Association of Polygenic Score for Schizophrenia and HLA Antigen and Inflammation Genes With Response to Lithium in Bipolar Affective Disorder A Genome-Wide Association Study

被引：132

作者：

Amare, Azmeraw T. ^{[1
,2
]}

Schubert, Klaus Oliver ^{[1
,2
,3
]}

Hou, Liping ^{[4
]}

Clark, Scott R. ^{[1
,2
]}

Papiol, Sergi ^{[5
,6
]}

Heilbronner, Urs ^{[5
,7
]}

Degenhardt, Franziska ^{[8
,9
]}

Tekola-Ayele, Fasil ^{[10
]}

Hsu, Yi-Hsiang ^{[11
,12
,13
]}

Shekhtman, Tatyana ^{[14
]}

Adli, Mazda ^{[15
]}

Akula, Nirmala ^{[4
]}

Akiyama, Kazufumi ^{[16
]}

Ardau, Raffaella ^{[17
]}

Arias, Barbara ^{[18
,19
]}

Aubry, Jean-Michel ^{[20
]}

Backlund, Lena ^{[21
,22
]}

Bhattacharjee, Abesh Kumar ^{[14
]}

Bellivier, Frank ^{[23
]}

Benabarre, Antonio ^{[24
]}

Bengesser, Susanne ^{[25
]}

Biernacka, Joanna M. ^{[26
,27
]}

Birner, Armin ^{[25
]}

Brichant-Petitjean, Clara ^{[23
]}

Cervantes, Pablo ^{[28
]}

Chen, Hsi-Chung ^{[29
,30
]}

Chillotti, Caterina ^{[17
]}

Cichon, Sven ^{[8
,9
,31
]}

Cruceanu, Cristiana ^{[32
]}

Czerski, Piotr M. ^{[33
]}

Dalkner, Nina ^{[25
]}

Dayer, Alexandre ^{[20
]}

Del Zompo, Maria ^{[34
]}

DePaulo, J. Raymond ^{[35
]}

Etain, Bruno ^{[23
]}

Falkai, Peter ^{[6
]}

Forstner, Andreas J. ^{[8
,9
,31
,36
]}

Frisen, Louise ^{[21
,22
]}

Frye, Mark A. ^{[27
]}

Fullerton, Janice M. ^{[37
,38
]}

Gard, Sebastien ^{[39
]}

Garnham, Julie S. ^{[40
]}

Goes, Fernando S. ^{[35
]}

Grigoroiu-Serbanescu, Maria ^{[41
]}

Grof, Paul ^{[42
]}

Hashimoto, Ryota ^{[43
,44
]}

Hauser, Joanna ^{[33
]}

Herms, Stefan ^{[8
,9
,31
]}

Hoffmann, Per ^{[8
,9
,31
]}

Hofmann, Andrea ^{[8
,9
]}

机构：

[1] Univ Adelaide, Sch Med, Discipline Psychiat, 57 N Terrace, Adelaide, SA 5000, Australia

[2] Univ Adelaide, Discipline Psychiat, Sch Med, Adelaide, SA, Australia

[3] Northern Adelaide Local Hlth Network, Mental Hlth Serv, Adelaide, SA, Australia

[4] US Dept HHS, Intramural Res Program, Natl Inst Mental Hlth, Natl Inst Hlth, Bethesda, MD USA

[5] Conclusions We demonstrated first time lower SCZ, Inst Psychiat Phen & Gen, Univ Hosp, Munich, Germany

[6] Ludwig Maximilian Univ Munich, Dept Psychiat & Psychotherapy, Munich, Germany

[7] Georg August Univ Gottingen, Dept Psychiat & Psychotherapy, Univ Med Ctr, Gottingen, Germany

[8] Univ Bonn, Inst Human Genet, Bonn, Germany

[9] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany

[10] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Intramural Populat Hlth Res, Natl Inst Hlth, Bethesda, MD USA

[11] Harvard Med Sch, Hebrew SeniorLife Inst Aging Res, Boston, MA USA

[12] Harvard Sch Publ Hlth, Program Quantitat Gen, Boston, MA USA

[13] Broad Inst Massachusetts Inst Technol & Harvard, Cambridge, MA USA

[14] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[15] Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Berlin, Germany

