Identifying novel Parkinson'Âs disease genes exploring understudied Latino populations

探索未被充分研究的拉丁裔人群，识别新的帕金森病基因

• 批准号: 10675094
• 负责人: Ignacio Fernandez Mata
• 金额: $ 60.85万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675094
• 关键词: Acceleration; Admixture; Affect; Age; Americas; Argentina; Asian ancestry; Brazil; Candidate Disease Gene; Caribbean region; Chile; Chromosomes; Clinical Trials; Code; Collaborations; Colombia; Complex; Copy Number Polymorphism; Costa Rica; Country; Data; Data Set; Databases; Development; Diagnosis; Disease; Ecuador; Enrollment; Ethnic Origin; European; European ancestry; Family; Family history of; Family member; Frequencies; Funding; Future; Gene Mutation; Genes; Genetic; Genetic Diseases; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Goals; Haplotypes; Heritability; Hispanic Populations; Honduras; Human Genetics; Individual; Institution; International; Knowledge; LRRK2 gene; Latin America; Latin American; Latino; Latino Population; Maps; Meta-Analysis; Methods; Mexico; Mutation; Neurodegenerative Disorders; Other Genetics; PARK2 gene; PARK7 gene; PINK1 gene; Parkinson Disease; Participant; Pathogenicity; Patients; Persons; Peru; Phase; Play; Population; Population Heterogeneity; Predisposition; Puerto Rico; Recording of previous events; Reporting; Research; Rest; Risk; Role; Sampling; Screening procedure; Series; Single Nucleotide Polymorphism; South America; Surveys; Susceptibility Gene; Testing; Uruguay; Variant; Work; admixture mapping; alpha synuclein; bioinformatics tool; case control; causal variant; cohort; disorder risk; dosage; exome; gene discovery; genetic analysis; genetic architecture; genetic resource; genetic variant; genome sequencing; genome wide association study; genome-wide; health disparity; improved; large datasets; multi-ethnic; nervous system disorder; new therapeutic target; novel; personalized medicine; polygenic risk score; proband; public database; recruit; risk prediction; risk variant; segregation; success; therapeutic target; therapy design; trait; virulence gene; whole genome

Human genetic studies have greatly accelerated progress in understanding the etiopathogenesis of Parkinson's disease (PD). To date, six causal genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, and VPS35) and ninety susceptibility genes/loci (e.g., MAPT, GBA) have been identified for PD, mostly in populations of European or Asian ancestry. However, these genes explain only a small proportion of PD heritability. Thus, additional novel genes await discovery, and we believe that the highest likelihood of success is in understudied populations such as those of from Latin America. To fill in this gap we created the Latin American Research Consortium on the Genetics of PD (LARGE-PD), a growing collaboration between thirty two institutions in eleven countries across South America/Caribe (Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Honduras, Mexico, Peru, Puerto Rico and Uruguay). LARGE-PD is the largest PD case-control sample series in Latin America (3,857 individuals), with a target to include at least 8,000 individuals in by 2021, thus serving as a unique resource for genetic analysis in this understudied population. As LARGE-PD has progressed, several multiplex PD families (with three or more affected individuals) have been identified and enrolled. With the goal of replicating our preliminary findings and identifying novel risk-modifying variants we propose in Aim 1 to perform a Genome-Wide Association Study (GWAS) in an additional 6,000 cases and healthy controls (1:1) ascertained through LARGE-PD. Our preliminary study in a subset of LARGE-PD (N=1,498) identified 7 interesting novel candidate loci. Genotyping this additional 6,000 individuals (N= 7,498) allows replication of these findings and quadruples our statistical power to find novel associations. We will also perform the first trans-ethnic GWAS in collaboration with the largest European consortium. In Aim 2, we will perform Whole- Genome Sequencing (WGS) in 25 LARGE-PD families negative for mutations in all known PD-genes. Finally, in Aim 3 we will use all our data to generate and test a Latino specific Polygenic Risk Score (PRS), which will account for possible additive effects between all associated variants and will help improve PD risk prediction in this population. This project will identify novel PD genes associated with both familial and sporadic forms of PD using an understudied population, thus improving our knowledge of the etiopatogenesis of the disease and identifying novel therapeutic targets for the treatment of PD, not only in Latin America, but also in other countries with a growing Latino population such as the US. We will also test the validity of current PD risk prediction, based on European populations, in Latinos and generate a Latino specific risk score using our data. We also believe that our study and others like it, will reduce existing health disparities by allowing Latinos to be active participants in clinical trials and novel treatments designed to protect and/or treat individuals with specific genetic variants, the so called personalized medicine. .

