Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Colm O'Dushlaine; Lizzy Rossin; Phil H. Lee; Laramie Duncan; Neelroop N. Parikshak; Stephen Newhouse; Stephan Ripke; Benjamin M. Neale; Shaun M. Purcell; Danielle Posthuma; John I. Nurnberger; S. Hong Lee; Stephen V. Faraone; Roy H. Perlis; Bryan J. Mowry; Anita Thapar; Michael E. Goddard; John S. Witte; Devin Absher; Ingrid Agartz; Huda Akil; Farooq Amin; Ole A. Andreassen; Adebayo Anjorin; Richard Anney; Verneri Anttila; Dan E. Arking; Philip Asherson; Maria H. Azevedo; Lena Backlund; Judith A. Badner; Anthony J. Bailey; Tobias Banaschewski; Jack D. Barchas; Michael R. Barnes; Thomas B. Barrett; Nicholas Bass; Agatino Battaglia; Michael Bauer; Monica Bayes; Frank Bellivier; Sarah E. Bergen; Wade Berrettini; Catalina Betancur; Thomas Bettecken; Joseph Biederman; Elisabeth B. Binder; Richard Bruggeman; Willem A. Nolen; Brenda W. Penninx; IIBDGC; Network & Pathway Anal Subgrp Psyc

doi:10.1038/nn.3922

Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Colm O'Dushlaine, Lizzy Rossin, Phil H. Lee, Laramie Duncan, Neelroop N. Parikshak, Stephen Newhouse, Stephan Ripke, Benjamin M. Neale, Shaun M. Purcell, Danielle Posthuma, John I. Nurnberger, S. Hong Lee, Stephen V. Faraone, Roy H. Perlis, Bryan J. Mowry, Anita Thapar, Michael E. Goddard, John S. Witte, Devin Absher, Ingrid AgartzHuda Akil, Farooq Amin, Ole A. Andreassen, Adebayo Anjorin, Richard Anney, Verneri Anttila, Dan E. Arking, Philip Asherson, Maria H. Azevedo, Lena Backlund, Judith A. Badner, Anthony J. Bailey, Tobias Banaschewski, Jack D. Barchas, Michael R. Barnes, Thomas B. Barrett, Nicholas Bass, Agatino Battaglia, Michael Bauer, Monica Bayes, Frank Bellivier, Sarah E. Bergen, Wade Berrettini, Catalina Betancur, Thomas Bettecken, Joseph Biederman, Elisabeth B. Binder, Richard Bruggeman, Willem A. Nolen, Brenda W. Penninx, IIBDGC, Network & Pathway Anal Subgrp Psyc

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

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Abstract

Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

Original language	English
Pages (from-to)	199-209
Number of pages	11
Journal	Nature neuroscience
Volume	18
Issue number	2
DOIs	https://doi.org/10.1038/nn.3922
Publication status	Published - Feb-2015

Keywords

DE-NOVO MUTATIONS
SCHIZOPHRENIA
METHYLATION
DISORDERS
AUTISM
BRAIN
PROMOTERS
BURDEN
LOCI

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O'Dushlaine, C., Rossin, L., Lee, P. H., Duncan, L., Parikshak, N. N., Newhouse, S., Ripke, S., Neale, B. M., Purcell, S. M., Posthuma, D., Nurnberger, J. I., Lee, S. H., Faraone, S. V., Perlis, R. H., Mowry, B. J., Thapar, A., Goddard, M. E., Witte, J. S., Absher, D., ... Network & Pathway Anal Subgrp Psyc (2015). Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways. Nature neuroscience, 18(2), 199-209. https://doi.org/10.1038/nn.3922

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abstract = "Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.",

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author = "Colm O'Dushlaine and Lizzy Rossin and Lee, {Phil H.} and Laramie Duncan and Parikshak, {Neelroop N.} and Stephen Newhouse and Stephan Ripke and Neale, {Benjamin M.} and Purcell, {Shaun M.} and Danielle Posthuma and Nurnberger, {John I.} and Lee, {S. Hong} and Faraone, {Stephen V.} and Perlis, {Roy H.} and Mowry, {Bryan J.} and Anita Thapar and Goddard, {Michael E.} and Witte, {John S.} and Devin Absher and Ingrid Agartz and Huda Akil and Farooq Amin and Andreassen, {Ole A.} and Adebayo Anjorin and Richard Anney and Verneri Anttila and Arking, {Dan E.} and Philip Asherson and Azevedo, {Maria H.} and Lena Backlund and Badner, {Judith A.} and Bailey, {Anthony J.} and Tobias Banaschewski and Barchas, {Jack D.} and Barnes, {Michael R.} and Barrett, {Thomas B.} and Nicholas Bass and Agatino Battaglia and Michael Bauer and Monica Bayes and Frank Bellivier and Bergen, {Sarah E.} and Wade Berrettini and Catalina Betancur and Thomas Bettecken and Joseph Biederman and Binder, {Elisabeth B.} and Richard Bruggeman and Nolen, {Willem A.} and Penninx, {Brenda W.} and IIBDGC and {Network & Pathway Anal Subgrp Psyc}",