[16] Dokkyo Med Univ, Sch Med, Dept Biol Psychiat & Neurosci, Mibu, Tochigi, Japan

[17] Hosp Univ Agcy Cagliari, Unit Clin Pharmacol, Cagliari, Italy

[18] Univ Barcelona, Unitat Zool & Antropol Biolog, Ecol & Ciencies Ambientals, Ctr Invest Biomed Red,Dept Biol Evolutiva,Fac Bio, Barcelona, Spain

[19] Univ Barcelona, Inst Biomed, Ctr Invest Biomed Red Salud Mental, Barcelona, Spain

[20] Geneva Univ Hosp, Dept Psychiat, Mood Disorders Unit, Geneva, Switzerland

[21] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[22] Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden

[23] Univ Paris Diderot, Grp Hosp St Louis Lariboisiere Widal, Dept Psychiat & Med Addictolog, INSERM,Unite Mixte Rech Sci 1144,AP HP, Paris, France

[24] Conclusions We demonstrated first time lower SCZ, Inst Invest Biomed August Pi & Sunyer, Ctr Invest Biomed Red Salud Mental, Hosp Clin,Inst Neurosci,Bipolar Disorder Program, Barcelona, Catalonia, Spain

[25] Med Univ Graz, Dept Psychiat & Psychotherapeut Med, Res Unit Bipolar Affect Disorder, Graz, Austria

[26] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[27] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN USA

[28] McGill Univ, Ctr Hlth, Neuromodulat Unit, Montreal, PQ, Canada

[29] Natl Taiwan Univ Hosp, Dept Psychiat, Taipei, Taiwan

[30] Natl Taiwan Univ Hosp, Ctr Sleep Disorders, Taipei, Taiwan

[31] Univ Basel Hosp, Human Genom Res Grp, Dept Biomed, Basel, Switzerland

[32] McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada

[33] Poznan Univ Med Sci, Psychiat Genet Unit, Poznan, Poland

[34] Univ Cagliari, Dept Biomed Sci, Cagliari, Italy

[35] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA

[36] Univ Basel, Dept Psychiat, Basel, Switzerland

[37] Neurosci Res Australia, Sydney, NSW, Australia

[38] Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia

[39] Hop Charles Perrens, Serv Psychiat, Bordeaux, France

[40] Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada

[41] Alexandru Obregia Clin Psychiat Hosp, Biometr Psychiat Genet Res Unit, Bucharest, Romania

[42] Mood Disorders Ctr, Ottawa, ON, Canada

[43] Osaka Univ, Mol Res Ctr Childrens Mental Dev, United Grad Sch Child Dev, Osaka, Japan

[44] Osaka Univ, Dept Psychiat, Grad Sch Med, Osaka, Japan

[45] INSERM, Psychiat Translat, Unite 955, Creteil, France

[46] Univ Lorraine, Serv Psychiat & Psychol Clin, Ctr Psychotherap Nancy, Nancy, France

[47] Natl Taiwan Univ, Dept Publ Hlth, Coll Publ Hlth, Taipei, Taiwan

[48] Natl Taiwan Univ, Inst Epidemiol & Prevent Med, Coll Publ Hlth, Taipei, Taiwan

[49] RIKEN Brain Sci Inst, Lab Mol Dynam Mental Disorders, Saitama, Japan

[50] Univ Hosp Frankfurt, Dept Psychiat Psychosomat Med & Psychotherapy, Frankfurt, Germany

来源：

JAMA PSYCHIATRY | 2018年 / 75卷 / 01期

基金：

美国国家卫生研究院; 瑞士国家科学基金会; 加拿大健康研究院; 瑞典研究理事会; 英国医学研究理事会;

关键词：

CYTOKINE PRODUCTION; PROPHYLACTIC LITHIUM; SPECTRUM DISORDER; RISK; PREVALENCE; GENETICS;

D O I：

10.1001/jamapsychiatry.2017.3433

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013. Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with ;lithium treatment response in the categorical outcome, at a threshold P < 5 x 10(-2). Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95% CI, 1.42-8.41) at the first decile to 2.03 (95% CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. CONCLUSIONS AND RELEVANCE This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

引用

页码：65 / 74

页数：10

共 70 条

[1] Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics [J].