人类遗传学研究极大地加速了理解疾病发病机制的进展 帕金森病（PD）。迄今为止，六个致病基因（SNCA、PARK2、PINK1、DJ-1、LRRK2 和 VPS35）和 已鉴定出 90 个 PD 易感基因/位点（例如 MAPT、GBA），主要存在于以下人群中： 欧洲或亚洲血统。然而，这些基因只能解释一小部分PD遗传性。因此， 其他新基因有待发现，我们相信成功的可能性最大的是尚未得到充分研究的基因 人口，例如来自拉丁美洲的人口。为了填补这一空白，我们创建了拉丁美洲研究中心 PD 遗传学联盟 (LARGE-PD)，是 32 个机构之间不断加强的合作 南美洲/加勒比地区的 11 个国家（阿根廷、巴西、智利、哥伦比亚、哥斯达黎加、厄瓜多尔、 洪都拉斯、墨西哥、秘鲁、波多黎各和乌拉圭）。 LARGE-PD 是最大的 PD 病例对照样本系列 拉丁美洲（3,857 人），目标是到 2021 年至少包括 8,000 人，从而服务 作为这一未被充分研究的人群进行遗传分析的独特资源。随着LARGE-PD的不断进步， 已确定并登记了几个多重 PD 家庭（有 3 名或更多受影响个体）。和 复制我们的初步发现并识别我们在目标 1 中提出的新的风险修改变体的目标 对另外 6,000 例病例和健康对照进行全基因组关联研究 (GWAS) (1:1) 通过 LARGE-PD 确定。我们对 LARGE-PD 子集 (N=1,498) 的初步研究确定了 7 有趣的新颖候选基因座。对另外 6,000 名个体 (N= 7,498) 进行基因分型可复制 这些发现使我们发现新关联的统计能力提高了四倍。我们也将进行第一场 与欧洲最大财团合作的跨种族 GWAS。在目标 2 中，我们将执行 Whole- 25 个大型 PD 家族的基因组测序 (WGS) 所有已知 PD 基因突变均为阴性。最后， 在目标 3 中，我们将使用所有数据来生成并测试拉丁裔特定的多基因风险评分 (PRS)，这将 考虑所有相关变异之间可能存在的累加效应，并将有助于改善 PD 风险预测 这个人口。 该项目将使用一种方法来鉴定与家族性和散发性 PD 相关的新 PD 基因 未充分研究的人群，从而提高我们对该疾病发病机制的了解并确定 帕金森病治疗的新治疗靶点，不仅在拉丁美洲，而且在其他有帕金森症的国家 拉丁裔人口不断增长，例如美国。我们还将测试当前 PD 风险预测的有效性，基于 欧洲人口、拉丁裔人口，并使用我们的数据生成拉丁裔特定风险评分。我们也相信 我们的研究和其他类似的研究将通过允许拉丁裔积极参与来减少现有的健康差距 旨在保护和/或治疗具有特定遗传变异的个体的临床试验和新疗法， 所谓的个性化医疗。 。

项目成果

Underrepresented Populations in Parkinson's Genetics Research: Current Landscape and Future Directions.

• DOI: 10.1002/mds.29126
• 发表时间: 2022-08
• 期刊: Movement disorders : official journal of the Movement Disorder Society

Identification and quantification of oligogenic loss-of-function disorders.

• DOI: 10.1016/j.gim.2021.10.026
• 发表时间: 2021-12
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: A. Stefanski;Eduardo Pérez-Palma;M. Mrdjen;M. McHugh;C. Leu;Dennis Lal

Delineation of functionally essential protein regions for 242 neurodevelopmental genes.

• DOI: 10.1093/brain/awac381
• 发表时间: 2023-02-13
• 期刊: Brain : a journal of neurology

Genome-Wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients.

拉丁美洲帕金森病患者拷贝数变异的全基因组分析。

• DOI: 10.1002/mds.28353
• 发表时间: 2021-03
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Sarihan EI;Pérez-Palma E;Niestroj LM;Loesch D;Inca-Martinez M;Horimoto ARVR;Cornejo-Olivas M;Torres L;Mazzetti P;Cosentino C;Sarapura-Castro E;Rivera-Valdivia A;Dieguez E;Raggio V;Lescano A;Tumas V;Borges V;Ferraz HB;Rieder CR;Schumacher-Schuh AF;Santos-Lobato BL;Velez-Pardo C;Jimenez-Del-Rio M;Lopera F;Moreno S;Chana-Cuevas P;Fernandez W;Arboleda G;Arboleda H;Arboleda-Bustos CE;Yearout D;Zabetian CP;Thornton TA;O'Connor TD;Lal D;Mata IF;Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD)‡
• 通讯作者: Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD)‡

Multi-ancestry genome-wide association meta-analysis of Parkinson's disease.

