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TitleA population-based study of KCNH7 p.Arg394His and bipolar spectrum disorder.
Publication TypeJournal Article
Year of Publication2014
AuthorsStrauss 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, Bućan M, Puffenberger EG
JournalHum Mol Genet
Volume23
Issue23
Pagination6395-406
Date Published2014 Dec 1
ISSN1460-2083
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.

DOI10.1093/hmg/ddu335
Alternate JournalHum. Mol. Genet.
PubMed ID24986916
PubMed Central IDPMC4222358
Grant List52006294 / / Howard Hughes Medical Institute / United States
52007538 / / Howard Hughes Medical Institute / United States
R01 GM057654 / GM / NIGMS NIH HHS / United States
R01-GM-057654 / GM / NIGMS NIH HHS / United States
R01-MH-093415-02 / MH / NIMH NIH HHS / United States