Analysis of the influence of microRNAs in lithium response in bipolar disorder

Céline S. Reinbold, Andreas J. Forstner, Julian Hecker, Janice M. Fullerton, Per Hoffmann, Liping Hou, Urs Heilbronner, Franziska Degenhardt, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Raffaella Ardau, Bárbara Arias, Lena Backlund, Antonio Benabarre, Susanne Bengesser, Abesh K. Bhattacharjee, Joanna M Biernacka, Armin Birner, Cynthia Marie-ClairePablo Cervantes, Guo Bo Chen, Hsi Chung Chen, Caterina Chillotti, Scott R. Clark, Francesc Colom, David A. Cousins, Cristiana Cruceanu, Piotr M. Czerski, Alexandre Dayer, Bruno Étain, Peter Falkai, Louise Frisén, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Stéphane Jamain, Esther Jiménez, Jean Pierre Kahn, Layla Kassem, Sarah Kittel-Schneider, Sebastian Kliwicki, Barbara König, Ichiro Kusumi, Nina Lackner, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Carlos A.López Jaramillo, Glenda MacQueen, Mirko Manchia, Lina Martinsson, Manuel Mattheisen, Michael J. McCarthy, Susan L. McElroy, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Urban Ösby, Norio Ozaki, Roy H. Perlis, Andrea Pfennig, Daniela Reich-Erkelenz, Guy A. Rouleau, Peter R. Schofield, K. Oliver Schubert, Barbara W. Schweizer, Florian Seemüller, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Kazutaka Shimoda, Christian Simhandl, Claire M. Slaney, Jordan W. Smoller, Alessio Squassina, Thomas J. Stamm, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Julia Volkert, Stephanie H. Witt, Adam J. Wright, L. Trevor Young, Peter P. Zandi, James B. Potash, J. Raymond DePaulo, Michael Bauer, Eva Reininghaus, Tomáš Novák, Jean Michel Aubry, Mario Maj, Bernhard T. Baune, Philip B. Mitchell, Eduard Vieta, Mark A Frye, Janusz K. Rybakowski, Po Hsiu Kuo, Tadafumi Kato, Maria Grigoroiu-Serbanescu, Andreas Reif, Maria Del Zompo, Frank Bellivier, Martin Schalling, Naomi R. Wray, John R. Kelsoe, Martin Alda, Francis J. McMahon, Thomas G. Schulze, Marcella Rietschel, Markus M. Nöthen, Sven Cichon

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Original languageEnglish (US)
Article number207
JournalFrontiers in Psychiatry
Volume9
Issue numberMAY
DOIs
StatePublished - May 31 2018

Fingerprint

MicroRNAs
Bipolar Disorder
Lithium
Genome-Wide Association Study
Genome
Phenotype
Genes
Therapeutics
Depression

Keywords

  • Bipolar disorder
  • Common variants
  • Genome-wide association study
  • Lithium response
  • MicroRNA

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Reinbold, C. S., Forstner, A. J., Hecker, J., Fullerton, J. M., Hoffmann, P., Hou, L., ... Cichon, S. (2018). Analysis of the influence of microRNAs in lithium response in bipolar disorder. Frontiers in Psychiatry, 9(MAY), [207]. https://doi.org/10.3389/fpsyt.2018.00207

