Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases

Alexander W. Charney; Eli A. Stahl; Elaine K. Green; Chia Yen Chen; Jennifer L. Moran; Kimberly Chambert; Richard A. Belliveau; Liz Forty; Katherine Gordon-Smith; Phil H. Lee; Evelyn J. Bromet; Peter F. Buckley; Michael A. Escamilla; Ayman H. Fanous; Laura J. Fochtmann; Douglas S. Lehrer; Dolores Malaspina; Stephen R. Marder; Christopher P. Morley; Humberto Nicolini; Diana O. Perkins; Jeffrey J. Rakofsky; Mark H. Rapaport; Helena Medeiros; Janet L. Sobell; Lena Backlund; Sarah E. Bergen; Anders Juréus; Martin Schalling; Paul Lichtenstein; James A. Knowles; Katherine E. Burdick; Ian Jones; Lisa A. Jones; Christina M. Hultman; Roy Perlis; Shaun M. Purcell; Steven A. McCarroll; Carlos N. Pato; Michele T. Pato; Ariana Di Florio; Nick Craddock; Mikael Landén; Jordan W. Smoller; Douglas M. Ruderfer; Pamela Sklar

doi:10.1016/j.biopsych.2018.12.009

Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases

Alexander W. Charney, Eli A. Stahl, Elaine K. Green, Chia Yen Chen, Jennifer L. Moran, Kimberly Chambert, Richard A. Belliveau, Liz Forty, Katherine Gordon-Smith, Phil H. Lee, Evelyn J. Bromet, Peter F. Buckley, Michael A. Escamilla, Ayman H. Fanous, Laura J. Fochtmann, Douglas S. Lehrer, Dolores Malaspina, Stephen R. Marder, Christopher P. Morley, Humberto NicoliniDiana O. Perkins, Jeffrey J. Rakofsky, Mark H. Rapaport, Helena Medeiros, Janet L. Sobell, Lena Backlund, Sarah E. Bergen, Anders Juréus, Martin Schalling, Paul Lichtenstein, James A. Knowles, Katherine E. Burdick, Ian Jones, Lisa A. Jones, Christina M. Hultman, Roy Perlis, Shaun M. Purcell, Steven A. McCarroll, Carlos N. Pato, Michele T. Pato, Ariana Di Florio, Nick Craddock, Mikael Landén, Jordan W. Smoller, Douglas M. Ruderfer, Pamela Sklar

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

31 Scopus citations

Abstract

Background: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. Methods: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. Results: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10⁻⁵). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. Conclusions: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

Original language	English (US)
Pages (from-to)	110-119
Number of pages	10
Journal	Biological Psychiatry
Volume	86
Issue number	2
DOIs	https://doi.org/10.1016/j.biopsych.2018.12.009
State	Published - Jul 15 2019
Externally published	Yes

Keywords

Bipolar disorder
Copy number variant
Genetics
Polygenic risk score
Rare variant burden
Schizophrenia

ASJC Scopus subject areas

Biological Psychiatry

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10.1016/j.biopsych.2018.12.009

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Charney, A. W., Stahl, E. A., Green, E. K., Chen, C. Y., Moran, J. L., Chambert, K., Belliveau, R. A., Forty, L., Gordon-Smith, K., 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. (2019). Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases. Biological Psychiatry, 86(2), 110-119. https://doi.org/10.1016/j.biopsych.2018.12.009

Charney, AW, Stahl, EA, Green, EK, Chen, CY, Moran, JL, Chambert, K, Belliveau, RA, Forty, L, Gordon-Smith, K, 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, Backlund, L, Bergen, SE, Juréus, A, Schalling, M, Lichtenstein, P, Knowles, JA, Burdick, KE, Jones, I, Jones, LA, Hultman, CM, Perlis, R, Purcell, SM, McCarroll, SA, Pato, CN, Pato, MT, Di Florio, A, Craddock, N, Landén, M, Smoller, JW, Ruderfer, DM & Sklar, P 2019, 'Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases', Biological Psychiatry, vol. 86, no. 2, pp. 110-119. https://doi.org/10.1016/j.biopsych.2018.12.009

@article{ff8fcde5287c45a8a744799f3b77b35d,

title = "Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases",

abstract = "Background: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. Methods: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. Results: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10−5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. Conclusions: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.",

keywords = "Bipolar disorder, Copy number variant, Genetics, Polygenic risk score, Rare variant burden, Schizophrenia",

