Abstract
Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.
| Original language | English (US) |
|---|---|
| Journal | Unknown Journal |
| DOIs | |
| State | Published - Nov 21 2017 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- Immunology and Microbiology(all)
- Neuroscience(all)
- Pharmacology, Toxicology and Pharmaceutics(all)
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Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes. / Huckins, Laura M.; Dobbyn, Amanda; McFadden, Whitney; Wang, Weiqing; Ruderfer, Douglas M.; Hoffman, Gabriel; Rajagopal, Veera; Nguyen, Hoang T.; Roussos, Panos; Fromer, Menachem; Kramer, Robin; Domenci, Enrico; Gamazon, Eric; Haroutunian, Vahram; Peters, Mette A.; Devlin, Bernie; Sieberts, Solveig K.; Cox, Nancy; Im, Hae Kyung; Sklar, Pamela; Stahl, Eli A.; Huckins, Laura; Boocock, James; Giambartolomei, Claudia; Roussos, Panos; Mullins, Niamh; Awasthi, Swapnil; Agerbo, Esben; Als, Thomas D.; Pedersen, Carsten Bøcker; Grove, Jakob; Kupka, Ralph; Regeer, Eline J.; Anjorin, Adebayo; Casas, Miquel; Sánchez-Mora, Cristina; Mahon, Pamela B.; Purcell, Shaun M.; McCarroll, Steve; Allardyce, Judith; Escott-Price, Valentina; Forty, Liz; Fraser, Christine; Hamshere, Marian L.; Kirov, George; Kogevinas, Manolis; Frank, Josef; Streit, Fabian; Strohmaier, Jana; Treutlein, Jens; Witt, Stephanie H.; Kennedy, James L.; Strauss, John S.; Garnham, Julie; O’Donovan, Claire; Slaney, Claire; Steinberg, Stacy; Thorgeirsson, Thorgeir E.; Hautzinger, Martin; Steffens, Michael; Kupka, Ralph; McCarroll, Steve; Perlis, Roy H.; Casas, Miquel; Sánchez-Mora, Cristina; Hipolito, Maria; Lawson, William B.; Nwulia, Evaristus A.; Levy, Shawn E.; Purcell, Shaun M.; Foroud, Tatiana M.; Jamain, Stéphane; Young, Allan H.; McKay, James D.; Als, Thomas D.; Pedersen, Carsten Bøcker; Grove, Jakob; Albani, Diego; Zandi, Peter; Mahon, Pamela Lynn Belmonte; Potash, James B.; Zhang, Peng; Raymond DePaulo, J.; Bergen, Sarah E.; Juréus, Anders; Karlsson, Robert; Kandaswamy, Radhika; McGuffin, Peter; Rivera, Margarita; Lissowska, Jolanta; Perlis, Roy H.; Cruceanu, Cristiana; Lucae, Susanne; Cervantes, Pablo; Budde, Monika; Gade, Katrin; Heilbronner, Urs; Pedersen, Marianne Giørtz; Pedersen, Carsten Bøcker; Morris, Derek W.; Weickert, Cynthia Shannon; Weickert, Thomas W.; MacIntyre, Donald J.; Lawrence, Jacob; Elvsåshagen, Torbjørn; Smeland, Olav B.; Djurovic, Srdjan; Xi, Simon; Green, Elaine K.; Czerski, Piotr M.; Hauser, Joanna; Xu, Wei; Vedder, Helmut; Oruc, Lilijana; Spijker, Anne T.; Gordon, Scott D.; Medland, Sarah E.; Curtis, David; Mühleisen, Thomas W.; Badner, Judith; Scheftner, William A.; Sigurdsson, Engilbert; Schork, Nicholas J.; Schatzberg, Alan F.; B¾kvad-Hansen, Marie; Bybjerg-Grauholm, Jonas; Hansen, Christine Søholm; Knowles, James A.; Medeiros, Helena; Szelinger, Szabolcs; Montgomery, Grant W.; Morris, Derek W.; Boks, Marco; Adolfsson, Annelie Nordin; Casas, Miquel; Jamain, Stéphane; Bass, Nicholas; Curtis, David; Hoffmann, Per; Bauer, Michael; Pfennig, Andrea; Leber, Markus; Kittel-Schneider, Sarah; Reif, Andreas; Gade, Katrin; Del-Favero, Jurgen; Fischer, Sascha B.; Herms, Stefan; Hoffmann, Per; Mühleisen, Thomas W.; Reinbold, Céline