Skip to main content
construction release_alert
Scholars@Duke will be undergoing maintenance April 11-15. Some features may be unavailable during this time.
cancel
Journal cover image

A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder.

Publication ,  Journal Article
Strauss, KA; Markx, S; Georgi, B; Paul, SM; Jinks, RN; Hoshi, T; McDonald, A; First, MB; Liu, W; Benkert, AR; Heaps, AD; Tian, Y; Bucan, M ...
Published in: Human molecular genetics
December 2014

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Human molecular genetics

DOI

EISSN

1460-2083

ISSN

0964-6906

Publication Date

December 2014

Volume

23

Issue

23

Start / End Page

6395 / 6406

Related Subject Headings

  • Neurons
  • Middle Aged
  • Male
  • Humans
  • Histidine
  • Genetics & Heredity
  • Genetic Association Studies
  • Female
  • Ether-A-Go-Go Potassium Channels
  • Cohort Studies
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Strauss, K. A., Markx, S., Georgi, B., Paul, S. M., Jinks, R. N., Hoshi, T., … Puffenberger, E. G. (2014). A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder. Human Molecular Genetics, 23(23), 6395–6406. https://doi.org/10.1093/hmg/ddu335
Strauss, Kevin A., Sander Markx, Benjamin Georgi, Steven M. Paul, Robert N. Jinks, Toshinori Hoshi, Ann McDonald, et al. “A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder.Human Molecular Genetics 23, no. 23 (December 2014): 6395–6406. https://doi.org/10.1093/hmg/ddu335.
Strauss KA, Markx S, Georgi B, Paul SM, Jinks RN, Hoshi T, et al. A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder. Human molecular genetics. 2014 Dec;23(23):6395–406.
Strauss, Kevin A., et al. “A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder.Human Molecular Genetics, vol. 23, no. 23, Dec. 2014, pp. 6395–406. Epmc, doi:10.1093/hmg/ddu335.
Strauss KA, Markx S, Georgi B, Paul SM, Jinks RN, Hoshi T, McDonald A, First MB, Liu W, Benkert AR, Heaps AD, Tian Y, Chakravarti A, Bucan M, Puffenberger EG. A population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder. Human molecular genetics. 2014 Dec;23(23):6395–6406.
Journal cover image

Published In

Human molecular genetics

DOI

EISSN

1460-2083

ISSN

0964-6906

Publication Date

December 2014

Volume

23

Issue

23

Start / End Page

6395 / 6406

Related Subject Headings

  • Neurons
  • Middle Aged
  • Male
  • Humans
  • Histidine
  • Genetics & Heredity
  • Genetic Association Studies
  • Female
  • Ether-A-Go-Go Potassium Channels
  • Cohort Studies