Leal Thiago P, Waldo Emily, Duarte-Zambrano Felipe, Inca-Martinez Miguel, Ramchandra Janvi, Chaparro-Solano Henry Mauricio, Anello Anna E, Borda Victor, Gouveia Mateus Henrique, Teixeira-Dos-Santos Daniel, Reyes-Pérez Paula, Gatto Emilia Mabel, Santos-Lobato Bruno Lopes, Eufraseo Gracivane, Letro Grace Helena, Arboleda Gonzalo, Bernal-Pacheco Oscar, Orozco Jorge L, Munoz Beatriz, Chana-Cuevas Pedro, Aguillon David, Moreno Sonia, Torrealba-Acosta Gabriel, Lobo-Prada Tanya, Muller Valentina, Razquin C Matias Lopez, Braga-Neto Pedro, Durón Reyna M, Rodríguez-Violante Mayela, Hernández-Medrano Ana Jimena, Cervantes-Arriaga Amin, Martinez-Ramirez Daniel, Schuh Artur F S, de Mello Rieder Carlos Roberto, Cornejo-Olivas Mario, Rios-Pinto Julia, Medina Angel C, Cornejo-Herrera Ivan, Mejia-Rojas Koni, Vinuela Angel, Tumas Vitor, Pimentel Angela Vieira, Borges Vanderci, Avila Cesar L, Olguin Patricio, Colombo Alicia, Nuñez Juan Cristobal, Medina-Rivera Alejandra, Ruiz-Contreras Alejandra E, Alcauter Sarael, Dieguez Elena, Nuytemans Karen, Mata Ignacio F
Genomic Medicine Institute, Cleveland Clinic Research, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, 44195, United States of America.
Instituto de Genética, Facultad de Medicina sede Bogotá, Universidad Nacional de Colombia, Calle 53 #37a-47, Bogotá, Colombia.
medRxiv. 2025 Jul 18:2025.07.18.25331793. doi: 10.1101/2025.07.18.25331793.
The Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE-PD) is a multicenter collaboration aimed at understanding the genetic architecture of Parkinson's disease (PD) in this underrepresented population using data from 15 countries across the Americas and the Caribbean. In this study, we conducted the largest genome-wide association studies (GWAS) for PD susceptibility in Latin Americans.
We analyzed genotype data from LARGE-PD Phase 1 (n = 1,498) and Phase 2 (n = 4,401) using multiple GWAS approaches: SAIGE, which incorporates a genetic relationship matrix in the model; ATT, which includes global ancestry on the model; TRACTOR, which splits allele dosages by ancestry to detect ancestry-specific risk loci; and admixture mapping. We also assessed linkage disequilibrium (LD) patterns and performed Meta-Regression of Multi-AncEstry Genetic Association (MR-MEGA), integrating data from both LARGE-PD phases and two South Asian GWAS.
We identified PD-associated loci on chromosomes 1 and 4. Our results replicated previous findings, including the well-established variant rs356182-A (OR = 1.517, p = 1.62×10). Notably, we identified a locus in (rs117185933-A, OR = 1.75, p = 3.8×10), which had the highest CADD Phred score (17.92, top ~3% most deleterious) among all candidate variants, suggesting strong functional relevance. Functional annotation predicted that this variant may create a premature start codon in the 5' UTR of . Although rs117185933-A is in high LD (r > 0.8) with a variant previously reported by Kishore et al., our LD analysis and MR-MEGA results indicate that this signal is correlated with ancestry heterogeneity and likely represents an independent PD risk locus and a novel putative causal variant. This variant is most frequent in Peruvians from the 1000 Genomes Project (MAF = 0.20) and more common in admixed American populations in gnomAD (MAF = 0.0835), but nearly absent in non-Finnish Europeans (MAF = 0.0002).
We identified PD-associated variants in SNCA and ITPKB, the latter not previously reported in European-ancestry studies. The ITPKB variant may lead to a start codon gain in a gene with known protective effects against α-synuclein aggregation and models. These findings underscore the critical importance of including underrepresented populations in genetic research to uncover ancestry-specific risk loci and advance precision medicine for Parkinson's disease.
拉丁美洲帕金森病遗传学研究联盟（LARGE-PD）是一个多中心合作项目，旨在利用来自美洲和加勒比地区15个国家的数据，了解帕金森病（PD）在这一代表性不足人群中的遗传结构。在本研究中，我们对拉丁美洲人进行了最大规模的帕金森病易感性全基因组关联研究（GWAS）。
我们使用多种GWAS方法分析了LARGE-PD第一阶段（n = 1498）和第二阶段（n = 4401）的基因型数据：SAIGE，该模型纳入了遗传关系矩阵；ATT，该模型包括全球祖先信息；TRACTOR，按祖先拆分等位基因剂量以检测特定祖先的风险位点；以及混合映射。我们还评估了连锁不平衡（LD）模式，并进行了多祖先遗传关联的元回归（MR-MEGA），整合了LARGE-PD两个阶段的数据以及两项南亚GWAS的数据。
我们在1号和4号染色体上鉴定出与PD相关的位点。我们的结果重复了先前的发现，包括已确定的变体rs356182 - A（OR = 1.517，p = 1.62×10）。值得注意的是，我们在 中鉴定出一个位点（rs117185933 - A，OR = 1.75，p = 3.8×10），在所有候选变体中，该位点具有最高的CADD Phred评分（17.92，最有害的前约3%），表明其具有很强的功能相关性。功能注释预测该变体可能在 的5' UTR中产生一个提前的起始密码子。尽管rs117185933 - A与Kishore等人先前报道的一个变体处于高LD状态（r > 0.8），但我们的LD分析和MR-MEGA结果表明，该信号与祖先异质性相关，可能代表一个独立的PD风险位点和一个新的推定因果变体。该变体在千人基因组计划的秘鲁人中最为常见（MAF = 0.20），在gnomAD中混合的美洲人群中更常见（MAF = 0.0835），但在非芬兰欧洲人中几乎不存在（MAF = 0.0002）。
我们在SNCA和ITPKB中鉴定出与PD相关的变体，后者在欧洲血统研究中此前未被报道。ITPKB变体可能导致一个对α-突触核蛋白聚集具有已知保护作用的基因中起始密码子增加 以及 模型。这些发现强调了在遗传研究中纳入代表性不足人群以发现特定祖先风险位点并推进帕金森病精准医学的至关重要性。
