Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia.,JAMA Psychiatry

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Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia.
JAMA Psychiatry ( IF 22.5 ) Pub Date : 2022-03-01 , DOI: 10.1001/jamapsychiatry.2021.3799
Antonio F Pardiñas ₁ , Sophie E Smart _{1,

2} , Isabella R Willcocks ₁ , Peter A Holmans ₁ , Charlotte A Dennison ₁ , Amy J Lynham ₁ , Sophie E Legge ₁ , Bernhard T Baune _{3,

4,

5} , Tim B Bigdeli _{6,

7,

8} , Murray J Cairns _{9,

10,

11} , Aiden Corvin ₁₂ , Ayman H Fanous _{6,

7} , Josef Frank ₁₃ , Brian Kelly ₁₄ , Andrew McQuillin ₁₅ , Ingrid Melle _{16,

17} , Preben B Mortensen _{18,

19} , Bryan J Mowry _{20,

21} , Carlos N Pato _{7,

22,

23} , Sathish Periyasamy _{20,

21} , Marcella Rietschel ₁₃ , Dan Rujescu _{24,

25} , Carmen Simonsen _{16,

26} , David St Clair ₂₇ , Paul Tooney _{9,

11} , Jing Qin Wu ₂₈ , Ole A Andreassen _{16,

17} , Kaarina Kowalec _{29,

30} , Patrick F Sullivan _{30,

31,

32} , Robin M Murray ₂ , Michael J Owen ₁ , James H MacCabe ₂ , Michael C O'Donovan ₁ , James T R Walters ₁ , , Olesya Ajnakina _{33,

34} , Luis Alameda _{2,

35,

36,

37} , Thomas R E Barnes ₃₈ , Domenico Berardi ₃₉ , Elena Bonora ₄₀ , Sara Camporesi _{37,

41} , Martine Cleusix ₄₁ , Philippe Conus ₃₇ , Benedicto Crespo-Facorro _{35,

36} , Giuseppe D'Andrea ₃₉ , Arsime Demjaha ₂ , Kim Q Do ₄₁ , Gillian A Doody ₄₂ , Chin B Eap _{43,

44,

45,

46} , Aziz Ferchiou ₄₇ , Marta Di Forti _{48,

49} , Lorenzo Guidi ₄₀ , Lina Homman _{50,

51} , Raoul Jenni ₄₁ , Eileen M Joyce ₅₂ , Laura Kassoumeri ₂ , Inès Khadimallah ₄₁ , Ornella Lastrina ₃₉ , Roberto Muratori ₄₀ , Handan Noyan ₅₃ , Francis A O'Neill ₅₁ , Baptiste Pignon _{47,

54} , Romeo Restellini _{37,

41} , Jean-Romain Richard ₄₇ , Franck Schürhoff _{47,

54} , Filip Španiel _{55,

56} , Andrei Szöke _{47,

54} , Ilaria Tarricone ₄₀ , Andrea Tortelli _{47,

57} , Alp Üçok ₅₈ , Javier Vázquez-Bourgon _{59,

60,

61}

Affiliation

MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
Department of Psychiatry, University of Münster, Münster, Germany.
Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia.
Department of Psychiatry and the Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn.
Institute for Genomic Health, State University of New York Downstate Medical Center, Brooklyn.
Department of Psychiatry, Veterans Affairs New York Harbor Healthcare System, Brooklyn.
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
Centre for Brain and Mental Health Research, University of Newcastle, Newcastle, Australia.
Hunter Medical Research Institute, Newcastle, Australia.
Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Mannheim, Germany.
School of Medicine & Public Health, The University of Newcastle, Newcastle, Australia.
Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom.
Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Division of Mental Health and Addiction, Institute of Clinical Medicine, Oslo University Hospital, Oslo, Norway.
National Centre for Register-based Research, Aarhus University, Aarhus, Denmark.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, Australia.
Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn.
Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine, University of Southern California, Los Angeles.
University Clinic and Outpatient Clinic for Psychiatry, Psychotherapy and Psychosomatics, Martin Luther University of Halle-Wittenberg, Halle, Germany.
Division of General Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
Early Intervention in Psychosis Advisory Unit for South-East Norway, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
Baker Heart and Diabetes Institute, Melbourne, Australia.
College of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Psychiatry, Icahn School of Medicine, Mount Sinai Hospital, New York, New York.
Department of Genetics, University of North Carolina, Chapel Hill.
Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, University of London, London, United Kingdom.
Department of Behavioural Science and Health, Institute of Epidemiology and Health Care, University College London, London, United Kingdom.
Centro de Investigacion Biomedica en Red de Salud Mental, Spanish Network for Research in Mental Health, Sevilla, Spain.
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, Departamento de Psiquiatria, Universidad de Sevilla, Sevilla, Spain.
Treatment and Early Intervention in Psychosis Program, Service of General Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
Division of Psychiatry, Imperial College London, London, United Kingdom.
Department of Biomedical and Neuro-motor Sciences, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Bologna, Italy.
Department of Medical and Surgical Sciences, Bologna Transcultural Psychosomatic Team, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Unit for Research in Schizophrenia, Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland.
Department of Medical Education, University of Nottingham Faculty of Medicine and Health Sciences, Nottingham, United Kingdom.
Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, University of Lausanne, Prilly, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland.
University Paris-Est Créteil, Institut national de la santé et de la recherche médicale, Mondor Institute for Biomedical Research, Translational Neuropsychiatry, Fondation FondaMental, Créteil, France.
Social Genetics and Developmental Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
South London and Maudsley National Health Service Mental Health Foundation Trust, London, United Kingdom.
Department of Social and Welfare Studies, Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden.
Centre For Public Health, Institute Of Clinical Sciences, Queens University Belfast, Belfast, United Kingdom.
UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Faculty of Social Sciences, Department of Psychology, Beykoz University, Istanbul, Turkey.
Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires HMondor, Département Médico-Universitaire de Psychiatrie et d'Addictologie, Fédération Hospitalo-Universitaire de Médecine de Précision, Créteil, France.
Department of Applied Neuroscience and Neuroimaging, National Institute of Mental Health, Klecany, Czechia.
Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Prague, Czechia.
Groupe Hospitalier Universitaire Psychiatrie Neurosciences Paris, Pôle Psychiatrie Précarité, Paris, France.
Department of Psychiatry, Istanbul University, Istanbul, Turkey.
Department of Psychiatry, University Hospital Marques de Valdecilla-Instituto de Investigación Marques de Valdecilla, Santander, Spain.
Department of Medicine and Psychiatry, School of Medicine, University of Cantabria, Santander, Spain.
Centro de Investigacion Biomedica en Red de Salud Mental, Spanish Network for Research in Mental Health, Santander, Spain.