S.; Djurovic, Srdjan; Degenhardt, Franziska; Herms, Stefan; Hoffmann, Per; Koller, Anna C.; Maaser, Anna; Maier, Wolfgang; Freimer, Nelson B.; Ori, Anil; Dale, Anders M.; Fan, Chun Chieh; Greenwood, Tiffany A.; Nievergelt, Caroline M.; Shehktman, Tatyana; Shilling, Paul D.; Smeland, Olav B.; Byerley, William; Bunney, William; Alliey-Rodriguez, Ney; Blackwood, Douglas H.R.; Clarke, Toni Kim; MacIntyre, Donald J.; Rivera, Margarita; Liu, Chunyu; Coryell, William; Akil, Huda; Burmeister, Margit; Flickinger, Matthew; Li, Jun Z.; McInnis, Melvin G.; Meng, Fan; Thompson, Robert C.; Watson, Stanley J.; Zollner, Sebastian; Guan, Weihua; Green, Melissa J.; Weickert, Cynthia Shannon; Weickert, Thomas W.; Smeland, Olav B.; Craig, David; Sobell, Janet L.; Milani, Lili; Kennedy, James L.; Strauss, John S.; Xu, Wei; Gordon-Smith, Katherine; Knott, Sarah V.; Perry, Amy; Parra, José Guzman; Mayoral, Fermin; Rivas, Fabio; Casas, Miquel; Sánchez-Mora, Cristina; Nievergelt, Caroline M.; Kupka, Ralph; Rice, John P.; Barchas, Jack D.; Børglum, Anders D.; Mortensen, Preben Bo; Mors, Ole; Grigoroiu-Serbanescu, Maria; Bellivier, Frank; Etain, Bruno; Leboyer, Marion; Ramos-Quiroga, Josep Antoni; Ribasés, Marta; Esko, Tõnu; Smoller, Jordan W.; Craddock, Nicholas; Jones, Ian; Owen, Michael J.; Rietschel, Marcella; Schulze, Thomas G.; Vincent, John; Esko, Tõnu; Vieta, Eduard; Nordentoft, Merete; Alda, Martin; Stefansson, Hreinn; Stefansson, Kari; Posthuma, Danielle; Agartz, Ingrid; Bellivier, Frank; Esko, Tõnu; Oedegaard, Ketil J.; Stordal, Eystein; Ramos-Quiroga, Josep Antoni; Ribasés, Marta; Myers, Richard M.; Kahn, René S.; Bellivier, Frank; Etain, Bruno; Leboyer, Marion; Etain, Bruno; Børglum, Anders D.; Mors, Ole; Werge, Thomas; Li, Qingqin S.; Schulze, Thomas G.; Goes, Fernando; Agartz, Ingrid; Hultman, Christina M.; Landén, Mikael; Sullivan, Patrick F.; Lewis, Cathryn M.; McElroy, Susan L.; Smoller, Jordan W.; Müller-Myhsok, Bertram; Biernacka, Joanna M.; Frye, Mark; Turecki, Gustavo; Rouleau, Guy A.; Schulze, Thomas G.; Werge, Thomas; Rouleau, Guy A.; Müller-Myhsok, Bertram; Alda, Martin; McMahon, Francis J.; Schulze, Thomas G.; Fullerton, Janice M.; Schofield, Peter R.; Stordal, Eystein; Morken, Gunnar; Malt, Ulrik F.; Melle, Ingrid; Paciga, Sara A.; Martin, Nicholas G.; Vaaler, Arne E.; Morken, Gunnar; Hougaard, David M.; Pato, Carlos; Pato, Michele T.; Martin, Nicholas G.; Corvin, Aiden; Gill, Michael; Kahn, René S.; Adolfsson, Rolf; Ramos-Quiroga, Josep Antoni; Bellivier, Frank; Etain, Bruno; Leboyer, Marion; Schulze, Thomas G.; Baune, Bernhard T.; Oedegaard, Ketil J.; Serretti, Alessandro; Nöthen, Markus M.; Gershon, Elliot S.; Werge, Thomas; McIntosh, Andrew M.; Landén, Mikael; Stefansson, Kari; Müller-Myhsok, Bertram; Boehnke, Michael; Dannlowski, Udo; Fullerton, Janice M.; Mitchell, Philip B.; Schofield, Peter R.; Sullivan, Patrick F.; Agartz, Ingrid; Melle, Ingrid; Berrettini, Wade H.; Nimgaonkar, Vishwajit; Esko, Tõnu; Metspalu, Andres; Jones, Lisa A.; Ramos-Quiroga, Josep Antoni; Ribasés, Marta; Nurnberger, John; Wray, Naomi R.; Florio, Arianna Di; O’Donovan, Michael C.; Edenberg, Howard; Ophoff, Roel A.; Scott, Laura J.; Cichon, Sven; Andreassen, Ole A.; Sklar, Pamela; Kelsoe, John; Breen, Gerome.
