Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder

T. G. Schulze; S. D. Detera-Wadleigh; N. Akula; A. Gupta; L. Kassem; J. Steele; J. Pearl; J. Strohmaier; R. Breuer; M. Schwarz; P. Propping; M. M. Nöthen; S. Cichon; J. Schumacher; M. Rietschel; F. J. McMahon

doi:10.1038/mp.2008.134

Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder

T. G. Schulze, S. D. Detera-Wadleigh, N. Akula, A. Gupta, L. Kassem, J. Steele, J. Pearl, J. Strohmaier, R. Breuer, M. Schwarz, P. Propping, M. M. Nöthen, S. Cichon, J. Schumacher, M. Rietschel, F. J. McMahon

Research output: Contribution to journal › Article › peer-review

133 Scopus citations

Abstract

Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1-4 (P0.05; odds ratio (OR)1.24) and German (P0.0006; OR1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P0.017; OR1.38). A random-effects meta-analysis of all three samples was significant (P3 × 10⁶; OR1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P0.0001; OR1.70), and similar ORs in the NIMH 1-4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P1.7 × 10 ⁵; OR1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.

Original language	English (US)
Pages (from-to)	487-491
Number of pages	5
Journal	Molecular psychiatry
Volume	14
Issue number	5
DOIs	https://doi.org/10.1038/mp.2008.134
State	Published - May 2009
Externally published	Yes

Keywords

Allelic heterogeneity
Ankyrins
Genome-wide association study
Interaction
Linkage disequilibrium
Manic depressive illness

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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10.1038/mp.2008.134

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Schulze, T. G., Detera-Wadleigh, S. D., Akula, N., Gupta, A., Kassem, L., Steele, J., Pearl, J., Strohmaier, J., Breuer, R., Schwarz, M., Propping, P., Nöthen, M. M., Cichon, S., Schumacher, J., Rietschel, M., & McMahon, F. J. (2009). Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder. Molecular psychiatry, 14(5), 487-491. https://doi.org/10.1038/mp.2008.134

Schulze, TG, Detera-Wadleigh, SD, Akula, N, Gupta, A, Kassem, L, Steele, J, Pearl, J, Strohmaier, J, Breuer, R, Schwarz, M, Propping, P, Nöthen, MM, Cichon, S, Schumacher, J, Rietschel, M & McMahon, FJ 2009, 'Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder', Molecular psychiatry, vol. 14, no. 5, pp. 487-491. https://doi.org/10.1038/mp.2008.134

@article{084280f981b1432aaa73d808cbbd86dc,

title = "Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder",

abstract = "Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1-4 (P0.05; odds ratio (OR)1.24) and German (P0.0006; OR1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P0.017; OR1.38). A random-effects meta-analysis of all three samples was significant (P3 × 106; OR1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P0.0001; OR1.70), and similar ORs in the NIMH 1-4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P1.7 × 10 5; OR1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.",

keywords = "Allelic heterogeneity, Ankyrins, Genome-wide association study, Interaction, Linkage disequilibrium, Manic depressive illness",

author = "Schulze, {T. G.} and Detera-Wadleigh, {S. D.} and N. Akula and A. Gupta and L. Kassem and J. Steele and J. Pearl and J. Strohmaier and R. Breuer and M. Schwarz and P. Propping and N{\"o}then, {M. M.} and S. Cichon and J. Schumacher and M. Rietschel and McMahon, {F. J.}",

