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

  • Jobst Meyer (a1) (a2), Kirsten Johannssen (a1), Christine M. Freitag (a3) (a4), Kerstin Schraut (a1), Isabel Teuber (a5), Astrid Hahner (a1), Christian Mainhardt (a6), Rainald Mössner (a1), Hans-Peter Volz (a5), Thomas F. Wienker (a3), Darleen McKeane (a7), Dietrich A. Stephan (a8), Guy Rouleau (a9), Andreas Reif (a1) and Klaus-Peter Lesch (a1)...

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.

Corresponding author
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:
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The International Journal of Neuropsychopharmacology
  • ISSN: 1461-1457
  • EISSN: 1469-5111
  • URL: /core/journals/the-international-journal-of-neuropsychopharmacology
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