Analysis of the influence of microRNAs in lithium response in bipolar disorder. / Reinbold, Céline S.; Forstner, Andreas J.; Hecker, Julian; Fullerton, Janice M.; Hoffmann, Per; Hou, Liping; Heilbronner, Urs; Degenhardt, Franziska; Adli, Mazda; Akiyama, Kazufumi; Akula, Nirmala; Ardau, Raffaella; Arias, Bárbara; Backlund, Lena; Benabarre, Antonio; Bengesser, Susanne; Bhattacharjee, Abesh K.; Biernacka, Joanna M; Birner, Armin; Marie-Claire, Cynthia; Cervantes, Pablo; Chen, Guo Bo; Chen, Hsi Chung; Chillotti, Caterina; Clark, Scott R.; Colom, Francesc; Cousins, David A.; Cruceanu, Cristiana; Czerski, Piotr M.; Dayer, Alexandre; Étain, Bruno; Falkai, Peter; Frisén, Louise; Gard, Sébastien; Garnham, Julie S.; Goes, Fernando S.; Grof, Paul; Gruber, Oliver; Hashimoto, Ryota; Hauser, Joanna; Herms, Stefan; Jamain, Stéphane; Jiménez, Esther; Kahn, Jean Pierre; Kassem, Layla; Kittel-Schneider, Sarah; Kliwicki, Sebastian; König, Barbara; Kusumi, Ichiro; Lackner, Nina; Laje, Gonzalo; Landén, Mikael; Lavebratt, Catharina; Leboyer, Marion; Leckband, Susan G.; Jaramillo, Carlos A.López; MacQueen, Glenda; Manchia, Mirko; Martinsson, Lina; Mattheisen, Manuel; McCarthy, Michael J.; McElroy, Susan L.; Mitjans, Marina; Mondimore, Francis M.; Monteleone, Palmiero; Nievergelt, Caroline M.; Ösby, Urban; Ozaki, Norio; Perlis, Roy H.; Pfennig, Andrea; Reich-Erkelenz, Daniela; Rouleau, Guy A.; Schofield, Peter R.; Schubert, K. Oliver; Schweizer, Barbara W.; Seemüller, Florian; Severino, Giovanni; Shekhtman, Tatyana; Shilling, Paul D.; Shimoda, Kazutaka; Simhandl, Christian; Slaney, Claire M.; Smoller, Jordan W.; Squassina, Alessio; Stamm, Thomas J.; Stopkova, Pavla; Tighe, Sarah K.; Tortorella, Alfonso; Turecki, Gustavo; Volkert, Julia; Witt, Stephanie H.; Wright, Adam J.; Trevor Young, L.; Zandi, Peter P.; Potash, James B.; DePaulo, J. Raymond; Bauer, Michael; Reininghaus, Eva; Novák, Tomáš; Aubry, Jean Michel; Maj, Mario; Baune, Bernhard T.; Mitchell, Philip B.; Vieta, Eduard; Frye, Mark A; Rybakowski, Janusz K.; Kuo, Po Hsiu; Kato, Tadafumi; Grigoroiu-Serbanescu, Maria; Reif, Andreas; Zompo, Maria Del; Bellivier, Frank; Schalling, Martin; Wray, Naomi R.; Kelsoe, John R.; Alda, Martin; McMahon, Francis J.; Schulze, Thomas G.; Rietschel, Marcella; Nöthen, Markus M.; Cichon, Sven.

In: Frontiers in Psychiatry, Vol. 9, No. MAY, 207, 31.05.2018.