In: Unknown Journal, 21.11.2017.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Transcriptomic Imputation of Bipolar Disorder and Bipolar subtypes reveals 29 novel associated genes
AU - Huckins, Laura M.
AU - Dobbyn, Amanda
AU - McFadden, Whitney
AU - Wang, Weiqing
AU - Ruderfer, Douglas M.
AU - Hoffman, Gabriel
AU - Rajagopal, Veera
AU - Nguyen, Hoang T.
AU - Roussos, Panos
AU - Fromer, Menachem
AU - Kramer, Robin
AU - Domenci, Enrico
AU - Gamazon, Eric
AU - Haroutunian, Vahram
AU - Peters, Mette A.
AU - Devlin, Bernie
AU - Sieberts, Solveig K.
AU - Cox, Nancy
AU - Im, Hae Kyung
AU - Sklar, Pamela
AU - Stahl, Eli A.
AU - Huckins, Laura
AU - Boocock, James
AU - Giambartolomei, Claudia
AU - Roussos, Panos
AU - Mullins, Niamh
AU - Awasthi, Swapnil
AU - Agerbo, Esben
AU - Als, Thomas D.
AU - Pedersen, Carsten Bøcker
AU - Grove, Jakob
AU - Kupka, Ralph
AU - Regeer, Eline J.
AU - Anjorin, Adebayo
AU - Casas, Miquel
AU - Sánchez-Mora, Cristina
AU - Mahon, Pamela B.
AU - Purcell, Shaun M.
AU - McCarroll, Steve
AU - Allardyce, Judith
AU - Escott-Price, Valentina
AU - Forty, Liz
AU - Fraser, Christine
AU - Hamshere, Marian L.
AU - Kirov, George
AU - Kogevinas, Manolis
AU - Frank, Josef
AU - Streit, Fabian
AU - Strohmaier, Jana
AU - Treutlein, Jens
AU - Witt, Stephanie H.
AU - Kennedy, James L.
AU - Strauss, John S.
AU - Garnham, Julie
AU - O’Donovan, Claire
AU - Slaney, Claire
AU - Steinberg, Stacy
AU - Thorgeirsson, Thorgeir E.
AU - Hautzinger, Martin
AU - Steffens, Michael
AU - Kupka, Ralph
AU - McCarroll, Steve
AU - Perlis, Roy H.
AU - Casas, Miquel
AU - Sánchez-Mora, Cristina
AU - Hipolito, Maria
AU - Lawson, William B.
AU - Nwulia, Evaristus A.
AU - Levy, Shawn E.
AU - Purcell, Shaun M.
AU - Foroud, Tatiana M.
AU - Jamain, Stéphane
AU - Young, Allan H.
AU - McKay, James D.
AU - Als, Thomas D.
AU - Pedersen, Carsten Bøcker
AU - Grove, Jakob
AU - Albani, Diego
AU - Zandi, Peter
AU - Mahon, Pamela Lynn Belmonte
AU - Potash, James B.
AU - Zhang, Peng
AU - Raymond DePaulo, J.
AU - Bergen, Sarah E.
AU - Juréus, Anders
AU - Karlsson, Robert
AU - Kandaswamy, Radhika
AU - McGuffin, Peter
AU - Rivera, Margarita
AU - Lissowska, Jolanta
AU - Perlis, Roy H.
AU - Cruceanu, Cristiana
AU - Lucae, Susanne
AU - Cervantes, Pablo
AU - Budde, Monika
AU - Gade, Katrin
AU - Heilbronner, Urs
AU - Pedersen, Marianne Giørtz
AU - Pedersen, Carsten Bøcker
AU - Morris, Derek W.
