a thymidine insertion in intron 4 were found. The two G variants and the insertion variant were co-inherited with chromosome 15-related schizophrenia in a large family that strongly supports the region on chromosome 15q14-15 between markers D15S144 and D15S132. Furthermore, they are in linkage disequilibrium with each other, and significantly associated with bipolar disorder in a case-control study. Our data strongly suggest that rare variants of SLC12A6 may represent risk factors for bipolar disorder.(Received March 2 2005)
(Reviewed March 31 2005)
(Revised May 17 2005)
(Accepted May 18 2005)
Key Words: Association study; bipolar disorder; KCC3; potassium chloride co-transporter 3; mutation analysis; SLC12A6.
c1 Department of Neuro-Behavioural Genetics, University of Trier, Johanniterufer 15, D-54290 Trier, Germany. Tel.: +49 651 201 3713 Fax: +49 651 201 3738 E-mail: firstname.lastname@example.org