Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

A. W. Charney; D. M. Ruderfer; E. A. Stahl; J. L. Moran; K. Chambert; R. A. Belliveau; L. Forty; K. Gordon-Smith; A. Di Florio; P. H. Lee; E. J. Bromet; Peter F Buckley; M. A. Escamilla; A. H. Fanous; L. J. Fochtmann; D. S. Lehrer; D. Malaspina; S. R. Marder; C. P. Morley; H. Nicolini; D. O. Perkins; J. J. Rakofsky; M. H. Rapaport; H. Medeiros; J. L. Sobell; E. K. Green; L. Backlund; S. E. Bergen; A. Juréus; M. Schalling; P. Lichtenstein; P. Roussos; J. A. Knowles; I. Jones; L. A. Jones; C. M. Hultman; R. H. Perlis; S. M. Purcell; S. A. McCarroll; C. N. Pato; M. T. Pato; N. Craddock; M. Landén; J. W. Smoller; P. Sklar

doi:10.1038/tp.2016.242

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

A. W. Charney, D. M. Ruderfer, E. A. Stahl, J. L. Moran, K. Chambert, R. A. Belliveau, L. Forty, K. Gordon-Smith, A. Di Florio, P. H. Lee, E. J. Bromet, Peter F Buckley, M. A. Escamilla, A. H. Fanous, L. J. Fochtmann, D. S. Lehrer, D. Malaspina, S. R. Marder, C. P. Morley, H. NicoliniD. O. Perkins, J. J. Rakofsky, M. H. Rapaport, H. Medeiros, J. L. Sobell, E. K. Green, L. Backlund, S. E. Bergen, A. Juréus, M. Schalling, P. Lichtenstein, P. Roussos, J. A. Knowles, I. Jones, L. A. Jones, C. M. Hultman, R. H. Perlis, S. M. Purcell, S. A. McCarroll, C. N. Pato, M. T. Pato, N. Craddock, M. Landén, J. W. Smoller, P. Sklar

Graduate Studies

Research output: Contribution to journal › Article

62 Scopus citations

Abstract

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P = 3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2 = 0.35; BD II SNP-h2 = 0.25; P = 0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Original language	English (US)
Article number	e993
Journal	Translational Psychiatry
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/tp.2016.242
State	Published - 2017

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Biological Psychiatry

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Charney, A. W., Ruderfer, D. M., Stahl, E. A., Moran, J. L., Chambert, K., Belliveau, R. A., Forty, L., Gordon-Smith, K., Di Florio, A., Lee, P. H., Bromet, E. J., Buckley, P. F., Escamilla, M. A., Fanous, A. H., Fochtmann, L. J., Lehrer, D. S., Malaspina, D., Marder, S. R., Morley, C. P., ... Sklar, P. (2017). Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. Translational Psychiatry, 7(1), [e993]. https://doi.org/10.1038/tp.2016.242

Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. / Charney, A. W.; Ruderfer, D. M.; Stahl, E. A.; Moran, J. L.; Chambert, K.; Belliveau, R. A.; Forty, L.; Gordon-Smith, K.; Di Florio, A.; Lee, P. H.; Bromet, E. J.; Buckley, Peter F; Escamilla, M. A.; Fanous, A. H.; Fochtmann, L. J.; Lehrer, D. S.; Malaspina, D.; Marder, S. R.; Morley, C. P.; Nicolini, H.; Perkins, D. O.; Rakofsky, J. J.; Rapaport, M. H.; Medeiros, H.; Sobell, J. L.; Green, E. K.; Backlund, L.; Bergen, S. E.; Juréus, A.; Schalling, M.; Lichtenstein, P.; Roussos, P.; Knowles, J. A.; Jones, I.; Jones, L. A.; Hultman, C. M.; Perlis, R. H.; Purcell, S. M.; McCarroll, S. A.; Pato, C. N.; Pato, M. T.; Craddock, N.; Landén, M.; Smoller, J. W.; Sklar, P.