author = "Charney, {Alexander W.} and Stahl, {Eli A.} and Green, {Elaine K.} and Chen, {Chia Yen} and Moran, {Jennifer L.} and Kimberly Chambert and Belliveau, {Richard A.} and Liz Forty and Katherine Gordon-Smith and Lee, {Phil H.} and Bromet, {Evelyn J.} and Buckley, {Peter F.} and Escamilla, {Michael A.} and Fanous, {Ayman H.} and Fochtmann, {Laura J.} and Lehrer, {Douglas S.} and Dolores Malaspina and Marder, {Stephen R.} and Morley, {Christopher P.} and Humberto Nicolini and Perkins, {Diana O.} and Rakofsky, {Jeffrey J.} and Rapaport, {Mark H.} and Helena Medeiros and Sobell, {Janet L.} and Lena Backlund and Bergen, {Sarah E.} and Anders Jur{\'e}us and Martin Schalling and Paul Lichtenstein and Knowles, {James A.} and Burdick, {Katherine E.} and Ian Jones and Jones, {Lisa A.} and Hultman, {Christina M.} and Roy Perlis and Purcell, {Shaun M.} and McCarroll, {Steven A.} and Pato, {Carlos N.} and Pato, {Michele T.} and {Di Florio}, Ariana and Nick Craddock and Mikael Land{\'e}n and Smoller, {Jordan W.} and Ruderfer, {Douglas M.} and Pamela Sklar",

note = "Funding Information: This work was supported by National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) Grant No. R01MH085542 (to AWC, JWS, and PS), NIH/NIMH Grant No. R01 MH106547 (to JWS, PS, and SAM), NIH/NIMH Grant No. R01MH085548 (to AHF, CNP, CPM, DM, DOP, DSL, EJB, HM, HN, JAK, JJR, JLS, LJF, MAE, MHR, MTP, PFB, and SRM), NIH/NIMH Grant No. K99MH101367 (to PHL), the Stanley Medical Research Institute (to JLM, KC, RAB, and SAM), philanthropic gifts from Kent and Elizabeth Dauten and Ted and Vada Stanley (to JLM, KC, RAB, and SAM), Swedish Research Council Grant No. 2013-3196 (to CMH), Swedish Medical Research Council Grant Nos. K2014-62X-14647-12-51 and K2010-61P-21568-01-4 (to ML), Swedish Foundation for Strategic Research Grant No. KF10-0039 (to ML), Swedish Federal Government under the LUA/ALF agreement Grant Nos. ALF 20130032 and ALFGBG-142041 (to ML), a European Commission–Marie Curie Fellowship (to AD), and Wellcome Trust (to IJ, KG-S, LAJ, LF, and NC). JWS is a Tepper Family MGH (Massachusetts General Hospital) Research Scholar. Work at the Icahn School of Medicine at Mount Sinai was also supported by the Institute for Genomics and Multiscale Biology and the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The funders had no role in study design, execution, analysis, or manuscript preparation. Funding Information: This work was supported by National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) Grant No. R01MH085542 (to AWC, JWS, and PS), NIH/NIMH Grant No. R01 MH106547 (to JWS, PS, and SAM), NIH/NIMH Grant No. R01MH085548 (to AHF, CNP, CPM, DM, DOP, DSL, EJB, HM, HN, JAK, JJR, JLS, LJF, MAE, MHR, MTP, PFB, and SRM), NIH/NIMH Grant No. K99MH101367 (to PHL), the Stanley Medical Research Institute (to JLM, KC, RAB, and SAM), philanthropic gifts from Kent and Elizabeth Dauten and Ted and Vada Stanley (to JLM, KC, RAB, and SAM), Swedish Research Council Grant No. 2013-3196 (to CMH), Swedish Medical Research Council Grant Nos. K2014-62X-14647-12-51 and K2010-61P-21568-01-4 (to ML), Swedish Foundation for Strategic Research Grant No. KF10-0039 (to ML), Swedish Federal Government under the LUA/ALF agreement Grant Nos. ALF 20130032 and ALFGBG-142041 (to ML), a European Commission–Marie Curie Fellowship (to AD), and Wellcome Trust (to IJ, KG-S, LAJ, LF, and NC). JWS is a Tepper Family MGH (Massachusetts General Hospital) Research Scholar. Work at the Icahn School of Medicine at Mount Sinai was also supported by the Institute for Genomics and Multiscale Biology and the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The funders had no role in study design, execution, analysis, or manuscript preparation. We are grateful for the participation of all subjects contributing to this research and to the collection team that worked to recruit them. Pamela Sklar, who led this work, passed away on November 20, 2017. We dedicate this publication to her. JWS is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. JWS reports no other biomedical financial interests or potential conflicts of interest. The other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2019 Society of Biological Psychiatry",

year = "2019",

month = jul,

day = "15",

doi = "10.1016/j.biopsych.2018.12.009",

language = "English (US)",

volume = "86",

pages = "110--119",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "2",

}

TY - JOUR

T1 - Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases

AU - Charney, Alexander W.

AU - Stahl, Eli A.

AU - Green, Elaine K.

AU - Chen, Chia Yen

AU - Moran, Jennifer L.

AU - Chambert, Kimberly

AU - Belliveau, Richard A.

AU - Forty, Liz

AU - Gordon-Smith, Katherine

AU - Lee, Phil H.

AU - Bromet, Evelyn J.

AU - Buckley, Peter F.

AU - Escamilla, Michael A.

AU - Fanous, Ayman H.

AU - Fochtmann, Laura J.

AU - Lehrer, Douglas S.

