Dataset Information

Mexican Biobank advances population and medical genomics of diverse ancestries.

ABSTRACT: Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data¹. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics^2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS^7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.

SUBMITTER: Sohail M

PROVIDER: S-EPMC10600006 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Mexican Biobank advances population and medical genomics of diverse ancestries.

Sohail Mashaal M Palma-Martínez María J MJ Chong Amanda Y AY Quinto-Cortés Consuelo D CD Barberena-Jonas Carmina C Medina-Muñoz Santiago G SG Ragsdale Aaron A Delgado-Sánchez Guadalupe G Cruz-Hervert Luis Pablo LP Ferreyra-Reyes Leticia L Ferreira-Guerrero Elizabeth E Mongua-Rodríguez Norma N Canizales-Quintero Sergio S Jimenez-Kaufmann Andrés A Moreno-Macías Hortensia H Aguilar-Salinas Carlos A CA Auckland Kathryn K Cortés Adrián A Acuña-Alonzo Víctor V Gignoux Christopher R CR Wojcik Genevieve L GL Ioannidis Alexander G AG Fernández-Valverde Selene L SL Hill Adrian V S AVS Tusié-Luna María Teresa MT Mentzer Alexander J AJ Novembre John J García-García Lourdes L Moreno-Estrada Andrés A

Nature 20231011 7984

Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data<sup>1</sup>. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. H ...[more]

PMID: 37821706

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Project description:Alzheimer's disease and related dementias (AD/ADRDs) pose a significant global public health challenge, underscored by the intricate interplay of genetic and environmental factors that differ across ancestries. To effectively implement equitable, personalized therapeutic interventions on a global scale, it is essential to identify disease-causing mutations and genetic risk and resilience factors across diverse ancestral backgrounds. Exploring genetic-phenotypic correlations across the globe enhances the generalizability of research findings, contributing to a more inclusive and universal understanding of disease. This study leveraged biobank-scale data to conduct the largest multi-ancestry whole-genome sequencing characterization of AD/ADRDs. We aimed to build a valuable catalog of potential disease-causing, genetic risk and resilience variants impacting the etiology of these conditions. We thoroughly characterized genetic variants from key genes associated with AD/ADRDs across 11 genetic ancestries, utilizing data from All of Us, UK Biobank, 100,000 Genomes Project, Alzheimer's Disease Sequencing Project, and the Accelerating Medicines Partnership in Parkinson's Disease, including a total of 25,001 cases and 93,542 controls. We prioritized 116 variants possibly linked to disease, including 18 known pathogenic and 98 novel variants. We detected previously described disease-causing variants among controls, leading us to question their pathogenicity. Notably, we showed a higher frequency of APOE ε4/ε4 carriers among individuals of African and African Admixed ancestry compared to other ancestries, confirming ancestry-driven modulation of APOE-associated AD/ADRDs. A thorough assessment of APOE revealed a disease-modifying effect conferred by the TOMM40:rs11556505, APOE:rs449647, 19q13.31:rs10423769, NOCT:rs13116075, CASS4:rs6024870, and LRRC37A:rs2732703 variants among APOE ε4 carriers across different ancestries. In summary, we compiled the most extensive catalog of established and novel genetic variants in known genes increasing risk or conferring resistance to AD/ADRDs across diverse ancestries, providing clinical insights into their genetic-phenotypic correlations. The findings from this investigation hold significant implications for potential clinical trials and therapeutic interventions on a global scale. Finally, we present an accessible and user-friendly platform for the AD/ADRDs research community to help inform and support basic, translational, and clinical research on these debilitating conditions (https://niacard.shinyapps.io/MAMBARD_browser/).

Project description:BackgroundLimited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF.MethodsWe analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of CFTR variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific CFTR variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant CFTR genotypes.ResultsWe detected over 4000 CFTR variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique CFTR variants [n = 2212], while the American group had the least unique variants [n = 23]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G > A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted p < 0.05].ConclusionsWe leveraged the UKBB database to comprehensively characterize the broad spectrum of CFTR variants across ancestries. The detection of over 4000 CFTR variants, including several ancestry-specific and uncharacterized CFTR variants, warrants the need for further characterization of their functional and clinical relevance. Overall, the presentation of classical CF phenotypes seen in non-CF diagnosed participants with more than one CF-causing variant indicates that they may benefit from current CFTR modulator therapies.

Dataset Information

Mexican Biobank advances population and medical genomics of diverse ancestries.

Publications

Mexican Biobank advances population and medical genomics of diverse ancestries.

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