Research output: Contribution to journalArticle

Reinbold, CS, Forstner, AJ, Hecker, J, Fullerton, JM, Hoffmann, P, Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Marie-Claire, C, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dayer, A, Étain, B, Falkai, P, Frisén, L, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, MacQueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, TJ, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, SH, Wright, AJ, Trevor Young, L, Zandi, PP, Potash, JB, DePaulo, JR, Bauer, M, Reininghaus, E, Novák, T, Aubry, JM, Maj, M, Baune, BT, Mitchell, PB, Vieta, E, Frye, MA, Rybakowski, JK, Kuo, PH, Kato, T, Grigoroiu-Serbanescu, M, Reif, A, Zompo, MD, Bellivier, F, Schalling, M, Wray, NR, Kelsoe, JR, Alda, M, McMahon, FJ, Schulze, TG, Rietschel, M, Nöthen, MM & Cichon, S 2018, 'Analysis of the influence of microRNAs in lithium response in bipolar disorder', Frontiers in Psychiatry, vol. 9, no. MAY, 207. https://doi.org/10.3389/fpsyt.2018.00207
Reinbold CS, Forstner AJ, Hecker J, Fullerton JM, Hoffmann P, Hou L et al. Analysis of the influence of microRNAs in lithium response in bipolar disorder. Frontiers in Psychiatry. 2018 May 31;9(MAY). 207. https://doi.org/10.3389/fpsyt.2018.00207
Reinbold, Céline S. ; Forstner, Andreas J. ; Hecker, Julian ; Fullerton, Janice M. ; Hoffmann, Per ; Hou, Liping ; Heilbronner, Urs ; Degenhardt, Franziska ; Adli, Mazda ; Akiyama, Kazufumi ; Akula, Nirmala ; Ardau, Raffaella ; Arias, Bárbara ; Backlund, Lena ; Benabarre, Antonio ; Bengesser, Susanne ; Bhattacharjee, Abesh K. ; Biernacka, Joanna M ; Birner, Armin ; Marie-Claire, Cynthia ; Cervantes, Pablo ; Chen, Guo Bo ; Chen, Hsi Chung ; Chillotti, Caterina ; Clark, Scott R. ; Colom, Francesc ; Cousins, David A. ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Dayer, Alexandre ; Étain, Bruno ; Falkai, Peter ; Frisén, Louise ; Gard, Sébastien ; Garnham, Julie S. ; Goes, Fernando S. ; Grof, Paul ; Gruber, Oliver ; Hashimoto, Ryota ; Hauser, Joanna ; Herms, Stefan ; Jamain, Stéphane ; Jiménez, Esther ; Kahn, Jean Pierre ; Kassem, Layla ; Kittel-Schneider, Sarah ; Kliwicki, Sebastian ; König, Barbara ; Kusumi, Ichiro ; Lackner, Nina ; Laje, Gonzalo ; Landén, Mikael ; Lavebratt, Catharina ; Leboyer, Marion ; Leckband, Susan G. ; Jaramillo, Carlos A.López ; MacQueen, Glenda ; Manchia, Mirko ; Martinsson, Lina ; Mattheisen, Manuel ; McCarthy, Michael J. ; McElroy, Susan L. ; Mitjans, Marina ; Mondimore, Francis M. ; Monteleone, Palmiero ; Nievergelt, Caroline M. ; Ösby, Urban ; Ozaki, Norio ; Perlis, Roy H. ; Pfennig, Andrea ; Reich-Erkelenz, Daniela ; Rouleau, Guy A. ; Schofield, Peter R. ; Schubert, K. Oliver ; Schweizer, Barbara W. ; Seemüller, Florian ; Severino, Giovanni ; Shekhtman, Tatyana ; Shilling, Paul D. ; Shimoda, Kazutaka ; Simhandl, Christian ; Slaney, Claire M. ; Smoller, Jordan W. ; Squassina, Alessio ; Stamm, Thomas J. ; Stopkova, Pavla ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Volkert, Julia ; Witt, Stephanie H. ; Wright, Adam J. ; Trevor Young, L. ; Zandi, Peter P. ; Potash, James B. ; DePaulo, J. Raymond ; Bauer, Michael ; Reininghaus, Eva ; Novák, Tomáš ; Aubry, Jean Michel ; Maj, Mario ; Baune, Bernhard T. ; Mitchell, Philip B. ; Vieta, Eduard ; Frye, Mark A ; Rybakowski, Janusz K. ; Kuo, Po Hsiu ; Kato, Tadafumi ; Grigoroiu-Serbanescu, Maria ; Reif, Andreas ; Zompo, Maria Del ; Bellivier, Frank ; Schalling, Martin ; Wray, Naomi R. ; Kelsoe, John R. ; Alda, Martin ; McMahon, Francis J. ; Schulze, Thomas G. ; Rietschel, Marcella ; Nöthen, Markus M. ; Cichon, Sven. / Analysis of the influence of microRNAs in lithium response in bipolar disorder. In: Frontiers in Psychiatry. 2018 ; Vol. 9, No. MAY.
