title: A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder.
abstract: We conducted blinded psychiatric assessments of 26 Amish subjects (52 ± 11 years) from four families with prevalent bipolar spectrum disorder, identified 10 potentially pathogenic alleles by exome sequencing, tested association of these alleles with clinical diagnoses in the larger Amish Study of Major Affective Disorder (ASMAD) cohort, and studied mutant potassium channels in neurons. Fourteen of 26 Amish had bipolar spectrum disorder. The only candidate allele shared among them was rs78247304, a non-synonymous variant of KCNH7 (c.1181G>A, p.Arg394His). KCNH7 c.1181G>A and nine other potentially pathogenic variants were subsequently tested within the ASMAD cohort, which consisted of 340 subjects grouped into controls subjects and affected subjects from overlapping clinical categories (bipolar 1 disorder, bipolar spectrum disorder and any major affective disorder). KCNH7 c.1181G>A had the highest enrichment among individuals with bipolar spectrum disorder (χ(2) = 7.3) and the strongest family-based association with bipolar 1 (P = 0.021), bipolar spectrum (P = 0.031) and any major affective disorder (P = 0.016). In vitro, the p.Arg394His substitution allowed normal expression, trafficking, assembly and localization of HERG3/Kv11.3 channels, but altered the steady-state voltage dependence and kinetics of activation in neuronal cells. Although our genome-wide statistical results do not alone prove association, cumulative evidence from multiple independent sources (parallel genome-wide study cohorts, pharmacological studies of HERG-type potassium channels, electrophysiological data) implicates neuronal HERG3/Kv11.3 potassium channels in the pathophysiology of bipolar spectrum disorder. Such a finding, if corroborated by future studies, has implications for mental health services among the Amish, as well as development of drugs that specifically target HERG3/Kv11.3.
authors.affiliation: Clinic for Special Children, Strasburg, PA, USA, Franklin & Marshall College, Lancaster, PA, USA, Lancaster General Hospital, Lancaster, PA, USA, kstrauss@clinicforspecialchildren.org.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
authors.affiliation: Department of Psychiatry, Columbia University, New York, New York, USA.
authors.forename: Sander
authors.initials: S
authors.lastname: Markx
authors.affiliation: Department of Genetics, Perelman School of Medicine and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Georgi
authors.affiliation: Departments of Neuroscience, Psychiatry and Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.affiliation: Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA, USA and.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jinks
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
authors.affiliation: Department of Psychiatry, Columbia University, New York, New York, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: McDonald
authors.affiliation: Department of Psychiatry, Columbia University, New York, New York, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: First
authors.affiliation: Departments of Neuroscience, Psychiatry and Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York, USA.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Liu
authors.affiliation: Clinic for Special Children, Strasburg, PA, USA, Biological Foundations of Behavior Program, Franklin & Marshall College, Lancaster, PA, USA and.
authors.forename: Abigail R
authors.initials: AR
authors.lastname: Benkert
authors.affiliation: Clinic for Special Children, Strasburg, PA, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Heaps
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Yutao
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: Department of Genetics, Perelman School of Medicine and.
authors.forename: Maja
authors.initials: M
authors.lastname: Bucan
authors.affiliation: Clinic for Special Children, Strasburg, PA, USA, Franklin & Marshall College, Lancaster, PA, USA.
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
mesh_terms: D000328:Adult; D000368:Aged; D061365:Amish; D001120:Arginine / Q000235:genetics*; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D006639:Histidine / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C486376:KCNH7 protein, human; D006639:Histidine; D001120:Arginine