year = "2015",

month = feb,

doi = "10.1038/nn.3922",

language = "English",

volume = "18",

pages = "199--209",

journal = "Nature neuroscience",

issn = "1097-6256",

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O'Dushlaine, C, Rossin, L, Lee, PH, Duncan, L, Parikshak, NN, Newhouse, S, Ripke, S, Neale, BM, Purcell, SM, Posthuma, D, Nurnberger, JI, Lee, SH, Faraone, SV, Perlis, RH, Mowry, BJ, Thapar, A, Goddard, ME, Witte, JS, Absher, D, Agartz, I, Akil, H, Amin, F, Andreassen, OA, Anjorin, A, Anney, R, Anttila, V, Arking, DE, Asherson, P, Azevedo, MH, Backlund, L, Badner, JA, Bailey, AJ, Banaschewski, T, Barchas, JD, Barnes, MR, Barrett, TB, Bass, N, Battaglia, A, Bauer, M, Bayes, M, Bellivier, F, Bergen, SE, Berrettini, W, Betancur, C, Bettecken, T, Biederman, J, Binder, EB, Bruggeman, R , Nolen, WA, Penninx, BW, IIBDGC & Network & Pathway Anal Subgrp Psyc 2015, 'Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways', Nature neuroscience, vol. 18, no. 2, pp. 199-209. https://doi.org/10.1038/nn.3922

TY - JOUR

T1 - Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

AU - O'Dushlaine, Colm

AU - Rossin, Lizzy

AU - Lee, Phil H.

AU - Duncan, Laramie

AU - Parikshak, Neelroop N.

AU - Newhouse, Stephen

AU - Ripke, Stephan

AU - Neale, Benjamin M.

AU - Purcell, Shaun M.

AU - Posthuma, Danielle

AU - Nurnberger, John I.

AU - Lee, S. Hong

AU - Faraone, Stephen V.

AU - Perlis, Roy H.

AU - Mowry, Bryan J.

AU - Thapar, Anita

AU - Goddard, Michael E.

AU - Witte, John S.

AU - Absher, Devin

AU - Agartz, Ingrid

AU - Akil, Huda

AU - Amin, Farooq

AU - Andreassen, Ole A.

AU - Anjorin, Adebayo

AU - Anney, Richard

AU - Anttila, Verneri

AU - Arking, Dan E.

AU - Asherson, Philip

AU - Azevedo, Maria H.

AU - Backlund, Lena

AU - Badner, Judith A.

AU - Bailey, Anthony J.

AU - Banaschewski, Tobias

AU - Barchas, Jack D.

AU - Barnes, Michael R.

AU - Barrett, Thomas B.

AU - Bass, Nicholas

AU - Battaglia, Agatino

AU - Bauer, Michael

AU - Bayes, Monica

AU - Bellivier, Frank

AU - Bergen, Sarah E.

AU - Berrettini, Wade

AU - Betancur, Catalina

AU - Bettecken, Thomas

AU - Biederman, Joseph

AU - Binder, Elisabeth B.

AU - Bruggeman, Richard

AU - Nolen, Willem A.

AU - Penninx, Brenda W.

AU - IIBDGC

AU - Network & Pathway Anal Subgrp Psyc

PY - 2015/2

Y1 - 2015/2

N2 - Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

AB - Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.

KW - DE-NOVO MUTATIONS

KW - SCHIZOPHRENIA

KW - METHYLATION

KW - DISORDERS

KW - AUTISM

KW - BRAIN

KW - PROMOTERS

KW - BURDEN

KW - LOCI

U2 - 10.1038/nn.3922

DO - 10.1038/nn.3922

M3 - Article

SN - 1097-6256

VL - 18

SP - 199

EP - 209

JO - Nature neuroscience

JF - Nature neuroscience

IS - 2

ER -