Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Douglas M. Ruderfer; Stephan Ripke; Andrew McQuillin; James Boocock; Eli A. Stahl; Jennifer M.Whitehead Pavlides; Niamh Mullins; Alexander W. Charney; Anil P.S. Ori; Loes M.Olde Loohuis; Enrico Domenici; Arianna Di Florio; Sergi Papiol; Janos L. Kalman; Vassily Trubetskoy; Rolf Adolfsson; Ingrid Agartz; Esben Agerbo; Huda Akil; Diego Albani; Margot Albus; Martin Alda; Madeline Alexander; Ney Alliey-Rodriguez; Thomas D. Als; Farooq Amin; Adebayo Anjorin; Maria J. Arranz; Swapnil Awasthi; Silviu A. Bacanu; Judith A. Badner; Marie Baekvad-Hansen; Steven Bakker; Gavin Band; Jack D. Barchas; Ines Barroso; Nicholas Bass; Michael Bauer; Bernhard T. Baune; Martin Begemann; Celine Bellenguez; Richard A. Belliveau; Frank Bellivier; Stephan Bender; Marco Boks; Wiepke Cahn; Rene S. Kahn; Jim Van Os; Eric Strengman; Roel A. Ophoff

doi:10.1016/j.cell.2018.05.046

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Douglas M. Ruderfer, Stephan Ripke, Andrew McQuillin, James Boocock, Eli A. Stahl, Jennifer M.Whitehead Pavlides, Niamh Mullins, Alexander W. Charney, Anil P.S. Ori, Loes M.Olde Loohuis, Enrico Domenici, Arianna Di Florio, Sergi Papiol, Janos L. Kalman, Vassily Trubetskoy, Rolf Adolfsson, Ingrid Agartz, Esben Agerbo, Huda Akil, Diego AlbaniMargot Albus, Martin Alda, Madeline Alexander, Ney Alliey-Rodriguez, Thomas D. Als, Farooq Amin, Adebayo Anjorin, Maria J. Arranz, Swapnil Awasthi, Silviu A. Bacanu, Judith A. Badner, Marie Baekvad-Hansen, Steven Bakker, Gavin Band, Jack D. Barchas, Ines Barroso, Nicholas Bass, Michael Bauer, Bernhard T. Baune, Martin Begemann, Celine Bellenguez, Richard A. Belliveau, Frank Bellivier, Stephan Bender, Marco Boks, Wiepke Cahn, Rene S. Kahn, Jim Van Os, Eric Strengman, Roel A. Ophoff, , , , ,

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

Abstract

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment. Genetic analysis of multiple bipolar disorder and schizophrenia cohorts reveals loci and polygenic risk scores that differentiate the clinical symptoms of these two highly correlated disorders.

Original language	English
Pages (from-to)	1705-1715.e16
Journal	Cell
Volume	173
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2018.05.046
Publication status	Published - 14 Jun 2018

Keywords

Bipolar Disorder/genetics
Case-Control Studies
European Continental Ancestry Group/genetics
Genetic Loci
Genome-Wide Association Study
Humans
Multifactorial Inheritance/genetics
Odds Ratio
Phenotype
Risk
Schizophrenia/genetics

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Ruderfer, D. M., Ripke, S., McQuillin, A., Boocock, J., Stahl, E. A., Pavlides, J. M. W., Mullins, N., Charney, A. W., Ori, A. P. S., Loohuis, L. M. O., Domenici, E., Di Florio, A., Papiol, S., Kalman, J. L., Trubetskoy, V., Adolfsson, R., Agartz, I., Agerbo, E., Akil, H. (2018). Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes. Cell, 173(7), 1705-1715.e16. https://doi.org/10.1016/j.cell.2018.05.046

@article{e355dfe7b6ee41b7851ac379999b526d,

title = "Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes",

abstract = "Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment. Genetic analysis of multiple bipolar disorder and schizophrenia cohorts reveals loci and polygenic risk scores that differentiate the clinical symptoms of these two highly correlated disorders.",

keywords = "Bipolar Disorder/genetics, Case-Control Studies, European Continental Ancestry Group/genetics, Genetic Loci, Genome-Wide Association Study, Humans, Multifactorial Inheritance/genetics, Odds Ratio, Phenotype, Risk, Schizophrenia/genetics",

author = "Ruderfer, {Douglas M.} and Stephan Ripke and Andrew McQuillin and James Boocock and Stahl, {Eli A.} and Pavlides, {Jennifer M.Whitehead} and Niamh Mullins and Charney, {Alexander W.} and Ori, {Anil P.S.} and Loohuis, {Loes M.Olde} and Enrico Domenici and {Di Florio}, Arianna and Sergi Papiol and Kalman, {Janos L.} and Vassily Trubetskoy and Rolf Adolfsson and Ingrid Agartz and Esben Agerbo and Huda Akil and Diego Albani and Margot Albus and Martin Alda and Madeline Alexander and Ney Alliey-Rodriguez and Als, {Thomas D.} and Farooq Amin and Adebayo Anjorin and Arranz, {Maria J.} and Swapnil Awasthi and Bacanu, {Silviu A.} and Badner, {Judith A.} and Marie Baekvad-Hansen and Steven Bakker and Gavin Band and Barchas, {Jack D.} and Ines Barroso and Nicholas Bass and Michael Bauer and Baune, {Bernhard T.} and Martin Begemann and Celine Bellenguez and Belliveau, {Richard A.} and Frank Bellivier and Stephan Bender and Marco Boks and Wiepke Cahn and Kahn, {Rene S.} and {Van Os}, Jim and Eric Strengman and Ophoff, {Roel A.}",

