Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.,Molecular Psychiatry

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Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2020-02-03 , DOI: 10.1038/s41380-020-0654-3
Isabelle Cleynen ₁ , Worrawat Engchuan ₂ , Matthew S Hestand _{1,

3,

4} , Tracy Heung _{5,

6} , Aaron M Holleman ₇ , H Richard Johnston ₈ , Thomas Monfeuga ₉ , Donna M McDonald-McGinn _{10,

11} , Raquel E Gur ₁₂ , Bernice E Morrow ₁₃ , Ann Swillen _{1,

14} , Jacob A S Vorstman _{15,

16,

17} , Carrie E Bearden ₁₈ , Eva W C Chow _{5,

17} , Marianne van den Bree ₉ , Beverly S Emanuel ₁₁ , Joris R Vermeesch ₁ , Stephen T Warren ₈ , Michael J Owen ₉ , Pankaj Chopra ₈ , David J Cutler ₈ , Richard Duncan ₈ , Alex V Kotlar ₈ , Jennifer G Mulle ₈ , Anna J Voss ₈ , Michael E Zwick ₈ , Alexander Diacou ₁₃ , Aaron Golden ₁₃ , Tingwei Guo ₁₃ , Jhih-Rong Lin ₁₃ , Tao Wang ₁₉ , Zhengdong Zhang ₁₃ , Yingjie Zhao ₁₃ , Christian Marshall _{20,

21} , Daniele Merico _{2,

22} , Andrea Jin ₁₁ , Brenna Lilley ₁₁ , Harold I Salmons ₁₁ , Oanh Tran ₁₁ , Peter Holmans ₉ , Antonio Pardinas ₉ , James T R Walters ₉ , Wolfram Demaerel ₁ , Erik Boot ₆ , Nancy J Butcher ₅ , Gregory A Costain _{5,

23} , Chelsea Lowther ₅ , Rens Evers ₂₄ , Therese A M J van Amelsvoort ₂₄ , Esther van Duin ₂₄ , Claudia Vingerhoets ₂₄ , Jeroen Breckpot _{1,

14} , Koen Devriendt _{1,

14} , Elfi Vergaelen ₁₄ , Annick Vogels _{1,

14} , T Blaine Crowley ₁₁ , Daniel E McGinn ₁₁ , Edward M Moss ₁₁ , Robert J Sharkus ₁₁ , Marta Unolt ₁₁ , Elaine H Zackai _{10,

11} , Monica E Calkins ₁₂ , Robert S Gallagher ₁₂ , Ruben C Gur ₁₂ , Sunny X Tang ₁₂ , Rosemarie Fritsch ₂₅ , Claudia Ornstein ₂₅ , Gabriela M Repetto ₂₆ , Elemi Breetvelt _{17,

27} , Sasja N Duijff ₂₈ , Ania Fiksinski _{5,

29} , Hayley Moss ₉ , Maria Niarchou ₉ , Kieran C Murphy ₃₀ , Sarah E Prasad ₃₀ , Eileen M Daly ₃₁ , Maria Gudbrandsen ₃₁ , Clodagh M Murphy ₃₁ , Declan G Murphy ₃₁ , Antonio Buzzanca ₃₂ , Fabio Di Fabio ₃₂ , Maria C Digilio ₃₃ , Maria Pontillo ₃₄ , Bruno Marino ₃₅ , Stefano Vicari ₃₄ , Karlene Coleman ₈ , Joseph F Cubells _{8,

36} , Opal Y Ousley ₃₆ , Miri Carmel _{37,

38} , Doron Gothelf _{38,

39} , Ehud Mekori-Domachevsky _{38,

39} , Elena Michaelovsky _{37,

38} , Ronnie Weinberger ₃₉ , Abraham Weizman _{37,

38,

40} , Leila Kushan ₁₈ , Maria Jalbrzikowski ₄₁ , Marco Armando ₄₂ , Stéphan Eliez ₄₂ , Corrado Sandini ₄₂ , Maude Schneider ₄₂ , Frédérique Sloan Béna ₄₃ , Kevin M Antshel ₄₄ , Wanda Fremont ₄₅ , Wendy R Kates ₄₅ , Raoul Belzeaux ₄₆ , Tiffany Busa ₄₇ , Nicole Philip ₄₈ , Linda E Campbell ₄₉ , Kathryn L McCabe _{49,

