Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder
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 evide...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2013-05-01
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| Series: | Frontiers in Genetics |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fgene.2013.00087/full |
| _version_ | 1818622736598040576 |
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| author | Jennifer Toolan Judy Fayaz eSeifuddin Mehdi ePirooznia Pamela Belmonte Mahon Fernando S. Goes Dubravka eJancic Thomas eSchultze Thomas eSchultze Sven eCichon Markus M Nöthen Marcella eRietschel Bipolar Genome Study e(BiGS) Consortium J. Raymond eDePaulo James B. Potash Peter P. Zandi Peter P. Zandi |
| author_facet | Jennifer Toolan Judy Fayaz eSeifuddin Mehdi ePirooznia Pamela Belmonte Mahon Fernando S. Goes Dubravka eJancic Thomas eSchultze Thomas eSchultze Sven eCichon Markus M Nöthen Marcella eRietschel Bipolar Genome Study e(BiGS) Consortium J. Raymond eDePaulo James B. Potash Peter P. Zandi Peter P. Zandi |
| author_sort | Jennifer Toolan Judy |
| collection | DOAJ |
| description | 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 x 10-8). A total of 31 pairwise interactions involving combinations between two SNPs from KCNQ2 and 16 different SNPs in ANK3 were significant after permutation. Of these, 28 pairwise 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 5 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. |
| first_indexed | 2024-12-16T18:29:55Z |
| format | Article |
| id | doaj.art-5df6cecb86a24930bddd685726e668b2 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-16T18:29:55Z |
| publishDate | 2013-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj.art-5df6cecb86a24930bddd685726e668b22022-12-21T22:21:19ZengFrontiers Media S.A.Frontiers in Genetics1664-80212013-05-01410.3389/fgene.2013.0008748273Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorderJennifer Toolan Judy0Fayaz eSeifuddin1Mehdi ePirooznia2Pamela Belmonte Mahon3Fernando S. Goes4Dubravka eJancic5Thomas eSchultze6Thomas eSchultze7Sven eCichon8Markus M Nöthen9Marcella eRietschel10Bipolar Genome Study e(BiGS) Consortium11J. Raymond eDePaulo12James B. Potash13Peter P. Zandi14Peter P. Zandi15Johns Hopkins UniversityJohns Hopkins UniversityJohns Hopkins UniversityJohns Hopkins UniversityJohns Hopkins UniversityUniversity of Iowa Hospitals & ClinicsUniversity of HeidelbergNational Institute of HealthUniversity of BonnUniversity of BonnUniversity of HeidelbergBiGS ConsortiumJohns Hopkins UniversityUniversity of Iowa Hospitals & ClinicsJohns Hopkins UniversityJohns Hopkins Bloomberg School of Public HealthGenome-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 x 10-8). A total of 31 pairwise interactions involving combinations between two SNPs from KCNQ2 and 16 different SNPs in ANK3 were significant after permutation. Of these, 28 pairwise 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 5 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.http://journal.frontiersin.org/Journal/10.3389/fgene.2013.00087/fullBipolar DisorderInteractionion channelEpistasisANK3KCNQ2 |
| spellingShingle | Jennifer Toolan Judy Fayaz eSeifuddin Mehdi ePirooznia Pamela Belmonte Mahon Fernando S. Goes Dubravka eJancic Thomas eSchultze Thomas eSchultze Sven eCichon Markus M Nöthen Marcella eRietschel Bipolar Genome Study e(BiGS) Consortium J. Raymond eDePaulo James B. Potash Peter P. Zandi Peter P. Zandi Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder Frontiers in Genetics Bipolar Disorder Interaction ion channel Epistasis ANK3 KCNQ2 |
| title | Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder |
| title_full | Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder |
| title_fullStr | Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder |
| title_full_unstemmed | Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder |
| title_short | Converging evidence for epistasis between ANK3 and potassium channel gene KCNQ2 in bipolar disorder |
| title_sort | converging evidence for epistasis between ank3 and potassium channel gene kcnq2 in bipolar disorder |
| topic | Bipolar Disorder Interaction ion channel Epistasis ANK3 KCNQ2 |
| url | http://journal.frontiersin.org/Journal/10.3389/fgene.2013.00087/full |
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