Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study

Liping Hou, Urs Heilbronner, Franziska Degenhardt, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Raffaella Ardau, Bárbara Arias, Lena Backlund, Claudio E M Banzato, Antoni Benabarre, Susanne Bengesser, Abesh Kumar Bhattacharjee, Joanna M Biernacka, Armin Birner, Clara Brichant-Petitjean, Elise T. Bui, Pablo Cervantes, Guo Bo Chen, Hsi Chung ChenCaterina Chillotti, Sven Cichon, Scott R. Clark, Francesc Colom, David A. Cousins, Cristiana Cruceanu, Piotr M. Czerski, Clarissa R. Dantas, Alexandre Dayer, Bruno Étain, Peter Falkai, Andreas J. Forstner, Louise Frisén, Janice M. Fullerton, Sébastien Gard, Julie S. Garnham, Fernando S. Goes, Paul Grof, Oliver Gruber, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Per Hoffmann, Andrea Hofmann, Stephane 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, Markus M. Nöthen, 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 Stamm, Pavla Stopkova, Sarah K. Tighe, Alfonso Tortorella, Gustavo Turecki, Julia Volkert, Stephanie Witt, Adam Wright, L. Trevor Young, Peter P. Zandi, James B. Potash, J. Raymond Depaulo, Michael Bauer, Eva Z. Reininghaus, Tomas 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, Marcella Rietschel, Francis J. McMahon, Thomas G. Schulze

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37×10-8; rs78015114, p=1·31×10-8; rs74795342, p=3·31×10-9; and rs75222709, p=3·50×10-9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

Original languageEnglish (US)
Pages (from-to)1085-1093
Number of pages9
JournalThe Lancet
Volume387
Issue number10023
DOIs
StatePublished - Mar 12 2016

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Genome-Wide Association Study
Bipolar Disorder
Lithium
Single Nucleotide Polymorphism
Therapeutics
Alleles
Long Noncoding RNA
National Institute of Mental Health (U.S.)
Chromosomes, Human, Pair 21
Regulator Genes
Genetic Markers
Meta-Analysis
Biomarkers
Genotype
Genome
Prospective Studies
Gene Expression
Recurrence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hou, L., Heilbronner, U., Degenhardt, F., Adli, M., Akiyama, K., Akula, N., ... Schulze, T. G. (2016). Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study. The Lancet, 387(10023), 1085-1093. https://doi.org/10.1016/S0140-6736(16)00143-4

Genetic variants associated with response to lithium treatment in bipolar disorder : A genome-wide association study. / Hou, Liping; Heilbronner, Urs; Degenhardt, Franziska; Adli, Mazda; Akiyama, Kazufumi; Akula, Nirmala; Ardau, Raffaella; Arias, Bárbara; Backlund, Lena; Banzato, Claudio E M; Benabarre, Antoni; Bengesser, Susanne; Bhattacharjee, Abesh Kumar; Biernacka, Joanna M; Birner, Armin; Brichant-Petitjean, Clara; Bui, Elise T.; Cervantes, Pablo; Chen, Guo Bo; Chen, Hsi Chung; Chillotti, Caterina; Cichon, Sven; Clark, Scott R.; Colom, Francesc; Cousins, David A.; Cruceanu, Cristiana; Czerski, Piotr M.; Dantas, Clarissa R.; Dayer, Alexandre; Étain, Bruno; Falkai, Peter; Forstner, Andreas J.; Frisén, Louise; Fullerton, Janice M.; Gard, Sébastien; Garnham, Julie S.; Goes, Fernando S.; Grof, Paul; Gruber, Oliver; Hashimoto, Ryota; Hauser, Joanna; Herms, Stefan; Hoffmann, Per; Hofmann, Andrea; Jamain, Stephane; 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.; Nöthen, Markus 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; Stopkova, Pavla; Tighe, Sarah K.; Tortorella, Alfonso; Turecki, Gustavo; Volkert, Julia; Witt, Stephanie; Wright, Adam; Young, L. Trevor; Zandi, Peter P.; Potash, James B.; Depaulo, J. Raymond; Bauer, Michael; Reininghaus, Eva Z.; Novák, Tomas; 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; Del Zompo, Maria; Bellivier, Frank; Schalling, Martin; Wray, Naomi R.; Kelsoe, John R.; Alda, Martin; Rietschel, Marcella; McMahon, Francis J.; Schulze, Thomas G.

In: The Lancet, Vol. 387, No. 10023, 12.03.2016, p. 1085-1093.

