A novel variant in the HERG3 voltage-gated potassium ion channel gene (KCNH7) is associated with bipolar spectrum disorder among the Old Order Amish. A. R. Benkert1,2, E. G. Puffenberger1,2, S. Markx3, S. M. Paul4, R. N. Jinks2, B. Georgi5, T. Hoshi6, A. McDonald3, M. B. First3, W. Liu4, A. Heaps1, Y. Tian6, A. Chakravarti7, D. H. Morton1,2,8, M. Bucan5, K. A. Strauss1,2,8 1) Clinic for Special Children, Strasburg, PA; 2) Franklin & Marshall College, Lancaster, PA; 3) Dept. of Psychiatry, Columbia University, New York, NY; 4) Depts. of Neuroscience, Psychiatry, and Pharmacology, Weil Cornell Medical College of Cornell University, New York, NY; 5) Dept. of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 6) Dept. of Physiology, University of Pennsylvania, Philadelphia, PA; 7) Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; 8) Lancaster General Hospital, Lancaster, PA.

   To identify genetic variants associated with bipolar spectrum disorder among the Pennsylvania Amish, we conducted blinded psychiatric assessments of 26 Amish subjects from four families. Potentially pathogenic variants were identified by whole exome sequencing and tested for association with psychiatric phenotypes within the larger Amish Study of Major Affective Disorder (ASMAD, N=394) (Am J Psychiatry 140:56). Fourteen of 26 Amish subjects had bipolar spectrum disorder. The only rare allele shared among all of them was a missense variant in KCNH7 c.1181GA (p.Arg394His), which we predicted to be pathogenic based on conservation, control allele frequencies, and in silico modeling. Ten rare variants with potentially high pathogenicity were subsequently tested within the ASMAD cohort (N=394); KCNH7 c.1181GA had the highest enrichment among individuals with bipolar spectrum disorder 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). KCNH7 (HERG3/Kv11.3) wild-type and Arg394His voltage-gated potassium ion channels were studied using immunofluorescence, western blotting, and patch-clamp electrophysiology. Heterologously expressed KCNH7 Arg394His channel subunits traffic normally to the plasma membrane in neuroblastoma cells in vitro without loss of abundance relative to wild-type HERG3 subunits. However, the histidine substitution at the highly conserved N-terminal cytoplasmic arginine394 shifts voltage dependent channel activation in the positive direction, slows activation kinetics, and is predicted to increase neuronal excitability in vivo. Penetrance and severity of mental illness were similar among KCNH7 c.1181GA heterozygotes and homozygotes. This may reflect the heterotetrameric nature of ERG channels and/or a high degree of potassium channel redundancy in the nervous system that attenuates the biological impact of modest functional abnormalities of any one channel subunit. The novel KCNH7 c.1181GA missense variant alters the electrophysiological properties of voltage-gated HERG3/Kv11.3 potassium ion channels and may be a specific risk allele for bipolar spectrum disorder among the Pennsylvania Amish.

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