@article{7f5378b7c3fc4ab083f4a44e25866b05,
title = "Analysis of the influence of microRNAs in lithium response in bipolar disorder",
abstract = "Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.",
keywords = "Bipolar disorder, Common variants, Genome-wide association study, Lithium response, MicroRNA",
author = "Reinbold, {C{\'e}line S.} and Forstner, {Andreas J.} and Julian Hecker and Fullerton, {Janice M.} and Per Hoffmann and Liping Hou and Urs Heilbronner and Franziska Degenhardt and Mazda Adli and Kazufumi Akiyama and Nirmala Akula and Raffaella Ardau and B{\'a}rbara Arias and Lena Backlund and Antonio Benabarre and Susanne Bengesser and Bhattacharjee, {Abesh K.} and Biernacka, {Joanna M} and Armin Birner and Cynthia Marie-Claire and Pablo Cervantes and Chen, {Guo Bo} and Chen, {Hsi Chung} and Caterina Chillotti and Clark, {Scott R.} and Francesc Colom and Cousins, {David A.} and Cristiana Cruceanu and Czerski, {Piotr M.} and Alexandre Dayer and Bruno {\'E}tain and Peter Falkai and Louise Fris{\'e}n and S{\'e}bastien Gard and Garnham, {Julie S.} and Goes, {Fernando S.} and Paul Grof and Oliver Gruber and Ryota Hashimoto and Joanna Hauser and Stefan Herms and St{\'e}phane Jamain and Esther Jim{\'e}nez and Kahn, {Jean Pierre} and Layla Kassem and Sarah Kittel-Schneider and Sebastian Kliwicki and Barbara K{\"o}nig and Ichiro Kusumi and Nina Lackner and Gonzalo Laje and Mikael Land{\'e}n and Catharina Lavebratt and Marion Leboyer and Leckband, {Susan G.} and Jaramillo, {Carlos A.L{\'o}pez} and Glenda MacQueen and Mirko Manchia and Lina Martinsson and Manuel Mattheisen and McCarthy, {Michael J.} and McElroy, {Susan L.} and Marina Mitjans and Mondimore, {Francis M.} and Palmiero Monteleone and Nievergelt, {Caroline M.} and Urban {\"O}sby and Norio Ozaki and Perlis, {Roy H.} and Andrea Pfennig and Daniela Reich-Erkelenz and Rouleau, {Guy A.} and Schofield, {Peter R.} and Schubert, {K. Oliver} and Schweizer, {Barbara W.} and Florian Seem{\"u}ller and Giovanni Severino and Tatyana Shekhtman and Shilling, {Paul D.} and Kazutaka Shimoda and Christian Simhandl and Slaney, {Claire M.} and Smoller, {Jordan W.} and Alessio Squassina and Stamm, {Thomas J.} and Pavla Stopkova and Tighe, {Sarah K.} and Alfonso Tortorella and Gustavo Turecki and Julia Volkert and Witt, {Stephanie H.} and Wright, {Adam J.} and {Trevor Young}, L. and Zandi, {Peter P.} and Potash, {James B.} and DePaulo, {J. Raymond} and Michael Bauer and Eva Reininghaus and Tom{\'a}š Nov{\'a}k and Aubry, {Jean Michel} and Mario Maj and Baune, {Bernhard T.} and Mitchell, {Philip B.} and Eduard Vieta and Frye, {Mark A} and Rybakowski, {Janusz K.} and Kuo, {Po Hsiu} and Tadafumi Kato and Maria Grigoroiu-Serbanescu and Andreas Reif and Zompo, {Maria Del} and Frank Bellivier and Martin Schalling and Wray, {Naomi R.} and Kelsoe, {John R.} and Martin Alda and McMahon, {Francis J.} and Schulze, {Thomas G.} and Marcella Rietschel and N{\"o}then, {Markus M.} and Sven Cichon",
year = "2018",
month = "5",
day = "31",
doi = "10.3389/fpsyt.2018.00207",
language = "English (US)",
volume = "9",
journal = "Frontiers in Psychiatry",
issn = "1664-0640",
publisher = "Frontiers Research Foundation",
number = "MAY",