Research output: Contribution to journalArticle

Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Banzato, CEM, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Bui, ET, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dantas, CR, Dayer, A, Étain, B, Falkai, P, Forstner, AJ, Frisén, L, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, 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, Nöthen, MM, 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, T, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, S, Wright, A, Young, LT, Zandi, PP, Potash, JB, Depaulo, JR, Bauer, M, Reininghaus, EZ, 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, Del Zompo, M, Bellivier, F, Schalling, M, Wray, NR, Kelsoe, JR, Alda, M, Rietschel, M, McMahon, FJ & Schulze, TG 2016, 'Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study', The Lancet, vol. 387, no. 10023, pp. 1085-1093. https://doi.org/10.1016/S0140-6736(16)00143-4
Hou, Liping ; Heilbronner, Urs ; Degenhardt, Franziska ; Adli, Mazda ; Akiyama, Kazufumi ; Akula, Nirmala ; Ardau, Raffaella ; Arias, Bárbara ; Backlund, Lena ; Banzato, Claudio E M ; Benabarre, Antoni ; Bengesser, Susanne ; Bhattacharjee, Abesh Kumar ; Biernacka, Joanna M ; Birner, Armin ; Brichant-Petitjean, Clara ; Bui, Elise T. ; Cervantes, Pablo ; Chen, Guo Bo ; Chen, Hsi Chung ; Chillotti, Caterina ; Cichon, Sven ; Clark, Scott R. ; Colom, Francesc ; Cousins, David A. ; Cruceanu, Cristiana ; Czerski, Piotr M. ; Dantas, Clarissa R. ; Dayer, Alexandre ; Étain, Bruno ; Falkai, Peter ; Forstner, Andreas J. ; Frisén, Louise ; Fullerton, Janice M. ; Gard, Sébastien ; Garnham, Julie S. ; Goes, Fernando S. ; Grof, Paul ; Gruber, Oliver ; Hashimoto, Ryota ; Hauser, Joanna ; Herms, Stefan ; Hoffmann, Per ; Hofmann, Andrea ; Jamain, Stephane ; 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. ; Nöthen, Markus 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 ; Stopkova, Pavla ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Volkert, Julia ; Witt, Stephanie ; Wright, Adam ; Young, L. Trevor ; Zandi, Peter P. ; Potash, James B. ; Depaulo, J. Raymond ; Bauer, Michael ; Reininghaus, Eva Z. ; Novák, Tomas ; 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 ; Del Zompo, Maria ; Bellivier, Frank ; Schalling, Martin ; Wray, Naomi R. ; Kelsoe, John R. ; Alda, Martin ; Rietschel, Marcella ; McMahon, Francis J. ; Schulze, Thomas G. / Genetic variants associated with response to lithium treatment in bipolar disorder : A genome-wide association study. In: The Lancet. 2016 ; Vol. 387, No. 10023. pp. 1085-1093.
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title = "Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study",
abstract = "Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37×10-8; rs78015114, p=1·31×10-8; rs74795342, p=3·31×10-9; and rs75222709, p=3·50×10-9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95{\%} CI 1·1-13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.",
author = "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 Banzato, {Claudio E M} and Antoni Benabarre and Susanne Bengesser and Bhattacharjee, {Abesh Kumar} and Biernacka, {Joanna M} and Armin Birner and Clara Brichant-Petitjean and Bui, {Elise T.} and Pablo Cervantes and Chen, {Guo Bo} and Chen, {Hsi Chung} and Caterina Chillotti and Sven Cichon and Clark, {Scott R.} and Francesc Colom and Cousins, {David A.} and Cristiana Cruceanu and Czerski, {Piotr M.} and Dantas, {Clarissa R.} and Alexandre Dayer and Bruno {\'E}tain and Peter Falkai and Forstner, {Andreas J.} and Louise Fris{\'e}n and Fullerton, {Janice M.} 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 Per Hoffmann and Andrea Hofmann and Stephane 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 N{\"o}then, {Markus 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 Thomas Stamm and Pavla Stopkova and Tighe, {Sarah K.} and Alfonso Tortorella and Gustavo Turecki and Julia Volkert and Stephanie Witt and Adam Wright and Young, {L. Trevor} and Zandi, {Peter P.} and Potash, {James B.} and Depaulo, {J. Raymond} and Michael Bauer and Reininghaus, {Eva Z.} and Tomas 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 {Del Zompo}, Maria and Frank Bellivier and Martin Schalling and Wray, {Naomi R.} and Kelsoe, {John R.} and Martin Alda and Marcella Rietschel and McMahon, {Francis J.} and Schulze, {Thomas G.}",
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month = "3",
day = "12",
doi = "10.1016/S0140-6736(16)00143-4",
language = "English (US)",
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pages = "1085--1093",
journal = "The Lancet",
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TY - JOUR

T1 - Genetic variants associated with response to lithium treatment in bipolar disorder

T2 - A genome-wide association study

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 - Banzato, Claudio E M

AU - Benabarre, Antoni

AU - Bengesser, Susanne

AU - Bhattacharjee, Abesh Kumar

AU - Biernacka, Joanna M

AU - Birner, Armin

AU - Brichant-Petitjean, Clara

AU - Bui, Elise T.

AU - Cervantes, Pablo

AU - Chen, Guo Bo

AU - Chen, Hsi Chung

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Clark, Scott R.

AU - Colom, Francesc

AU - Cousins, David A.

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dantas, Clarissa R.

AU - Dayer, Alexandre

AU - Étain, Bruno

AU - Falkai, Peter

AU - Forstner, Andreas J.

AU - Frisén, Louise

AU - Fullerton, Janice M.

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 - Hoffmann, Per

AU - Hofmann, Andrea

AU - Jamain, Stephane

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 - Nöthen, Markus 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

AU - Stopkova, Pavla

AU - Tighe, Sarah K.

AU - Tortorella, Alfonso

AU - Turecki, Gustavo

AU - Volkert, Julia

AU - Witt, Stephanie

AU - Wright, Adam

AU - Young, L. Trevor

AU - Zandi, Peter P.

AU - Potash, James B.

AU - Depaulo, J. Raymond

AU - Bauer, Michael

AU - Reininghaus, Eva Z.

AU - Novák, Tomas

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 - Del Zompo, Maria

AU - Bellivier, Frank

AU - Schalling, Martin

AU - Wray, Naomi R.

AU - Kelsoe, John R.

AU - Alda, Martin

AU - Rietschel, Marcella

AU - McMahon, Francis J.

AU - Schulze, Thomas G.

PY - 2016/3/12

Y1 - 2016/3/12

N2 - Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37×10-8; rs78015114, p=1·31×10-8; rs74795342, p=3·31×10-9; and rs75222709, p=3·50×10-9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

AB - Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37×10-8; rs78015114, p=1·31×10-8; rs74795342, p=3·31×10-9; and rs75222709, p=3·50×10-9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

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SN - 0140-6736

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