In: Translational Psychiatry, Vol. 7, No. 1, e993, 2017.

Research output: Contribution to journal › Article

Charney, AW, Ruderfer, DM, Stahl, EA, Moran, JL, Chambert, K, Belliveau, RA, Forty, L, Gordon-Smith, K, Di Florio, A, Lee, PH, Bromet, EJ, Buckley, PF, Escamilla, MA, Fanous, AH, Fochtmann, LJ, Lehrer, DS, Malaspina, D, Marder, SR, Morley, CP, Nicolini, H, Perkins, DO, Rakofsky, JJ, Rapaport, MH, Medeiros, H, Sobell, JL, Green, EK, Backlund, L, Bergen, SE, Juréus, A, Schalling, M, Lichtenstein, P, Roussos, P, Knowles, JA, Jones, I, Jones, LA, Hultman, CM, Perlis, RH, Purcell, SM, McCarroll, SA, Pato, CN, Pato, MT, Craddock, N, Landén, M, Smoller, JW & Sklar, P 2017, 'Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder', Translational Psychiatry, vol. 7, no. 1, e993. https://doi.org/10.1038/tp.2016.242

Charney, A. W. ; Ruderfer, D. M. ; Stahl, E. A. ; Moran, J. L. ; Chambert, K. ; Belliveau, R. A. ; Forty, L. ; Gordon-Smith, K. ; Di Florio, A. ; Lee, P. H. ; Bromet, E. J. ; Buckley, Peter F ; Escamilla, M. A. ; Fanous, A. H. ; Fochtmann, L. J. ; Lehrer, D. S. ; Malaspina, D. ; Marder, S. R. ; Morley, C. P. ; Nicolini, H. ; Perkins, D. O. ; Rakofsky, J. J. ; Rapaport, M. H. ; Medeiros, H. ; Sobell, J. L. ; Green, E. K. ; Backlund, L. ; Bergen, S. E. ; Juréus, A. ; Schalling, M. ; Lichtenstein, P. ; Roussos, P. ; Knowles, J. A. ; Jones, I. ; Jones, L. A. ; Hultman, C. M. ; Perlis, R. H. ; Purcell, S. M. ; McCarroll, S. A. ; Pato, C. N. ; Pato, M. T. ; Craddock, N. ; Landén, M. ; Smoller, J. W. ; Sklar, P. / Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder. In: Translational Psychiatry. 2017 ; Vol. 7, No. 1.

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abstract = "We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P = 3.28 × 10-8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-h2 = 0.35; BD II SNP-h2 = 0.25; P = 0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.",

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AU - Charney, A. W.

AU - Ruderfer, D. M.

AU - Stahl, E. A.

AU - Moran, J. L.

AU - Chambert, K.

AU - Belliveau, R. A.

AU - Forty, L.

AU - Gordon-Smith, K.

AU - Di Florio, A.

AU - Lee, P. H.

AU - Bromet, E. J.

AU - Buckley, Peter F

AU - Escamilla, M. A.

AU - Fanous, A. H.

AU - Fochtmann, L. J.

AU - Lehrer, D. S.

AU - Malaspina, D.

AU - Marder, S. R.

AU - Morley, C. P.

AU - Nicolini, H.

AU - Perkins, D. O.

AU - Rakofsky, J. J.

AU - Rapaport, M. H.

AU - Medeiros, H.

AU - Sobell, J. L.

AU - Green, E. K.

AU - Backlund, L.

AU - Bergen, S. E.

AU - Juréus, A.

AU - Schalling, M.

AU - Lichtenstein, P.

AU - Roussos, P.

AU - Knowles, J. A.

AU - Jones, I.

AU - Jones, L. A.

AU - Hultman, C. M.

AU - Perlis, R. H.

AU - Purcell, S. M.

AU - McCarroll, S. A.

AU - Pato, C. N.

AU - Pato, M. T.

AU - Craddock, N.

AU - Landén, M.

AU - Smoller, J. W.

AU - Sklar, P.

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