• DOI: 10.1038/s41588-023-01584-8
• 发表时间: 2024-01
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Kim, Jonggeol Jeffrey;Vitale, Dan;Otani, Diego Veliz;Lian, Michelle Mulan;Heilbron, Karl;Aslibekyan, Stella;Auton, Adam;Babalola, Elizabeth;Bell, Robert K.;Bielenberg, Jessica;Bryc, Katarzyna;Bullis, Emily;Cannon, Paul;Coker, Daniella;Partida, Gabriel Cuellar;Dhamija, Devika;Das, Sayantan;Elson, Sarah L.;Eriksson, Nicholas;Filshtein, Teresa;Fitch, Alison;Fletez-Brant, Kipper;Fontanillas, Pierre;Freyman, Will;Granka, Julie M.;Hernandez, Alejandro;Hicks, Barry;Hinds, David A.;Jewett, Ethan M.;Jiang, Yunxuan;Kukar, Katelyn;Kwong, Alan;Lin, Keng-Han;Llamas, Bianca A.;Lowe, Maya;McCreight, Jey C.;McIntyre, Matthew H.;Micheletti, Steven J.;Moreno, Meghan E.;Nandakumar, Priyanka;Nguyen, Dominique T.;Noblin, Elizabeth S.;O'Connell, Jared;Petrakovitz, Aaron A.;Poznik, G. David;Reynoso, Alexandra;Schloetter, Madeleine;Schumacher, Morgan;Shastri, Anjali J.;Shelton, Janie F.;Shi, Jingchunzi;Shringarpure, Suyash;Su, Qiaojuan Jane;Tat, Susana A.;Tchakoute, Christophe Toukam;Tran, Vinh;Tung, Joyce Y.;Wang, Xin;Wang, Wei;Weldon, Catherine H.;Wilton, Peter;Wong, Corinna D.;Iwaki, Hirotaka;Lake, Julie;Solsberg, Caroline Warly;Leonard, Hampton;Makarious, Mary B.;Tan, Eng-King;Singleton, Andrew B.;Bandres-Ciga, Sara;Noyce, Alastair J.;Gatto, Emilia M.;Kauffman, Marcelo;Khachatryan, Samson;Tavadyan, Zaruhi;Shepherd, Claire E.;Hunter, Julie;Kumar, Kishore;Ellis, Melina;Renteria, Miguel E.;Koks, Sulev;Zimprich, Alexander;Schumacher-Schuh, Artur F.;Rieder, Carlos;Awad, Paula Saffie;Tumas, Vitor;Camargos, Sarah;Fon, Edward A.;Monchi, Oury;Fon, Ted;Galleguillos, Benjamin Pizarro;Miranda, Marcelo;Bustamante, Maria Leonor;Olguin, Patricio;Chana, Pedro;Tang, Beisha;Shang, Huifang;Guo, Jifeng;Chan, Piu;Luo, Wei;Arboleda, Gonzalo;Orozc, Jorge;del Rio, Marlene Jimenez;Hernandez, Alvaro;Salama, Mohamed;Kamel, Walaa A.;Zewde, Yared Z.;Brice, Alexis;Corvol, Jean-Christophe;Westenberger, Ana;Illarionova, Anastasia;Mollenhauer, Brit;Klein, Christine;Vollstedt, Eva-Juliane;Hopfner, Franziska;Hoglinger, Gunter;Madoev, Harutyun;Trinh, Joanne;Junker, Johanna;Lohmann, Katja;Lange, Lara M.;Sharma, Manu;Groppa, Sergiu;Gasser, Thomas;Fang, Zih-Hua;Akpalu, Albert;Xiromerisiou, Georgia;Hadjigorgiou, Georgios;Dagklis, Ioannis;Tarnanas, Ioannis;Stefanis, Leonidas;Stamelou, Maria;Dadiotis, Efthymios;Medina, Alex;Chan, Germaine Hiu-Fai;Ip, Nancy;Cheung, Nelson Yuk-Fai;Chan, Phillip;Zhou, Xiaopu;Kishore, Asha;Divya, K. P.;Pal, Pramod;Kukkle, Prashanth