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

Area of Science:

• Genetics
• Neuroscience
• Psychiatry

Background:

• Bipolar spectrum disorder (BSD) has a complex genetic component.
• Previous studies suggest ion channel dysfunction may play a role in BSD pathophysiology.

Purpose of the Study:

• To investigate genetic associations with bipolar spectrum disorder in Amish families.
• To identify specific gene variants and their functional impact on neuronal channels.

Main Methods:

• Exome sequencing in affected Amish families.
• Genome-wide association study (GWAS) in the Amish Study of Major Affective Disorder (ASMAD) cohort.
• In vitro electrophysiological studies of mutant potassium channels.

Main Results:

• A non-synonymous KCNH7 variant (rs78247304, p.Arg394His) showed significant association with bipolar spectrum disorder.
• The p.Arg394His substitution altered the activation kinetics of HERG3/Kv11.3 potassium channels in neuronal cells.
• Cumulative evidence implicates neuronal HERG3/Kv11.3 channels in BSD pathophysiology.

Conclusions:

• The KCNH7 gene and HERG3/Kv11.3 potassium channels are implicated in the pathophysiology of bipolar spectrum disorder.
• These findings may inform targeted drug development and mental health services for affected populations.