note = "Funding Information: The work of the contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Specifically, D.M.R. (R01MH111776) and N.R.W. (NHMRC 1078901, 1087889). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = jun,

day = "14",

doi = "10.1016/j.cell.2018.05.046",

language = "English",

volume = "173",

pages = "1705--1715.e16",

number = "7",

}

Ruderfer, DM, Ripke, S, McQuillin, A, Boocock, J, Stahl, EA, Pavlides, JMW, Mullins, N, Charney, AW, Ori, APS, Loohuis, LMO, Domenici, E, Di Florio, A, Papiol, S, Kalman, JL, Trubetskoy, V, Adolfsson, R, Agartz, I, Agerbo, E, Akil, H, Albani, D, Albus, M, Alda, M, Alexander, M, Alliey-Rodriguez, N, Als, TD, Amin, F, Anjorin, A, Arranz, MJ, Awasthi, S, Bacanu, SA, Badner, JA, Baekvad-Hansen, M, Bakker, S, Band, G, Barchas, JD, Barroso, I, Bass, N, Bauer, M, Baune, BT, Begemann, M, Bellenguez, C, Belliveau, RA, Bellivier, F, Bender, S, Boks, M , Cahn, W , Kahn, RS , Van Os, J, Strengman, E, Ophoff, RA 2018, 'Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes', Cell, vol. 173, no. 7, pp. 1705-1715.e16. https://doi.org/10.1016/j.cell.2018.05.046

TY - JOUR

T1 - Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

AU - Ruderfer, Douglas M.

AU - Ripke, Stephan

AU - McQuillin, Andrew

AU - Boocock, James

AU - Stahl, Eli A.

AU - Pavlides, Jennifer M.Whitehead

AU - Mullins, Niamh

AU - Charney, Alexander W.

AU - Ori, Anil P.S.

AU - Loohuis, Loes M.Olde

AU - Domenici, Enrico

AU - Di Florio, Arianna

AU - Papiol, Sergi

AU - Kalman, Janos L.

AU - Trubetskoy, Vassily

AU - Adolfsson, Rolf

AU - Agartz, Ingrid

AU - Agerbo, Esben

AU - Akil, Huda

AU - Albani, Diego

AU - Albus, Margot

AU - Alda, Martin

AU - Alexander, Madeline

AU - Alliey-Rodriguez, Ney

AU - Als, Thomas D.

AU - Amin, Farooq

AU - Anjorin, Adebayo

AU - Arranz, Maria J.

AU - Awasthi, Swapnil

AU - Bacanu, Silviu A.

AU - Badner, Judith A.

AU - Baekvad-Hansen, Marie

AU - Bakker, Steven

AU - Band, Gavin

AU - Barchas, Jack D.

AU - Barroso, Ines

AU - Bass, Nicholas

AU - Bauer, Michael

AU - Baune, Bernhard T.

AU - Begemann, Martin

AU - Bellenguez, Celine

AU - Belliveau, Richard A.

AU - Bellivier, Frank

AU - Bender, Stephan

AU - Boks, Marco

AU - Cahn, Wiepke

AU - Kahn, Rene S.

AU - Van Os, Jim

AU - Strengman, Eric

AU - Ophoff, Roel A.

N1 - Funding Information: The work of the contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Specifically, D.M.R. (R01MH111776) and N.R.W. (NHMRC 1078901, 1087889). Publisher Copyright: © 2018 Elsevier Inc.

PY - 2018/6/14

Y1 - 2018/6/14

N2 - Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment. Genetic analysis of multiple bipolar disorder and schizophrenia cohorts reveals loci and polygenic risk scores that differentiate the clinical symptoms of these two highly correlated disorders.

AB - Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment. Genetic analysis of multiple bipolar disorder and schizophrenia cohorts reveals loci and polygenic risk scores that differentiate the clinical symptoms of these two highly correlated disorders.

KW - Bipolar Disorder/genetics

KW - Case-Control Studies

KW - European Continental Ancestry Group/genetics

KW - Genetic Loci

KW - Genome-Wide Association Study

KW - Humans

KW - Multifactorial Inheritance/genetics

KW - Odds Ratio

KW - Phenotype

KW - Risk

KW - Schizophrenia/genetics

UR - http://www.scopus.com/inward/record.url?scp=85048172948&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.05.046

DO - 10.1016/j.cell.2018.05.046

M3 - Article

C2 - 29906448

AN - SCOPUS:85048172948

SN - 0092-8674

VL - 173

SP - 1705-1715.e16

JO - Cell

JF - Cell

IS - 7

ER -

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

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Keywords

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