AU - Malaspina, Dolores

AU - Marder, Stephen R.

AU - Morley, Christopher P.

AU - Nicolini, Humberto

AU - Perkins, Diana O.

AU - Rakofsky, Jeffrey J.

AU - Rapaport, Mark H.

AU - Medeiros, Helena

AU - Sobell, Janet L.

AU - Backlund, Lena

AU - Bergen, Sarah E.

AU - Juréus, Anders

AU - Schalling, Martin

AU - Lichtenstein, Paul

AU - Knowles, James A.

AU - Burdick, Katherine E.

AU - Jones, Ian

AU - Jones, Lisa A.

AU - Hultman, Christina M.

AU - Perlis, Roy

AU - Purcell, Shaun M.

AU - McCarroll, Steven A.

AU - Pato, Carlos N.

AU - Pato, Michele T.

AU - Di Florio, Ariana

AU - Craddock, Nick

AU - Landén, Mikael

AU - Smoller, Jordan W.

AU - Ruderfer, Douglas M.

AU - Sklar, Pamela

N1 - Funding Information: This work was supported by National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) Grant No. R01MH085542 (to AWC, JWS, and PS), NIH/NIMH Grant No. R01 MH106547 (to JWS, PS, and SAM), NIH/NIMH Grant No. R01MH085548 (to AHF, CNP, CPM, DM, DOP, DSL, EJB, HM, HN, JAK, JJR, JLS, LJF, MAE, MHR, MTP, PFB, and SRM), NIH/NIMH Grant No. K99MH101367 (to PHL), the Stanley Medical Research Institute (to JLM, KC, RAB, and SAM), philanthropic gifts from Kent and Elizabeth Dauten and Ted and Vada Stanley (to JLM, KC, RAB, and SAM), Swedish Research Council Grant No. 2013-3196 (to CMH), Swedish Medical Research Council Grant Nos. K2014-62X-14647-12-51 and K2010-61P-21568-01-4 (to ML), Swedish Foundation for Strategic Research Grant No. KF10-0039 (to ML), Swedish Federal Government under the LUA/ALF agreement Grant Nos. ALF 20130032 and ALFGBG-142041 (to ML), a European Commission–Marie Curie Fellowship (to AD), and Wellcome Trust (to IJ, KG-S, LAJ, LF, and NC). JWS is a Tepper Family MGH (Massachusetts General Hospital) Research Scholar. Work at the Icahn School of Medicine at Mount Sinai was also supported by the Institute for Genomics and Multiscale Biology and the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The funders had no role in study design, execution, analysis, or manuscript preparation. Funding Information: This work was supported by National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) Grant No. R01MH085542 (to AWC, JWS, and PS), NIH/NIMH Grant No. R01 MH106547 (to JWS, PS, and SAM), NIH/NIMH Grant No. R01MH085548 (to AHF, CNP, CPM, DM, DOP, DSL, EJB, HM, HN, JAK, JJR, JLS, LJF, MAE, MHR, MTP, PFB, and SRM), NIH/NIMH Grant No. K99MH101367 (to PHL), the Stanley Medical Research Institute (to JLM, KC, RAB, and SAM), philanthropic gifts from Kent and Elizabeth Dauten and Ted and Vada Stanley (to JLM, KC, RAB, and SAM), Swedish Research Council Grant No. 2013-3196 (to CMH), Swedish Medical Research Council Grant Nos. K2014-62X-14647-12-51 and K2010-61P-21568-01-4 (to ML), Swedish Foundation for Strategic Research Grant No. KF10-0039 (to ML), Swedish Federal Government under the LUA/ALF agreement Grant Nos. ALF 20130032 and ALFGBG-142041 (to ML), a European Commission–Marie Curie Fellowship (to AD), and Wellcome Trust (to IJ, KG-S, LAJ, LF, and NC). JWS is a Tepper Family MGH (Massachusetts General Hospital) Research Scholar. Work at the Icahn School of Medicine at Mount Sinai was also supported by the Institute for Genomics and Multiscale Biology and the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The funders had no role in study design, execution, analysis, or manuscript preparation. We are grateful for the participation of all subjects contributing to this research and to the collection team that worked to recruit them. Pamela Sklar, who led this work, passed away on November 20, 2017. We dedicate this publication to her. JWS is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. JWS reports no other biomedical financial interests or potential conflicts of interest. The other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2019 Society of Biological Psychiatry

PY - 2019/7/15

Y1 - 2019/7/15

N2 - Background: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. Methods: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. Results: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10−5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. Conclusions: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

AB - Background: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. Methods: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. Results: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10−5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. Conclusions: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

KW - Bipolar disorder

KW - Copy number variant

KW - Genetics

KW - Polygenic risk score

KW - Rare variant burden

KW - Schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=85067567787&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067567787&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2018.12.009

DO - 10.1016/j.biopsych.2018.12.009

M3 - Article

C2 - 30686506

AN - SCOPUS:85067567787

SN - 0006-3223

VL - 86

SP - 110

EP - 119

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 2

ER -

Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases

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