IMPORTANCE About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. OBJECTIVE To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. DESIGN, SETTING, AND PARTICIPANTS Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). MAIN OUTCOMES AND MEASURES GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. RESULTS The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04). CONCLUSIONS AND RELEVANCE In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance.

中文翻译：

相互作用测试和多基因风险评分以估计常见遗传变异与精神分裂症治疗耐药性的关联。

重要性大约 20% 到 30% 的精神分裂症患者有精神病症状，这些症状对一线抗精神病药物治疗反应不佳。这种慢性和高度致残的临床表现被称为难治性精神分裂症 (TRS)。治疗抵抗的原因及其与精神分裂症潜在原因的关系在很大程度上是未知的。由于难以从特征明确的 TRS 队列中收集数据，因此缺乏足够有力的 TRS 遗传学研究。目的通过重新评估精神分裂症研究的遗传数据及其在仔细确定的临床样本中的验证来检查 TRS 的遗传结构。设计、设置、和参与者进行了两项精神分裂症病例对照全基因组关联研究 (GWAS)，其中病例样本被定义为患有 TRS 的个体 (n = 10 501) 和患有非 TRS 的个体 (n = 20 325)。然后确定了两项研究之间等位基因关联的效应量差异，原因是这种差异反映了治疗抵抗而不是精神分裂症。从 CLOZUK 和 Psychiatric Genomics Consortium (PGC) 精神分裂症研究中检索基因型数据。使用 2 个具有 TRS 和非 TRS 的独立精神分裂症队列的多基因风险评分 (PRS) 分析来验证输出：817 人的患病率样本（精神分裂症的卡迪夫认知 [CardiffCOGS]）和 563 人的发病率样本（精神分裂症治疗耐药性和治疗进展的遗传学工作流 [STRATA-G]）。精神分裂症治疗耐药性的主要结果和测量 GWAS。GWAS 的结果通过遗传相关性方法与复杂的多基因性状进行比较，并用于使用相同 TRS 定义的独立验证队列的 PRS 分析。结果该研究共包括 85490 名处于 GWAS 阶段的参与者（48635 [56.9%] 男性）和 1380 名处于 PRS 验证阶段的参与者（859 [62.2%] 男性）。精神分裂症的治疗耐药性表现为具有可检测遗传性（1% 至 4%）的多基因特征，并且发现与智力和认知相关的几个特征与其具有遗传相关性（遗传相关性，0.41-0.69）。CardiffCOGS 患病率样本中的 PRS 分析显示 TRS 与服用氯氮平的历史呈正相关（r2 = 2.03%；P = .001），这在 STRATA-G 发病率样本中得到复制（r2 = 1.09%；P = . 04). 结论和相关性在此 GWAS 中，常见的遗传变异与 TRS 有差异关联，并且这些关联可能已通过先前广泛定义的精神分裂症研究中大量 GWAS 样本的合并而被掩盖。这项研究的结果表明元分析方法对研究患者结果（包括治疗耐药性）的有效性。CardiffCOGS 患病率样本中的 PRS 分析显示 TRS 与服用氯氮平的历史呈正相关（r2 = 2.03%；P = .001），这在 STRATA-G 发病率样本中得到复制（r2 = 1.09%；P = . 04). 结论和相关性在此 GWAS 中，常见的遗传变异与 TRS 有差异关联，并且这些关联可能已通过先前广泛定义的精神分裂症研究中大量 GWAS 样本的合并而被掩盖。这项研究的结果表明元分析方法对研究患者结果（包括治疗耐药性）的有效性。CardiffCOGS 患病率样本中的 PRS 分析显示 TRS 与服用氯氮平的历史呈正相关（r2 = 2.03%；P = .001），这在 STRATA-G 发病率样本中得到复制（r2 = 1.09%；P = . 04). 结论和相关性在此 GWAS 中，常见的遗传变异与 TRS 有差异关联，并且这些关联可能已通过先前广泛定义的精神分裂症研究中大量 GWAS 样本的合并而被掩盖。这项研究的结果表明元分析方法对研究患者结果（包括治疗耐药性）的有效性。常见的遗传变异与 TRS 有差异关联，并且这些关联可能已通过先前广泛定义的精神分裂症研究中大量 GWAS 样本的合并而被掩盖。这项研究的结果表明元分析方法对研究患者结果（包括治疗耐药性）的有效性。常见的遗传变异与 TRS 有差异关联，并且这些关联可能已通过先前广泛定义的精神分裂症研究中大量 GWAS 样本的合并而被掩盖。这项研究的结果表明元分析方法对研究患者结果（包括治疗耐药性）的有效性。

更新日期：2022-01-12

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