Lingappa;Rajan, Roopa;Borgohain, Rupam;Salari, Mehri;Quattrone, Andrea;Valente, Enza Maria;Parnetti, Lucilla;Avenali, Micol;Schirinzi, Tommaso;Funayama, Manabu;Hattori, Nobutaka;Shiraishi, Tomotaka;Karimova, Altynay;Kaishibayeva, Gulnaz;Shambetova, Cholpon;Krueger, Rejko;Tan, Ai Huey;Ahmad-Annuar, Azlina;Norlinah, Mohamed Ibrahim;Murad, Nor Azian Abdul;Azmin, Shahrul;Lim, Shen-Yang;Mohamed, Wael;Tay, Yi Wen;Martinez-Ramirez, Daniel;Rodriguez-Violante, Mayela;Reyes-Perez, Paula;Tserensodnom, Bayasgalan;Ojha, Rajeev;Anderson, Tim J.;Pitcher, Toni L.;Sanyaolu, Arinola;Okubadejo, Njideka;Ojo, Oluwadamilola;Aasly, Jan O.;Pihlstrom, Lasse;Tan, Manuela;Ur-Rehman, Shoaib;Veliz-Otani, Diego;Cornejo-Olivas, Mario;Doquenia, Maria Leila;Rosales, Raymond;Vinuela, Angel;Iakovenko, Elena;Al Mubarak, Bashayer;Umair, Muhammad;Amod, Ferzana;Carr, Jonathan;Bardien, Soraya;Jeon, Beomseok;Kim, Yun Joong;Cubo, Esther;Alvarez, Ignacio;Hoenicka, Janet;Beyer, Katrin;Perinan, Maria Teresa;Pastor, Pau;El-Sadig, Sarah;Brolin, Kajsa;Zweier, Christiane;Tinkhauser, Gerd;Krack, Paul;Lin, Chin-Hsien;Wu, Hsiu-Chuan;Kung, Pin-Jui;Wu, Ruey-Meei;Wu, Yihru;Amouri, Rim;Ben Sassi, Samia;Basak, A. Nazl;Genc, Gencer;Cakmak, Ozguer Oztop;Ertan, Sibel;Martinez-Carrasco, Alejandro;Schrag, Anette;Schapira, Anthony;Carroll, Camille;Bale, Claire;Grosset, Donald;Stafford, Eleanor J.;Houlden, Henry;Morris, Huw R.;Hardy, John;Mok, Kin Ying;Rizig, Mie;Wood, Nicholas;Williams, Nigel;Okunoye, Olaitan;Lewis, Patrick Alfryn;Kaiyrzhanov, Rauan;Weil, Rimona;Love, Seth;Stott, Simon;Jasaityte, Simona;Dey, Sumit;Obese, Vida;Espay, Alberto;O'Grady, Alyssa;Sobering, Andrew K.;Siddiqi, Bernadette;Casey, Bradford;Fiske, Brian;Jonas, Cabell;Cruchaga, Carlos;Pantazis, Caroline B.;Comart, Charisse;Wegel, Claire;Hall, Deborah;Hernandez, Dena;Shiamim, Ejaz;Riley, Ekemini;Faghri, Faraz;Serrano, Geidy E.;Chen, Honglei;Mata, Ignacio F.;Sarmiento, Ignacio Juan Keller;Williamson, Jared;Jankovic, Joseph;Shulman, Joshua;Solle, Justin C.;Murphy, Kaileigh;Nuytemans, Karen;Kieburtz, Karl;Markopoulou, Katerina;Marek, Kenneth;Levine, Kristin S.;Chahine, Lana M.;Ibanez, Laura;Screven, Laurel;Ruffrage, Lauren;Shulman, Lisa;Marsili, Luca;Kuhl, Maggie;Dean, Marissa;Koretsky, Mathew;Puckelwartz, Megan J.;Inca-Martinez, Miguel;Louie, Naomi;Mencacci, Niccolo Emanuele;Albin, Roger;Alcalay, Roy;Walker, Ruth;Chowdhury, Sohini;Dumanis, Sonya;Lubbe, Steven;Xie, Tao;Foroud, Tatiana;Beach, Thomas;Sherer, Todd;Song, Yeajin;Nguyen, Duan;Nguyen, Toan;Atadzhanov, Masharip;Blauwendraat, Cornelis;Nalls, Mike A.;Foo, Jia Nee;Mata, Ignacio
• 通讯作者: Mata, Ignacio