50} , Stephen R Hooper ₅₁ , Kelly Schoch ₅₂ , Vandana Shashi ₅₂ , Tony J Simon ₅₃ , Flora Tassone ₅₄ , Celso Arango ₅₅ , David Fraguas ₅₅ , Sixto García-Miñaúr ₅₆ , Jaume Morey-Canyelles ₅₇ , Jordi Rosell ₅₇ , Damià H Suñer ₅₈ , Jasna Raventos-Simic ₅₇ , , Michael P Epstein ₈ , Nigel M Williams ₉ , Anne S Bassett _{5,

6,

17}

Affiliation

Department of Human Genetics, KU Leuven, Leuven, Belgium.
The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON, Canada.
Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Dalglish Family 22q Clinic, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
Department of Epidemiology, Emory University, Atlanta, GA, USA.
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.
Division of Human Genetics and 22q and You Center, the Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Psychiatry and Lifespan Brain Institute, Penn Medicine-CHOP, University of Pennsylvania, Philadelphia, PA, USA.
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
Departments of Psychiatry and Biobehavioral Sciences and Psychology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
Deep Genomics Inc., Toronto, ON, Canada.
Hospital for Sick Children, Toronto, ON, Canada.
School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
Universidad de Chile, Santiago, Chile.
Clinica Alemana Universidad del Desarrollo, Santiago, Chile.
Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada.
Department of Pediatrics, University Medical Center Utrecht, Utrecht, Netherlands.
Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Royal College of Surgeons in Ireland, Dublin, Ireland.
Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK.
Department of Human Neurosciences, University Sapienza of Rome, Rome, Italy.
Ospedale Bambino Gesu Pediatric Hospital, Rome, Italy.
Child and Adolescence Neuropsychiatry Unit, Department of Neuroscience, IRCSS Bambino Gesù Children's Hospital of Rome, Rome, Italy.
Sapienza University, Rome, Italy.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
Felsenstein Medical Research Center, Petach Tikva, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
The Child Psychiatry Division, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
Geha Mental Health Center, Petach Tikva, Israel.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Developmental Imaging and Psychopathology, Department of Psychiatry, University of Geneva, Geneva, Switzerland.
Department of Medical Genetics, Geneva University Hospitals, Geneva, Switzerland.
Department of Psychology, Syracuse University, Syracuse, NY, USA.
Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
Pôle de psychiatrie, Hopital Sainte Marguerite, Batiment Solaris, APHM, Marseille, France.
Departement de Genetique Medicale Hôpital d'Enfants de la Timone, APHM, Marseille, France.
Departement de Genetique Medicale Aix Marseille Univ, INSERM, GMGF, APHM, Marseille, France.
University of Newcastle, Callaghan, Australia.
University of California Davis, Davis, CA, USA.
Department of Allied Health Sciences, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC, USA.
MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis, Davis, CA, USA.
Department of Microbiology and Molecular Medicine, University of California Davis, Davis, CA, USA.
Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, School of Medicine, Universidad Complutense, Madrid, Spain.
Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
Hospital Universitari Son Espases, Palma, Spain.
Laboratorio Unidad de Diagnóstico Molecular y Genética Clínica, Hospital Universitari Son Espases, Palma de Mallorca, Spain.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

中文翻译：

22q11.2 缺失时精神分裂症风险的遗传因素。

大约四分之一的 22q11.2 缺失综合征 (22q11.2DS) 患者患有精神分裂症。这项国际大脑与行为 22q11.2DS 联盟 (IBBC) 研究的目的是确定导致精神分裂症的遗传因素，以及 22q11.2 缺失带来的约 20 倍的风险增加。利用 519 名患有 22q11.2DS 的无关个体的全基因组测序数据，我们对年龄≥25 岁的精神分裂症患者和无精神病患者之间的常见和罕见变异进行了全基因组比较。可用的微阵列数据可以直接比较 22q11.2DS 和无 22q11.2 缺失的独立群体样本、患有或不患有精神分裂症的精神分裂症多基因风险（总 n = 35,182）。对于精神分裂症患者来说，22q11.2DS 内的精神分裂症多基因风险显着更高 (padj = 6.73 × 10-6)。 22q11.2DS 与基于人群的队列之间的新型相互病例对照比较表明，无论是否存在 22q11.2 缺失，患有精神病的个体的多基因风险评分显着更高。在 22q11.2DS 队列中，基因集分析的结果显示了影响突触基因的罕见变异的一些支持。 22q11.2 缺失区域内的常见或罕见变异均与精神分裂症显着相关。这些发现表明，除了该缺失会大大增加患精神分裂症的风险外，当 22q11.2 缺失和导致普通人群患精神分裂症的常见多基因风险因素同时存在时，该风险也会更高。

更新日期：2020-02-04

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