note = "Funding Information: Supported by the NIMH Intramural Research Program, Deutsche Forschungsgemeinschaft, the National German Genome Research Network of the Federal Ministry of Education and Research, the National Alliance for Research on Schizophrenia and Depression (FJM, TGS), and the Alfried Krupp von Bohlen und Halbach-Stiftung. We thank the study participants who made this research possible. Data and biomaterials for the NIMH samples were collected as part of 10 projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991 to 1998, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, U01 MH46282—John Nurnberger, MD, PhD, Marvin Miller, MD and Elizabeth Bowman, MD; Washington University, St Louis, MO, U01 MH46280—Theodore Reich, MD, Allison Goate, PhD and John Rice, PhD; Johns Hopkins University, Baltimore, MD U01 MH46274—J Raymond DePaulo Jr, MD Sylvia Simpson, MD, MPH and Colin Stine, PhD; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD—Elliot Gershon, MD, Diane Kazuba, BA and Elizabeth Maxwell, MSW. From 1999 to 2003, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545—John Nurnberger, MD, PhD, Marvin J Miller, MD, Elizabeth S Bowman, MD, N Leela Rau, MD, P Ryan Moe, MD, Nalini Samavedy, MD, Rif El-Mallakh, MD (at University of Louisville), Husseini Manji, MD (at Wayne State University), Debra A Glitz, MD (at Wayne State University), Eric T Meyer, MS, Carrie Smiley, RN, Tatiana Foroud, PhD, Leah Flury, MS, Danielle M Dick, PhD and Howard Edenberg, PhD; Washington University, St Louis, MO, R01 MH059534, John Rice, PhD, Theodore Reich, MD, Allison Goate, PhD and Laura Bierut, MD; Johns Hopkins University, Baltimore, MD, R01 MH59533—Melvin McInnis, MD, J Raymond DePaulo Jr, MD, Dean F MacKinnon, MD, Francis M Mondi-more, MD, James B Potash, MD, Peter P Zandi, PhD, Dimitrios Avramopoulos and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553—Wade Berrettini, MD, PhD; University of California at Irvine, CA, R01 MH60068—William Byerley, MD and Mark Vawter, MD; University of Iowa, IA, R01 MH059548— William Coryell, MD and Raymond Crowe, MD; University of Chicago, IL, R01 MH59535—Elliot Gershon, MD, Judith Badner, PhD, Francis McMahon, MD, Chunyu Liu, PhD, Alan Sanders, MD, Maria Caserta, Steven Dinwiddie, MD, Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567—John Kelsoe, MD, Rebecca McKinney, BA; Rush University, IL, R01 MH059556—William Scheft-ner, MD, Howard M Kravitz, DO, MPH, Diana Marta, BA, Annette Vaughn-Brown, MSN, RN and Laurie Bederow, MA; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J McMahon, MD, Layla Kassem, PsyD, Sevilla Detera-Wadleigh, PhD, Lisa Austin, PhD, Dennis L Murphy, MD. The NIMH control subjects were collected by the NIMH Schizophrenia Genetics Initiative {\textquoteleft}Molecular Genetics of Schizophrenia II{\textquoteright} (MGS-2) collaboration. The investigators and coinvestigators are: ENH/North-western University, Evanston, IL, MH059571—Pablo V Gejman, MD (Collaboration Coordinator; PI), Alan R Sanders, MD; Emory University School of Medicine, Atlanta, GA, MH59587—Farooq Amin, MD (PI); Louisiana State University Health Sciences Center; New Orleans, LA, MH067257—Nancy Buccola APRN, BC, MSN (PI); University of California-Irvine, Irvine, CA, MH60870—William Byerley, MD (PI); Washington University, St Louis, MO, U01, MH060879—C Robert Cloninger, MD (PI); University of Iowa, Iowa, IA, MH59566—Raymond Crowe, MD (PI), Donald Black, MD; University of Colorado, Denver, CO, MH059565— Robert Freedman, MD (PI); University of Pennsylvania, Philadelphia, PA, MH061675—Douglas Levinson, MD (PI); University of Queensland, QLD, Australia, MH059588—Bryan Mowry, MD (PI); Mt Sinai School of Medicine, New York, NY, MH59586—Jeremy Silverman, PhD (PI). We thank the following clinician colleagues for help in collecting German patients: Margot Albus, Margitta Borrmann-Hassenbach, Ernst Franzek, J{\"u}rgen Fritze, Magdalena Gross, Thilo Held, Roland Kreiner, Mario Lanczik, Dirk Lichtermann, Wolfgang Maier, J{\"u}rgen Minges, Stephanie Ohlraun, Ulrike Reuner, Monja Tullius, Bettina Weigelt. We thank Jay Tischfield and Douglas Fugman of the Rutgers Cell and DNA Repository for banking blood samples and providing DNA for the NIMH collections.",

year = "2009",

month = may,

doi = "10.1038/mp.2008.134",

language = "English (US)",

volume = "14",

pages = "487--491",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "5",

}

TY - JOUR

T1 - Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder

AU - Schulze, T. G.

