TY - JOUR
T1 - Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans
AU - Dao, David T.
AU - Mahon, Pamela Belmonte
AU - Cai, Xiang
AU - Kovacsics, Colleen E.
AU - Blackwell, Robert A.
AU - Arad, Michal
AU - Shi, Jianxin
AU - Zandi, Peter P.
AU - O'Donnell, Patricio
AU - Knowles, James A.
AU - Weissman, Myrna M.
AU - Coryell, William
AU - Scheftner, William A.
AU - Lawson, William B.
AU - Levinson, Douglas F.
AU - Thompson, Scott M.
AU - Potash, James B.
AU - Gould, Todd D.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants MH078151 (JAK), MH059542 (WC), MH059552 (JBP), MH061686 and K24MH64197 (DFL), MH059541 (WAS), and MH060912 (MMW).
Funding Information:
The Genetics of Recurrent Early-Onset Major Depression cell and data collections used in this study included contributions from Dr. George S. Zubenko and Dr. Wendy N. Zubenko, Department of Psychiatry, University of Pittsburgh School of Medicine, that were supported by R01 Grant MH60866 from the National Institute of Mental Health (NIMH) (GSZ, Principal Investigator [PI]). The NIMH Cell Repository at Rutgers University and the NIMH Center for Collaborative Genetic Studies on Mental Disorders made essential contributions to this project. Data and biomaterials were collected in six projects that participated in the NIMH Genetics of Recurrent Early-Onset Depression project. From 1999 to 2003, the principal investigators and co-investigators were New York State Psychiatric Institute, New York, New York, R01 MH060912, Myrna M. Weissman, Ph.D. and James K. Knowles, M.D., Ph.D.; University of Pittsburgh, Pittsburgh, Pennsylvania, R01 MH060866, George S. Zubenko, M.D., Ph.D. and Wendy N. Zubenko, Ed.D, R.N., C.S.; Johns Hopkins University, Baltimore, Maryland, R01 MH059552, J. Raymond DePaulo, M.D., Melvin G. McInnis, M.D., and Dean MacKinnon, M.D.; University of Pennsylvania, Philadelphia, Pennsylvania, RO1 MH61686, Douglas F. Levinson, M.D. (Genetics of Recurrent Early-Onset Depression coordinator), Madeleine M. Gladis, Ph.D., Kathleen Murphy-Eberenz, Ph.D., and Peter Holmans, Ph.D. (University of Wales College of Medicine). University of Iowa, Iowa City, Iowa, R01 MH059542, Raymond R. Crowe, M.D. and William H. Coryell, M.D.; Rush University Medical Center, Chicago, Illinois, R01 MH059541-05, William A. Scheftner, M.D., Rush-Presbyterian. 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, Indiana, U01 MH46282, John Nurnberger, M.D., Ph.D., Marvin Miller, M.D., and Elizabeth Bowman, M.D.; Washington University, St. Louis, Missouri, U01 MH46280, Theodore Reich, M.D., Allison Goate, Ph.D., and John Rice, Ph.D.; Johns Hopkins University, Baltimore, Maryland, U01 MH46274, J. Raymond DePaulo Jr, M.D., Sylvia Simpson, M.D., M.P.H., and Colin Stine, Ph.D.; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, Maryland, Elliot Gershon, M.D., Diane Kazuba, B.A., and Elizabeth Maxwell, M.S.W. From 1999 to 2003, the principal investigators and co-investigators were Indiana University, Indianapolis, Indiana, R01 MH59545, John Nurnberger, M.D., Ph.D., Marvin J. Miller, M.D., Elizabeth S. Bowman, M.D., N. Leela Rau, M.D., P. Ryan Moe, M.D., Nalini Samavedy, M.D., Rif El-Mallakh, M.D. (at University of Louisville), Husseini Manji, M.D. (at Wayne State University), Debra A Glitz, M.D. (at Wayne State University), Eric T Meyer, M.S., Carrie Smiley, R.N., Tatiana Foroud, Ph.D., Leah Flury, M.S., Danielle M. Dick, Ph.D., and Howard Edenburg, Ph.D.; Washington University, St. Louis, Missouri, R01 MH059534, John Rice, Ph.D., Theodore Reich, M.D., Allison Goate, Ph.D., and Laura Bierut, M.D.; Johns Hopkins University, Baltimore, Maryland, R01 MH59533, Melvin McInnis, M.D., J. Raymond DePaulo Jr, M.D., Dean F. MacKinnon, M.D., Francis M. Mondimore, M.D., James B. Potash, M.D., Peter P Zandi, Ph.D., Dimitrios Avramopoulos, and Jennifer Payne; University of