Genome-wide association studies (GWAS) have implicated ANK3 as a susceptibility gene for bipolar disorder (BP). We examined whether epistasis with ANK3 may contribute to the “missing heritability” in BP. We first identified via the STRING database 14 genes encoding proteins with prior biological evidence that they interact molecularly with ANK3. We then tested for statistical evidence of interactions between SNPs in these genes in association with BP in a discovery GWAS dataset and two replication GWAS datasets. The most significant interaction in the discovery GWAS was between SNPs in ANK3 and KCNQ2 (p = 3.18 × 10−8). A total of 31 pair-wise interactions involving combinations between two SNPs from KCNQ2 and 16 different SNPs in ANK3 were significant after permutation. Of these, 28 pair-wise interactions were significant in the first replication GWAS. None were significant in the second replication GWAS, but the two SNPs from KCNQ2 were found to significantly interact with five other SNPs in ANK3, suggesting possible allelic heterogeneity. KCNQ2 forms homo- and hetero-meric complexes with KCNQ3 that constitute voltage-gated potassium channels in neurons. ANK3 is an adaptor protein that, through its interaction with KCNQ2 and KCNQ3, directs the localization of this channel in the axon initial segment (AIS). At the AIS, the KCNQ2/3 complex gives rise to the M-current, which stabilizes the neuronal resting potential and inhibits repetitive firing of action potentials. Thus, these channels act as “dampening” components and prevent neuronal hyperactivity. The interactions between ANK3 and KCNQ2 merit further investigation, and if confirmed, may motivate a new line of research into a novel therapeutic target for BP.
Keywords: epistasis, interaction, bipolar disorder, ANK3, KCNQ2, channelopathy, ion channel
Citation: Judy JT, Seifuddin F, Pirooznia M, Mahon PB, The Bipolar Genome Study Consortium, Jancic D, Goes FS, Schulze T, Cichon S, Noethen M, Rietschel M, DePaulo JR, Potash JB and Zandi PP (2013) Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder. Front. Genet. 4:87. doi: 10.3389/fgene.2013.00087
Received: 28 February 2013; Paper pending published: 22 March 2013;
Accepted: 25 April 2013; Published online: 17 May 2013.
Edited by:Kathleen D. Askland, Brown University, USA
Reviewed by:Radka Kaneva, Medical University – Sofia, Bulgaria
Copyright: © 2013 Judy, Seifuddin, Pirooznia, Mahon, The Bipolar Genome Study Consortium, Jancic, Goes, Schulze, Cichon, Noethen, Rietschel, DePaulo, Potash and Zandi. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Peter P. Zandi, Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Hampton House, Room 857, 624 North Broadway, Baltimore, MD 21205, USA. e-mail: firstname.lastname@example.org