AU - Detera-Wadleigh, S. D.

AU - Akula, N.

AU - Gupta, A.

AU - Kassem, L.

AU - Steele, J.

AU - Pearl, J.

AU - Strohmaier, J.

AU - Breuer, R.

AU - Schwarz, M.

AU - Propping, P.

AU - Nöthen, M. M.

AU - Cichon, S.

AU - Schumacher, J.

AU - Rietschel, M.

AU - McMahon, F. J.

N1 - Funding Information: Supported by the NIMH Intramural Research Program, Deutsche Forschungsgemeinschaft, the National German Genome Research Network of the Federal Ministry of Education and Research, the National Alliance for Research on Schizophrenia and Depression (FJM, TGS), and the Alfried Krupp von Bohlen und Halbach-Stiftung. We thank the study participants who made this research possible. Data and biomaterials for the NIMH samples were collected as part of 10 projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991 to 1998, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, U01 MH46282—John Nurnberger, MD, PhD, Marvin Miller, MD and Elizabeth Bowman, MD; Washington University, St Louis, MO, U01 MH46280—Theodore Reich, MD, Allison Goate, PhD and John Rice, PhD; Johns Hopkins University, Baltimore, MD U01 MH46274—J Raymond DePaulo Jr, MD Sylvia Simpson, MD, MPH and Colin Stine, PhD; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD—Elliot Gershon, MD, Diane Kazuba, BA and Elizabeth Maxwell, MSW. From 1999 to 2003, the Principal Investigators and Co-Investigators were: Indiana University, Indianapolis, IN, R01 MH59545—John Nurnberger, MD, PhD, Marvin J Miller, MD, Elizabeth S Bowman, MD, N Leela Rau, MD, P Ryan Moe, MD, Nalini Samavedy, MD, Rif El-Mallakh, MD (at University of Louisville), Husseini Manji, MD (at Wayne State University), Debra A Glitz, MD (at Wayne State University), Eric T Meyer, MS, Carrie Smiley, RN, Tatiana Foroud, PhD, Leah Flury, MS, Danielle M Dick, PhD and Howard Edenberg, PhD; Washington University, St Louis, MO, R01 MH059534, John Rice, PhD, Theodore Reich, MD, Allison Goate, PhD and Laura Bierut, MD; Johns Hopkins University, Baltimore, MD, R01 MH59533—Melvin McInnis, MD, J Raymond DePaulo Jr, MD, Dean F MacKinnon, MD, Francis M Mondi-more, MD, James B Potash, MD, Peter P Zandi, PhD, Dimitrios Avramopoulos and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553—Wade Berrettini, MD, PhD; University of California at Irvine, CA, R01 MH60068—William Byerley, MD and Mark Vawter, MD; University of Iowa, IA, R01 MH059548— William Coryell, MD and Raymond Crowe, MD; University of Chicago, IL, R01 MH59535—Elliot Gershon, MD, Judith Badner, PhD, Francis McMahon, MD, Chunyu Liu, PhD, Alan Sanders, MD, Maria Caserta, Steven Dinwiddie, MD, Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567—John Kelsoe, MD, Rebecca McKinney, BA; Rush University, IL, R01 MH059556—William Scheft-ner, MD, Howard M Kravitz, DO, MPH, Diana Marta, BA, Annette Vaughn-Brown, MSN, RN and Laurie Bederow, MA; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J McMahon, MD, Layla Kassem, PsyD, Sevilla Detera-Wadleigh, PhD, Lisa Austin, PhD, Dennis L Murphy, MD. The NIMH control subjects were collected by the NIMH Schizophrenia Genetics Initiative ‘Molecular Genetics of Schizophrenia II’ (MGS-2) collaboration. The investigators and coinvestigators are: ENH/North-western University, Evanston, IL, MH059571—Pablo V Gejman, MD (Collaboration Coordinator; PI), Alan R Sanders, MD; Emory University School of Medicine, Atlanta, GA, MH59587—Farooq Amin, MD (PI); Louisiana State University Health Sciences Center; New Orleans, LA, MH067257—Nancy Buccola APRN, BC, MSN (PI); University of California-Irvine, Irvine, CA, MH60870—William Byerley, MD (PI); Washington University, St Louis, MO, U01, MH060879—C Robert Cloninger, MD (PI); University of Iowa, Iowa, IA, MH59566—Raymond Crowe, MD (PI), Donald Black, MD; University of Colorado, Denver, CO, MH059565— Robert Freedman, MD (PI); University of Pennsylvania, Philadelphia, PA, MH061675—Douglas Levinson, MD (PI); University of Queensland, QLD, Australia, MH059588—Bryan Mowry, MD (PI); Mt Sinai School of Medicine, New York, NY, MH59586—Jeremy Silverman, PhD (PI). We thank the following clinician colleagues for help in collecting German patients: Margot Albus, Margitta Borrmann-Hassenbach, Ernst Franzek, Jürgen Fritze, Magdalena Gross, Thilo Held, Roland Kreiner, Mario Lanczik, Dirk Lichtermann, Wolfgang Maier, Jürgen Minges, Stephanie Ohlraun, Ulrike Reuner, Monja Tullius, Bettina Weigelt. We thank Jay Tischfield and Douglas Fugman of the Rutgers Cell and DNA Repository for banking blood samples and providing DNA for the NIMH collections.