Pennsylvania, Philadelphia, Pennsylvania, R01 MH59553, Wade Berrettini, M.D., Ph.D.; University of California, Irvine, Irvine, California, R01 MH60068, William Byerley, M.D. and Mark Vawter, M.D.; University of Iowa, Iowa City, Iowa, R01 MH059548, William Coryell, M.D. and Raymond Crowe, M.D.; University of Chicago, Chicago, Illinois, R01 MH59535, Elliot Gershon, M.D., Judith Badner, Ph.D., Francis McMahon, M.D., Chunyu Liu, Ph.D., Alan Sanders, M.D., Maria Caserta, Steven Dinwiddie, M.D., Tu Nguyen, and Donna Harakal; University of California, San Diego, La Jolla, California, R01 MH59567, John Kelsoe, M.D., Rebecca McKinney, B.A.; Rush University, Chicago, Illinois, R01 MH059556, William Scheftner, M.D., Howard M Kravitz, D.O., M.P.H., Diana Marta, B.A., Annette Vaughn-Brown, M.S.N., R.N., and Laurie Bederow, M.A.; NIMH Intramural Research Program, Bethesda, Maryland, 1Z01MH002810-01, Francis J McMahon, M.D., Layla Kassem, Psy.D., Sevilla Detera-Wadleigh, Ph.D., Lisa Austin, Ph.D., and Dennis L Murphy, M.D. Control subjects from the National Institute of Mental Health Schizophrenia Genetics Initiative, data, and biomaterials were collected by the Molecular Genetics of Schizophrenia II collaboration. The investigators and co-investigators are Evanston-Northwestern Hospital/Northwestern University, Evanston, Illinois, MH059571, Pablo V. Gejman, M.D. (Collaboration Coordinator; PI), and Alan R. Sanders, M.D.; Emory University School of Medicine, Atlanta, Georgia, MH59587, Farooq Amin, M.D. (PI); Louisiana State University Health Sciences Center, New Orleans, Louisiana, MH067257, Nancy Buccola A.P.R.N., B.C., M.S.N. (PI); University of California-Irvine, Irvine, California, MH60870, William Byerley, M.D. (PI); Washington University, St. Louis, Missouri, U01, MH060879, C. Robert Cloninger, M.D. (PI); University of Iowa, Iowa City, Iowa, MH59566, Raymond Crowe, M.D. (PI), and Donald Black, M.D.; University of Colorado, Denver, Colorado, MH059565, Robert Freedman, M.D. (PI); University of Pennsylvania, Philadelphia, Pennsylvania, MH061675, Douglas Levinson, M.D. (PI); University of Queensland, Queensland, Australia, MH059588, Bryan Mowry, M.D. (PI); Mt. Sinai School of Medicine, New York, New York, MH59586, Jeremy Silverman, Ph.D. (PI). Genome-wide single nucleotide polymorphism genotyping of the NIMH samples was performed through the Genetic Association Information Network under the direction of the Bipolar Genetics Studies Collaboration.
PY - 2010/11/1
Y1 - 2010/11/1
N2 - Background Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Cav1.2, with a bipolar disorder and depression diagnosis. Methods The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene × sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects). Results In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p = 1.4 × 10-4, 2.1 × 10 -4; pcorrected = .03, .04) and were consistent across two large datasets. Conclusions Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype.
AB - Background Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Cav1.2, with a bipolar disorder and depression diagnosis. Methods The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene × sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects). Results In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p = 1.4 × 10-4, 2.1 × 10 -4; pcorrected = .03, .04) and were consistent across two large datasets. Conclusions Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype.
KW - Animal model
KW - CACNA1C
KW - Ca1.2
KW - bipolar disorder
KW - gender
KW - major depression
KW - sex differences
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U2 - 10.1016/j.biopsych.2010.06.019
DO - 10.1016/j.biopsych.2010.06.019
M3 - Article
C2 - 20723887
AN - SCOPUS:77957900975
SN - 0006-3223
VL - 68
SP - 801
EP - 810
JO - Biological psychiatry
JF - Biological psychiatry
IS - 9
ER -