}

TY - JOUR

T1 - Analysis of the influence of microRNAs in lithium response in bipolar disorder

AU - Reinbold, Céline S.

AU - Forstner, Andreas J.

AU - Hecker, Julian

AU - Fullerton, Janice M.

AU - Hoffmann, Per

AU - Hou, Liping

AU - Heilbronner, Urs

AU - Degenhardt, Franziska

AU - Adli, Mazda

AU - Akiyama, Kazufumi

AU - Akula, Nirmala

AU - Ardau, Raffaella

AU - Arias, Bárbara

AU - Backlund, Lena

AU - Benabarre, Antonio

AU - Bengesser, Susanne

AU - Bhattacharjee, Abesh K.

AU - Biernacka, Joanna M

AU - Birner, Armin

AU - Marie-Claire, Cynthia

AU - Cervantes, Pablo

AU - Chen, Guo Bo

AU - Chen, Hsi Chung

AU - Chillotti, Caterina

AU - Clark, Scott R.

AU - Colom, Francesc

AU - Cousins, David A.

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dayer, Alexandre

AU - Étain, Bruno

AU - Falkai, Peter

AU - Frisén, Louise

AU - Gard, Sébastien

AU - Garnham, Julie S.

AU - Goes, Fernando S.

AU - Grof, Paul

AU - Gruber, Oliver

AU - Hashimoto, Ryota

AU - Hauser, Joanna

AU - Herms, Stefan

AU - Jamain, Stéphane

AU - Jiménez, Esther

AU - Kahn, Jean Pierre

AU - Kassem, Layla

AU - Kittel-Schneider, Sarah

AU - Kliwicki, Sebastian

AU - König, Barbara

AU - Kusumi, Ichiro

AU - Lackner, Nina

AU - Laje, Gonzalo

AU - Landén, Mikael

AU - Lavebratt, Catharina

AU - Leboyer, Marion

AU - Leckband, Susan G.

AU - Jaramillo, Carlos A.López

AU - MacQueen, Glenda

AU - Manchia, Mirko

AU - Martinsson, Lina

AU - Mattheisen, Manuel

AU - McCarthy, Michael J.

AU - McElroy, Susan L.

AU - Mitjans, Marina

AU - Mondimore, Francis M.

AU - Monteleone, Palmiero

AU - Nievergelt, Caroline M.

AU - Ösby, Urban

AU - Ozaki, Norio

AU - Perlis, Roy H.

AU - Pfennig, Andrea

AU - Reich-Erkelenz, Daniela

AU - Rouleau, Guy A.

AU - Schofield, Peter R.

AU - Schubert, K. Oliver

AU - Schweizer, Barbara W.

AU - Seemüller, Florian

AU - Severino, Giovanni

AU - Shekhtman, Tatyana

AU - Shilling, Paul D.

AU - Shimoda, Kazutaka

AU - Simhandl, Christian

AU - Slaney, Claire M.

AU - Smoller, Jordan W.

AU - Squassina, Alessio

AU - Stamm, Thomas J.

AU - Stopkova, Pavla

AU - Tighe, Sarah K.

AU - Tortorella, Alfonso

AU - Turecki, Gustavo

AU - Volkert, Julia

AU - Witt, Stephanie H.

AU - Wright, Adam J.

AU - Trevor Young, L.

AU - Zandi, Peter P.

AU - Potash, James B.

AU - DePaulo, J. Raymond

AU - Bauer, Michael

AU - Reininghaus, Eva

AU - Novák, Tomáš

AU - Aubry, Jean Michel

AU - Maj, Mario

AU - Baune, Bernhard T.

AU - Mitchell, Philip B.

AU - Vieta, Eduard

AU - Frye, Mark A

AU - Rybakowski, Janusz K.

AU - Kuo, Po Hsiu

AU - Kato, Tadafumi

AU - Grigoroiu-Serbanescu, Maria

AU - Reif, Andreas

AU - Zompo, Maria Del

AU - Bellivier, Frank

AU - Schalling, Martin

AU - Wray, Naomi R.

AU - Kelsoe, John R.

AU - Alda, Martin

AU - McMahon, Francis J.

AU - Schulze, Thomas G.

AU - Rietschel, Marcella

AU - Nöthen, Markus M.

AU - Cichon, Sven

PY - 2018/5/31

Y1 - 2018/5/31

N2 - Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

AB - Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

KW - Bipolar disorder

KW - Common variants

KW - Genome-wide association study

KW - Lithium response

KW - MicroRNA

UR - http://www.scopus.com/inward/record.url?scp=85047859367&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047859367&partnerID=8YFLogxK

U2 - 10.3389/fpsyt.2018.00207

DO - 10.3389/fpsyt.2018.00207

M3 - Article

AN - SCOPUS:85047859367

VL - 9

JO - Frontiers in Psychiatry

JF - Frontiers in Psychiatry

SN - 1664-0640

IS - MAY

M1 - 207

ER -