Alda, M. .

MOLECULAR PSYCHIATRY, 2015, 20 (06) :661-670

[2]

[Anonymous], MOL PSYCHIAT

[3] Cytokine production in bipolar affective disorder patients under lithium treatment [J].

Boufidou, F ;

Nikolaou, C ;

Alevizos, B ;

Liappas, LA ;

Christodoulou, GN .

JOURNAL OF AFFECTIVE DISORDERS, 2004, 82 (02) :309-313

[4] LITHIUM SALTS IN THE TREATMENT OF PSYCHOTIC EXCITEMENT [J].

CADE, JFJ .

MEDICAL JOURNAL OF AUSTRALIA, 1949, 2 (10) :349-352

[5] Variant GADL1 and Response to Lithium Therapy in Bipolar I Disorder [J].

Chen, C. -H. ;

Lee, C. -S. ;

Lee, M. -T. M. ;

Ouyang, W. -C. ;

Chen, Chiao-Chicy ;

Chong, M. -Y. ;

Wu, J. -Y. ;

Tan, H. K. -L. ;

Lee, Y. -C. ;

Chuo, L. -J. ;

Chiu, N. -Y. ;

Tsang, H. -Y. ;

Chang, T. -J. ;

Lung, F. -W. ;

Chiu, C. -H. ;

Chang, C. -H. ;

Chen, Y. -S. ;

Hou, Y. -M. ;

Chen, Cheng-Chung ;

Lai, T. -J. ;

Tung, C. -L. ;

Chen, C. -Y. ;

Lane, H. -Y. ;

Su, T. -P. ;

Feng, J. ;

Lin, J. -J. ;

Chang, C. -J. ;

Teng, P. -R. ;

Liu, C. -Y. ;

Chen, C. -K. ;

Liu, I. -C. ;

Chen, J. -J. ;

Lu, T. ;

Fan, C. -C. ;

Wu, C. -K. ;

Li, C. -F. ;

Wang, K. H. -T. ;

Wu, L. S. -H. ;

Peng, H. -L. ;

Chang, C. -P. ;

Lu, L. -S. ;

Chen, Y. -T. ;

Cheng, A. T. -A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2014, 370 (02) :119-128

[6] Risks of all-cause and suicide mortality in mental disorders: a meta-review [J].

Chesney, Edward ;

Goodwin, Guy M. ;

Fazel, Seena .

WORLD PSYCHIATRY, 2014, 13 (02) :153-160

[7]

Cichon S, 2011, AM J HUM GENET, V88, P372, DOI 10.1016/j.ajhg.2011.01.017

[8] Early improvement of psychotic symptoms with lithium monotherapy as a predictor of later response in mania [J].

de Sousa, Rafael T. ;

Busnello, Joao V. ;

Forlenza, Orestes V. ;

Zanetti, Marcus V. ;

Soeiro-de-Souza, Marcio G. ;

van de Bilt, Martinus T. ;

Moreno, Ricardo A. ;

Zarate, Carlos A., Jr. ;

Gattaz, Wagner F. ;

Machado-Vieira, Rodrigo .

JOURNAL OF PSYCHIATRIC RESEARCH, 2012, 46 (12) :1564-1568

[9] CELL-MEMBRANE PREDICTORS OF RESPONSE TO LITHIUM PROPHYLAXIS OF AFFECTIVE-DISORDERS [J].

DELVECCHIO, M ;

FARZATI, B ;

MAJ, M ;

MINUCCI, P ;

GUIDA, L ;

KEMALI, D .

NEUROPSYCHOBIOLOGY, 1981, 7 (05) :243-247

[10] A consecutive series of treated affected offspring of parents with bipolar disorder: Is response associated with the clinical profile? [J].

Duffy, Anne ;

Alda, Martin ;

Milin, Robert ;

Grof, Paul .

CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE, 2007, 52 (06) :369-376

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