AU - Weickert, Cynthia Shannon
AU - Weickert, Thomas W.
AU - MacIntyre, Donald J.
AU - Lawrence, Jacob
AU - Elvsåshagen, Torbjørn
AU - Smeland, Olav B.
AU - Djurovic, Srdjan
AU - Xi, Simon
AU - Green, Elaine K.
AU - Czerski, Piotr M.
AU - Hauser, Joanna
AU - Xu, Wei
AU - Vedder, Helmut
AU - Oruc, Lilijana
AU - Spijker, Anne T.
AU - Gordon, Scott D.
AU - Medland, Sarah E.
AU - Curtis, David
AU - Mühleisen, Thomas W.
AU - Badner, Judith
AU - Scheftner, William A.
AU - Sigurdsson, Engilbert
AU - Schork, Nicholas J.
AU - Schatzberg, Alan F.
AU - B¾kvad-Hansen, Marie
AU - Bybjerg-Grauholm, Jonas
AU - Hansen, Christine Søholm
AU - Knowles, James A.
AU - Medeiros, Helena
AU - Szelinger, Szabolcs
AU - Montgomery, Grant W.
AU - Morris, Derek W.
AU - Boks, Marco
AU - Adolfsson, Annelie Nordin
AU - Casas, Miquel
AU - Jamain, Stéphane
AU - Bass, Nicholas
AU - Curtis, David
AU - Hoffmann, Per
AU - Bauer, Michael
AU - Pfennig, Andrea
AU - Leber, Markus
AU - Kittel-Schneider, Sarah
AU - Reif, Andreas
AU - Gade, Katrin
AU - Del-Favero, Jurgen
AU - Fischer, Sascha B.
AU - Herms, Stefan
AU - Hoffmann, Per
AU - Mühleisen, Thomas W.
AU - Reinbold, Céline S.
AU - Djurovic, Srdjan
AU - Degenhardt, Franziska
AU - Herms, Stefan
AU - Hoffmann, Per
AU - Koller, Anna C.
AU - Maaser, Anna
AU - Maier, Wolfgang
AU - Freimer, Nelson B.
AU - Ori, Anil
AU - Dale, Anders M.
AU - Fan, Chun Chieh
AU - Greenwood, Tiffany A.
AU - Nievergelt, Caroline M.
AU - Shehktman, Tatyana
AU - Shilling, Paul D.
AU - Smeland, Olav B.
AU - Byerley, William
AU - Bunney, William
AU - Alliey-Rodriguez, Ney
AU - Blackwood, Douglas H.R.
AU - Clarke, Toni Kim
AU - MacIntyre, Donald J.
AU - Rivera, Margarita
AU - Liu, Chunyu
AU - Coryell, William
AU - Akil, Huda
AU - Burmeister, Margit
AU - Flickinger, Matthew
AU - Li, Jun Z.
AU - McInnis, Melvin G.
AU - Meng, Fan
AU - Thompson, Robert C.
AU - Watson, Stanley J.
AU - Zollner, Sebastian
AU - Guan, Weihua
AU - Green, Melissa J.
AU - Weickert, Cynthia Shannon
AU - Weickert, Thomas W.
AU - Smeland, Olav B.
AU - Craig, David
AU - Sobell, Janet L.
AU - Milani, Lili
AU - Kennedy, James L.
AU - Strauss, John S.
AU - Xu, Wei
AU - Gordon-Smith, Katherine
AU - Knott, Sarah V.
AU - Perry, Amy
AU - Parra, José Guzman
AU - Mayoral, Fermin
AU - Rivas, Fabio
AU - Casas, Miquel
AU - Sánchez-Mora, Cristina
AU - Nievergelt, Caroline M.
AU - Kupka, Ralph
AU - Rice, John P.
AU - Barchas, Jack D.
AU - Børglum, Anders D.
AU - Mortensen, Preben Bo
AU - Mors, Ole
AU - Grigoroiu-Serbanescu, Maria
AU - Bellivier, Frank
AU - Etain, Bruno
AU - Leboyer, Marion
AU - Ramos-Quiroga, Josep Antoni
AU - Ribasés, Marta
AU - Esko, Tõnu
AU - Smoller, Jordan W.
