The International Journal of Neuropsychopharmacology



Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder


Jobst Meyer a1a2c1, Kirsten Johannssen a1, Christine M. Freitag a3a7, Kerstin Schraut a1, Isabel Teuber a4, Astrid Hahner a1, Christian Mainhardt a5, Rainald Mössner a1, Hans-Peter Volz a4, Thomas F. Wienker a3, Darleen McKeane a8, Dietrich A. Stephan a9, Guy Rouleau a6, Andreas Reif a1 and Klaus-Peter Lesch a1
a1 Clinical and Molecular Psychobiology, Department of Psychiatry and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany
a2 Department of Neuro-Behavioural Genetics, University of Trier, Trier, Germany
a3 Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
a4 Psychiatric District Hospital Werneck, Werneck, Germany
a5 Department of Transfusion Medicine, University of Wuerzburg, Wuerzburg, Germany
a6 Department of Molecular Neurogenetics, McGill University, Quebec, Canada
a7 Department of Child and Adolescent Psychiatry, University Hospital Saarland, Homburg, Germany
a8 Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA
a9 Translational Genomics Research Institute, Neurogenomics Division, Phoenix, Arizona, USA

Article author query
meyer j   [PubMed][Google Scholar] 
johannssen k   [PubMed][Google Scholar] 
freitag cm   [PubMed][Google Scholar] 
schraut k   [PubMed][Google Scholar] 
teuber i   [PubMed][Google Scholar] 
hahner a   [PubMed][Google Scholar] 
mainhardt c   [PubMed][Google Scholar] 
mossner r   [PubMed][Google Scholar] 
volz hp   [PubMed][Google Scholar] 
wienker tf   [PubMed][Google Scholar] 
mckeane d   [PubMed][Google Scholar] 
stephan da   [PubMed][Google Scholar] 
rouleau g   [PubMed][Google Scholar] 
reif a   [PubMed][Google Scholar] 
lesch kp   [PubMed][Google Scholar] 

Abstract

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.

Correspondence:
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: meyerjo@uni-trier.de