title: Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia.
abstract: Patients with schizophrenia show decreased processing speed on neuropsychological testing and decreased white matter integrity as measured by diffusion tensor imaging, two traits shown to be both heritable and genetically associated indicating that there may be genes that influence both traits as well as schizophrenia disease risk. The potassium channel gene family is a reasonable candidate to harbor such a gene given the prominent role potassium channels play in the central nervous system in signal transduction, particularly in myelinated axons. We genotyped members of the large potassium channel gene family focusing on putatively functional single nucleotide polymorphisms (SNPs) in a population of 363 controls, 194 patients with schizophrenia spectrum disorder (SSD) and 28 patients with affective disorders with psychotic features who completed imaging and neuropsychological testing. We then performed three association analyses using three phenotypes - processing speed, whole-brain white matter fractional anisotropy (FA) and schizophrenia spectrum diagnosis. We extracted SNPs showing an association at a nominal P value of <0.05 with all three phenotypes in the expected direction: decreased processing speed, decreased FA and increased risk of SSD. A single SNP, rs8234, in the 3' untranslated region of voltage-gated potassium channel subfamily Q member 1 (KCNQ1) was identified. Rs8234 has been shown to affect KCNQ1 expression levels, and KCNQ1 levels have been shown to affect neuronal action potentials. This exploratory analysis provides preliminary data suggesting that KCNQ1 may contribute to the shared risk for diminished processing speed, diminished white mater integrity and increased risk of schizophrenia.
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: H A
authors.identifier: 0000-0001-5630-3041
authors.initials: HA
authors.lastname: Bruce
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: P
authors.initials: P
authors.lastname: Kochunov
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Cambridge, MA.
authors.forename: S A
authors.initials: SA
authors.lastname: Paciga
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Cambridge, MA.
authors.forename: C L
authors.initials: CL
authors.lastname: Hyde
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Cambridge, MA.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Cambridge, MA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Cambridge, MA.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Cambridge, MA.
authors.forename: H S
authors.initials: HS
authors.lastname: Xi
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Cambridge, MA.
authors.forename: P
authors.initials: P
authors.lastname: O'Donnell
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Cambridge, MA.
authors.forename: C
authors.initials: C
authors.lastname: Whelan
authors.affiliation: Biogen, Cambridge, MA.
authors.forename: C R
authors.initials: CR
authors.lastname: Schubert
authors.affiliation: Department of Psychiatry, Penn State Hershey Medical Center, Hershey, PA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bellon
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: S A
authors.initials: SA
authors.lastname: Ament
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: D K
authors.initials: DK
authors.lastname: Shukla
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: X
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: L M
authors.initials: LM
authors.lastname: Rowland
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: H
authors.initials: H
authors.lastname: O'Neill
authors.affiliation: Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.
authors.forename: L E
authors.initials: LE
authors.lastname: Hong
mesh_terms: D020413:3' Untranslated Regions; D000200:Action Potentials; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011930:Reaction Time; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D066127:White Matter / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D020413:3' Untranslated Regions; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human
keywords: Diffusion tensor imaging; GWAS; KCNQ1; endophenotype; fractional anisotropy; imaging genetics; potassium channels; processing speed; psychiatric genetics; white matter