体重指数与帕金森病的关联：一项双向孟德尔随机化研究。

Association of Body Mass Index and Parkinson Disease: A Bidirectional Mendelian Randomization Study.

机构信息

From the Université Paris-Saclay (C.D., P.-E.S., B.P., A.E.), UVSQ, Inserm, Gustave Roussy, CESP, Villejuif, France; Centre for Genetic Epidemiology (A.A.K.S., M.S.), Institute for Clinical Epidemiology and Applied Biometry, and Department for Neurodegenerative Diseases (C.S., K.B., T.G.), Hertie Institute for Clinical Brain Research, University of Tubingen; German Center for Neurodegenerative Diseases (DZNE) (C.S., K.B., T.G.), Tubingen; Center for Human Genetics (S.G.), Universitatsklinikum Giessen und Marburg, Germany; Department of Public Health (P.-C.L.), National Cheng Kung University, Tainan, Taiwan; Translational Neuroscience (P.M., D.B., R.K.), Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-Belval; Institute of Human Genetics (M.R.B., P.L.), Helmholtz Zentrum München, Neuherberg, Germany; Molecular Genetics Section (A.B.S., D.H., C.E.), Laboratory of Neurogenetics, and Center for Alzheimer's and Related Dementias (A.B.S.), NIA, NIH, Bethesda, MD; Griffith Institute for Drug Discovery (G.D.M.), Griffith University, Nathan, Australia; Department of Neurology (A.A.Z.), Medical University of Vienna; Department of Neurology (W.P.), Wilhelminenspital, Austria; Tanz Centre for Research in Neurodegenerative Diseases (E.A.R., A.E.L.), University of Toronto; Edmond J. Safra Program in Parkinson's Disease (A.E.L.), Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN; Division of Neurology (A.E.L.), University of Toronto; Krembil Brain Institute (A.E.L.), Toronto, Ontario, Canada; Centre for Molecular Medicine and Innovative Therapeutics (S.K.), Murdoch University; Perron Institute for Neurological and Translational Science (S.K.), Nedlands, Australia; Department of Neurology and Neurosurgery (P.T.), University of Tartu; Neurology Clinic (P.T.), Tartu University Hospital, Estonia; Department of Neurologie (S.L., A.B., J.-C.C.), Institut du Cerveau-Paris Brain Institute-ICM, INSERM, CNRS, Assistance Publique Hôpitaux de Paris, Sorbonne Université; Assistance Publique Hôpitaux de Paris (J.-C.C.), Department of Neurology, CIC Neurosciences; Univ. Lille (M.-C.C.-H., E.M.), Inserm, CHU Lille, UMR-S 1172-LilNCog-Centre de Recherche Lille Neurosciences & Cognition, France; Department of Neurology (A.B.D.), Ludwig Maximilians University of Munich; Department of Neurology (A.B.D.), Max Planck Institute of Psychiatry, Munich, Germany; Department of Neurology and Department of Clinical Genomics (A.B.D.), Mayo Clinic Florida, Jacksonville; Department of Neurology (G.M.H., E.D.), Laboratory of Neurogenetics, University of Thessaly, University Hospital of Larissa, Greece; Department of Neurology (G.M.H.), Medical School, University of Cyprus, Nicosia; 1st Department of Neurology (L. Stefanis, A.M.S.), Eginition Hospital, Medical School, National and Kapodistrian University of Athens; Center of Clinical Research, Experimental Surgery and Translational Research (L. Stefanis), Biomedical Research Foundation of the Academy of Athens, Greece; Department of Molecular Medicine (E.M.V.), University of Pavia; Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Mondino Foundation (E.M.V.), Pavia; UOC Medical Genetics and Advanced Cell Diagnostics (S.P.), S. Andrea University Hospital, Rome; Department of Clinical and Molecular Medicine (S.P.), University of Rome; Department of Biomedical Sciences (L. Straniero), Humanitas University, Milan; Parkinson Institute (A.L.Z.), Azienda Socio Sanitaria Territoriale (ASST) Gaetano Pini/CTO, Milano; Parkinson Institute (G.P.), Fontazione Grigioni-Via Zuretti, Milan; Department of Neurology (L.B., C.F.), San Gerardo Hospital, Monza; Department of Medicine and Surgery and Milan Center for Neuroscience (L.B., C.F.), University of Milano Bicocca, Milano; Institute for Biomedical Research and Innovation (G.A.), National Research Council, Cosenza; Institute of Neurology (A.Q.), Magna Graecia University; Institute of Molecular Bioimaging and Physiology National Research Council (M.G.), Catanzaro, Italy; Department of Integrative Physiology and Bio-Nano Medicine (H.M., A.N.), National Defense Medical College, Saitama; Department of Neurology (N.H., K.N.), Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; Department of Neurology (S.J.C.), Asan Medical Center, University of Ulsan College of Medicine; Department of Neurology (Y.J.K.), Yonsei University College of Medicine, Seoul, South Korea; Neurology (P.K., R.K.), Centre Hospitalier de Luxembourg; Department of Neurology (B.P.C.V.D.W., B.R.B.), Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Radboud University Medical Centre, the Netherlands; Department of Neurology (M.T., L.P.), Oslo University Hospital, Norway; Instituto de Medicina Molecular João Lobo Antunes (L.C.G., J.J.F.), Faculdade de Medicina, Universidade de Lisboa; Department of Neurosciences and Mental Health (L.C.G.), Neurology, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte (CHULN); Laboratory of Clinical Pharmacology and Therapeutics (J.J.F.), Faculdade de Medicina, Universidade de Lisboa, Portugal; Division of Molecular Biology and Human Genetics (S.B.), Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa; Division of Neurology (J.C.), Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa; Parkinson's disease & Movement Disorders Unit (E.T.), Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII) (E.T.); Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders (M.E.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Institut de Neurociències, Universitat de Barcelona; Fundació per la Recerca Biomèdica i Social Mútua Terrassa (P.P., M.D.-F.), Terrassa; Movement Disorders Unit (P.P., M.D.-F.), Department of Neurology, Hospital Universitari Mutua de Terrassa, Barcelona, Spain; Department of Clinical Neuroscience (K.W.), Department of Medical Epidemiology and Biostatistics (K.W., N.L.P.), and Department of Neuroscience (C.R., A.C.B.), Karolinska Institutet, Stockholm; Department of Clinical Sciences Lund (A.P., C.H.), Neurology, Skåne University Hospital, Lund University, Sweden; University of Birmingham and Sandwell and West Birmingham Hospitals NHS Trust (C.E.C.); Faculty of Medicine (K.E.M.), Health and Life Sciences, Queens University, Belfast; Department of Clinical and Movement Neurosciences (M.M.T.), UCL Queen Square Institute of Neurology, University College London, United Kingdom; Department of Neurology (D.K., L.F.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Metabolic Biochemistry (L.F.B.), Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München; Munich Cluster for Systems Neurology (SyNergy) (L.F.B.); German Center for Neurodegenerative Diseases (DZNE) (L.F.B.), Munich, Germany; Department of Neurology (M.F.), McKnight Brain Institute, University of Florida, Gainesville; Parkinson's Research Clinic (R.K.), Centre Hospitalier de Luxembourg; and Transversal Translational Medicine (R.K.), Luxembourg Institute of Health (LIH), Strassen.