PY - 2009/5

Y1 - 2009/5

N2 - Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1-4 (P0.05; odds ratio (OR)1.24) and German (P0.0006; OR1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P0.017; OR1.38). A random-effects meta-analysis of all three samples was significant (P3 × 106; OR1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P0.0001; OR1.70), and similar ORs in the NIMH 1-4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P1.7 × 10 5; OR1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.

AB - Two recent reports have highlighted ANK3 as a susceptibility gene for bipolar disorder (BD). We first reported association between BD and the ANK3 marker rs9804190 in a genome-wide association study (GWAS) of two independent samples (Baum et al., 2008). Subsequently, a meta-analysis of GWAS data based on samples from the US and the UK reported association with a different ANK3 marker, rs10994336 (Ferreira et al., 2008). The markers lie about 340kb apart in the gene. Here, we test both markers in additional samples and characterize the contribution of each marker to BD risk. Our previously reported findings at rs9804190, which had been based on DNA pooling, were confirmed by individual genotyping in the National Institute of Mental Health (NIMH) waves 1-4 (P0.05; odds ratio (OR)1.24) and German (P0.0006; OR1.34) samples. This association was replicated in an independent US sample known as NIMH wave 5 (466 cases, 212 controls; P0.017; OR1.38). A random-effects meta-analysis of all three samples was significant (P3 × 106; OR1.32), with no heterogeneity. Individual genotyping of rs10994336 revealed a significant association in the German sample (P0.0001; OR1.70), and similar ORs in the NIMH 1-4 and NIMH 5 samples that were not significant at the P<0.05 level. Meta-analysis of all three samples supported an association with rs10994336 (P1.7 × 10 5; OR1.54), again with no heterogeneity. There was little linkage disequilibrium between the two markers. Further analysis suggested that each marker contributed independently to BD, with no significant marker × marker interaction. Our findings strongly support ANK3 as a BD susceptibility gene and suggest true allelic heterogeneity.

KW - Allelic heterogeneity

KW - Ankyrins

KW - Genome-wide association study

KW - Interaction

KW - Linkage disequilibrium

KW - Manic depressive illness

UR - http://www.scopus.com/inward/record.url?scp=67349153674&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67349153674&partnerID=8YFLogxK

U2 - 10.1038/mp.2008.134

DO - 10.1038/mp.2008.134

M3 - Article

C2 - 19088739

AN - SCOPUS:67349153674

SN - 1359-4184

VL - 14

SP - 487

EP - 491

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 5

ER -

Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder

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