Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.,Molecular Psychiatry

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Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2018-May-01 , DOI: 10.1038/mp.2017.88
L M Huckins _{1,

2} , K Hatzikotoulas ₁ , L Southam ₁ , L M Thornton ₃ , J Steinberg ₁ , F Aguilera-McKay ₁ , J Treasure ₄ , U Schmidt ₄ , C Gunasinghe _{4,

5} , A Romero _{4,

5} , C Curtis _{4,

5} , D Rhodes _{4,

5} , J Moens _{4,

5} , G Kalsi _{4,

5} , D Dempster _{4,

5} , R Leung _{4,

5} , A Keohane _{4,

5} , R Burghardt ₆ , S Ehrlich _{7,

8} , J Hebebrand ₉ , A Hinney ₉ , A Ludolph ₁₀ , E Walton _{11,

12} , P Deloukas ₁ , A Hofman ₁₃ , A Palotie _{14,

15} , P Palta ₁₅ , F J A van Rooij ₁₃ , K Stirrups ₁ , R Adan ₁₆ , C Boni ₁₇ , R Cone ₁₈ , G Dedoussis ₁₉ , E van Furth ₂₀ , F Gonidakis ₂₁ , P Gorwood ₁₇ , J Hudson ₂₂ , J Kaprio ₁₅ , M Kas ₂₃ , A Keski-Rahkonen ₂₄ , K Kiezebrink ₂₅ , G-P Knudsen ₂₆ , M C T Slof-Op 't Landt ₂₀ , M Maj ₂₇ , A M Monteleone ₂₇ , P Monteleone ₂₈ , A H Raevuori ₂₄ , T Reichborn-Kjennerud ₂₉ , F Tozzi ₃₀ , A Tsitsika ₃₁ , A van Elburg ₃₂ , , D A Collier ₃₃ , P F Sullivan _{34,

35} , G Breen ₃₆ , C M Bulik _{3,

35} , E Zeggini ₁

Affiliation

Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Section of Eating Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
NIHR BRC SLaM BioResource for Mental Health, SGDP Centre & Centre for Neuroimaging Sciences, Section of Eating Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Klinik für Kinder- und Jugendpsychiatrie, Psychotherapie und Psychosomatik Klinikum Frankfurt, Frankfurt, Germany.
Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany.
Eating Disorders Research and Treatment Center, Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Neuherberg, Germany.
Division of Psychological & Social Medicine and Developmental Neurosciences, Technische Universität Dresden, Faculty of Medicine, University Hospital C.G. Carus, Dresden, Germany.
Department of Psychology, Georgia State University, Atlanta, GA, USA.
Erasmus University Medical Center, Rotterdam, The Netherlands.
Center for Human Genome Research at the Massachusetts General Hospital, Boston, MA, USA.
Department of Public Health & Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
Brain Center Rudolf Magnus, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands.
INSERM U984, Centre of Psychiatry and Neuroscience, Paris, France.
Mary Sue Coleman Director, Life Sciences Institute, Professor of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.
Rivierduinen Eating Disorders Ursula, Leiden, Zuid-Holland, The Netherlands.
Eating Disorders Unit, 1st Department of Psychiatry, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands.
Department of Public Health, Clinicum, University of Helsinki, Helsinki, Finland.
Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway.
Department of Psychiatry, University of Naples SUN, Naples, Italy.
Department of Medicine and Surgery, Section of Neurosciences, University of Salerno, Salerno, Italy.
Department of Genetics, Environment and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
eHealth Lab-Computer Science Department, University of Cyprus, Nicosia, Cyprus.
Adolescent Health Unit (A.H.U.), 2nd Department of Pediatrics - Medical School, University of Athens "P. & A. Kyriakou" Children's Hospital, Athens, Greece.
Center for Eating Disorders Rintveld, University of Utrecht, Utrecht, The Netherlands.
Eli Lilly and Company, Erl Wood Manor, Windlesham, UK.
Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Medical Epidemiology and Biostatistics, Karolinksa Institutet, Stockholm, Sweden.
Social Genetic and Developmental Psychiatry, King's College London, London, UK.

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10^-6), and rs7700147, an intergenic variant (P=2.93 × 10^-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

中文翻译：

神经性厌食症常见、低频和罕见全基因组变异的调查。

神经性厌食症（AN）是一种复杂的神经精神疾病，表现为危险的低体重，以及对体重增加的深刻而持续的恐惧。迄今为止，仅鉴定出一个与 AN 相关的全基因组重要位点。我们对来自 9 个欧洲起源人群的 2158 个病例和 15485 个祖先匹配的对照进行了基于外显子组芯片的全基因组关联研究 (GWAS)。与之前的研究不同，这项 GWAS 还探讨了低频和罕见变异的关联。 16 个独立变体被用于计算机模拟和从头复制（11 个常见变体和 5 个罕见变体）。没有发现达到全基因组意义。鉴定出两个值得注意的常见变异：rs10791286，OPCML 中的内含子变异（P=9.89 × 10 ^-6 ），和 rs7700147，基因间变异（P=2.93 × 10 ^-5 ）。尽管该研究能够很好地检测具有大效应大小的低频变异，但没有在全基因组范围内鉴定出低频变异关联，这表明在该基因组搜索空间中可能不存在具有大效应大小的 AN 位点。

更新日期：2018-05-07

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