出版信息

Neurology. 2024 Aug 13;103(3):e209620. doi: 10.1212/WNL.0000000000209620. Epub 2024 Jul 10.

DOI:10.1212/WNL.0000000000209620

PMID:38986057

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11759940/

Abstract

BACKGROUND AND OBJECTIVES

The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR.

METHODS

We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (OR per 4.8 kg/m [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI.

RESULTS

Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (OR 0.82 [0.70-0.97], = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, OR 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, OR 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (OR 0.85 [0.74-0.99], = 0.032) than men (OR 0.92 [0.80-1.04], = 0.18), but the interaction was not statistically significant (-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association.

DISCUSSION

Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.

摘要

背景与目的

体重指数（BMI）在帕金森病（PD）中的作用尚不清楚。基于全面无偏风险因素评估遗传与环境在 PD 中的作用（Courage-PD）联合会，我们使用 2 样本 Mendelian 随机化（MR）来复制先前报道的遗传预测 BMI 与 PD 呈负相关的发现，并研究了在分析中是否存在生存和发病-患病率偏倚的潜在影响。我们还通过进行反向 MR 来检查 BMI-PD 关系是否具有双向性。

方法

我们使用全基因组关联研究（GWAS）的汇总统计数据来提取 501 个单核苷酸多态性（SNP）与 BMI 的关联，并从 Courage-PD 和国际帕金森病基因组学联合会（iPDGC）中提取 SNP 与 PD 的关联。分析基于欧洲血统的参与者。我们使用逆加权法计算 PD 的比值比（每 4.8kg/m 的 OR [95%CI]）和其他稳健的多效性方法。我们按年龄、疾病持续时间和性别进行分层分析。对于反向 MR，我们使用来自 2 个 iPDGC GWAS 的与 PD 相关的 SNP 来评估 PD 遗传易感性对 BMI 的影响。

结果

BMI 的汇总统计数据基于 806834 名参与者（54%为女性）。PD 的汇总统计数据基于 Courage-PD 的 8919 名（40%为女性）病例和 7600 名（55%为女性）对照，以及 iPDGC 的 19438 名（38%为女性）病例和 24388 名（51%为女性）对照。在 Courage-PD 中，我们发现遗传预测 BMI 与 PD 之间呈负相关（OR 0.82 [0.70-0.97]， = 0.012），且不存在多效性证据。在较年轻的参与者（≤67 岁，OR 0.71 [0.55-0.92]）和疾病持续时间较短的病例（≤7 年，OR 0.75 [0.62-0.91]）中，这种关联更为明显。在合并的 Courage-PD+iPDGC 分析中，女性（OR 0.85 [0.74-0.99]， = 0.032）的关联强于男性（OR 0.92 [0.80-1.04]， = 0.18），但交互作用无统计学意义（-交互作用=0.48）。在反向 MR 中，存在多效性的证据，但稳健的多效性方法显示出与 BMI 呈显著负相关。