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.
Meyer
Jobst
J
Clinical and Molecular Psychobiology, Department of Psychiatry and Psychotherapy, University of Wuerzburg, Germany. meyerjo@uni-trier.de
Johannssen
Kirsten
K
Freitag
Christine M
CM
Schraut
Kerstin
K
Teuber
Isabel
I
Hahner
Astrid
A
Mainhardt
Christian
C
Mössner
Rainald
R
Volz
Hans-Peter
HP
Wienker
Thomas F
TF
McKeane
Darleen
D
Stephan
Dietrich A
DA
Rouleau
Guy
G
Reif
Andreas
A
Lesch
Klaus-Peter
KP
D020121:5' Untranslated Regions / Q000235:genetics; D001714:Bipolar Disorder / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005819:Genetic Markers; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics / Q000502:physiology; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics; D027981:Symporters / Q000235:genetics*; D000096922:K Cl- Cotransporters
D020121:5' Untranslated Regions; D005819:Genetic Markers; D027981:Symporters; C119650:SLC12A6 protein, human; D000096922:K Cl- Cotransporters