AU - Craddock, Nicholas
AU - Jones, Ian
AU - Owen, Michael J.
AU - Rietschel, Marcella
AU - Schulze, Thomas G.
AU - Vincent, John
AU - Esko, Tõnu
AU - Vieta, Eduard
AU - Nordentoft, Merete
AU - Alda, Martin
AU - Stefansson, Hreinn
AU - Stefansson, Kari
AU - Posthuma, Danielle
AU - Agartz, Ingrid
AU - Bellivier, Frank
AU - Esko, Tõnu
AU - Oedegaard, Ketil J.
AU - Stordal, Eystein
AU - Ramos-Quiroga, Josep Antoni
AU - Ribasés, Marta
AU - Myers, Richard M.
AU - Kahn, René S.
AU - Bellivier, Frank
AU - Etain, Bruno
AU - Leboyer, Marion
AU - Etain, Bruno
AU - Børglum, Anders D.
AU - Mors, Ole
AU - Werge, Thomas
AU - Li, Qingqin S.
AU - Schulze, Thomas G.
AU - Goes, Fernando
AU - Agartz, Ingrid
AU - Hultman, Christina M.
AU - Landén, Mikael
AU - Sullivan, Patrick F.
AU - Lewis, Cathryn M.
AU - McElroy, Susan L.
AU - Smoller, Jordan W.
AU - Müller-Myhsok, Bertram
AU - Biernacka, Joanna M.
AU - Frye, Mark
AU - Turecki, Gustavo
AU - Rouleau, Guy A.
AU - Schulze, Thomas G.
AU - Werge, Thomas
AU - Rouleau, Guy A.
AU - Müller-Myhsok, Bertram
AU - Alda, Martin
AU - McMahon, Francis J.
AU - Schulze, Thomas G.
AU - Fullerton, Janice M.
AU - Schofield, Peter R.
AU - Stordal, Eystein
AU - Morken, Gunnar
AU - Malt, Ulrik F.
AU - Melle, Ingrid
AU - Paciga, Sara A.
AU - Martin, Nicholas G.
AU - Vaaler, Arne E.
AU - Morken, Gunnar
AU - Hougaard, David M.
AU - Pato, Carlos
AU - Pato, Michele T.
AU - Martin, Nicholas G.
AU - Corvin, Aiden
AU - Gill, Michael
AU - Kahn, René S.
AU - Adolfsson, Rolf
AU - Ramos-Quiroga, Josep Antoni
AU - Bellivier, Frank
AU - Etain, Bruno
AU - Leboyer, Marion
AU - Schulze, Thomas G.
AU - Baune, Bernhard T.
AU - Oedegaard, Ketil J.
AU - Serretti, Alessandro
AU - Nöthen, Markus M.
AU - Gershon, Elliot S.
AU - Werge, Thomas
AU - McIntosh, Andrew M.
AU - Landén, Mikael
AU - Stefansson, Kari
AU - Müller-Myhsok, Bertram
AU - Boehnke, Michael
AU - Dannlowski, Udo
AU - Fullerton, Janice M.
AU - Mitchell, Philip B.
AU - Schofield, Peter R.
AU - Sullivan, Patrick F.
AU - Agartz, Ingrid
AU - Melle, Ingrid
AU - Berrettini, Wade H.
AU - Nimgaonkar, Vishwajit
AU - Esko, Tõnu
AU - Metspalu, Andres
AU - Jones, Lisa A.
AU - Ramos-Quiroga, Josep Antoni
AU - Ribasés, Marta
AU - Nurnberger, John
AU - Wray, Naomi R.
AU - Florio, Arianna Di
AU - O’Donovan, Michael C.
AU - Edenberg, Howard
AU - Ophoff, Roel A.
AU - Scott, Laura J.
AU - Cichon, Sven
AU - Andreassen, Ole A.
AU - Sklar, Pamela
AU - Kelsoe, John
AU - Breen, Gerome
N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2017/11/21
Y1 - 2017/11/21
N2 - Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.
AB - Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.
UR - http://www.scopus.com/inward/record.url?scp=85095629760&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095629760&partnerID=8YFLogxK
U2 - 10.1101/222786
DO - 10.1101/222786
M3 - Article
AN - SCOPUS:85095629760
JO - Advances in Water Resources
JF - Advances in Water Resources
SN - 0309-1708
ER -