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Mexican Population Studies Provide Ancestry, Complex Trait Clues

NEW YORK – In a pair of papers published in Nature on Wednesday, independent research teams turned to large Mexican population datasets to retrace ancestry, allele frequency, complex trait, and disease risk patterns in the country.

For the first of the studies, researchers with Regeneron Genetics Center, the National Autonomous University of Mexico, and other centers in the US, Mexico, and the UK focused on sequence data for more than 150,000 adult participants in a Coyoacán and Iztapalapa urban district-focused population study known as the Mexico City Prospective Study (MCPS).

The MCPS recruited participants some two decades ago, co-senior and co-corresponding author Jonathan Marchini, a researcher with Regeneron Genetics Center explained in an email, noting that the study is "much larger than previous genetic studies in Mexico, but more geographically focused."

For their study, he and his colleagues analyzed exome sequences spanning some 19,110 genes, uncovering 4 million coding variants — a set that included 1.4 million variants that were not found in exome sequences from individuals in the UK Biobank project, the Trans-Omics for Precision Medicine (TOPMed) program, or gnomAD database.

In a subset of whole-genome sequenced individuals from the MCPS, meanwhile, the team tracked down 131.9 million variants, including 31.5 million variants that may be Mexico City population-specific based on their absence in other UKB, TOPMed, or gnomAD collections.

Together, the MCPS sequences provided a look at ancestry patterns in individuals from Mexico City, who tended to have admixed European, African, and Indigenous American ancestry, including Indigenous ancestry that resembled populations from Central, Southern, and Southeastern populations.

With such ancestry patterns, the team went on to use local ancestry inference (LAI)-resolved approaches to tease out allele frequencies linked to Indigenous Mexican, African, and European ancestries. With effective population sizes of 91,856 Indigenous Mexican individuals, 4,312 African individuals, and more than 42,000 European individuals, for example, they got a look at ancestry-informed frequencies for more than 141.8 million variants.

"The ancestry-specific allele frequency resource allows researchers to interrogate allele frequencies at novel associated loci," Marchini explained. "Understanding the variation in allele frequencies across populations at such loci can inform the design of follow-up studies and clinical trials."

The new sequence data also provided the team with enhanced imputation abilities, making it possible to put together a body mass index polygenic risk score with enhanced performance in the Mexican population relative to a PRS established with genetic data from the UKB project.

"The implication is that researchers working with other Latino cohorts will be able to use the MCPS panel to increase the amount of genetic variation tested in genome-wide association studies, which may lead to novel drug target discoveries," Marchini explained, adding that the BMI PRS performance found so far "demonstrates the potential for the MCPS dataset to be a valuable resource for advancing polygenic prediction in admixed Latino populations."

In another Nature study, a team led by investigators in Mexico and the UK dug into array-based genotyping profiles for 6,057 Mexican Biobank (MXB) participants, recruited from 898 rural and urban sites in 32 Mexican states.

"This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architecture, both crucial for making precision and preventive medicine initiatives accessible worldwide," wrote the authors, led by co-supervising and co-corresponding authors Andres Moreno-Estrada, a researcher affiliated with the Center for Research and Advanced Studies of the National Polytechnic Institute in Mexico, and Lourdes Garcia-Garcia, with the National Institute of Public Health in Mexico.

Using data spanning some 1.8 million SNPs — together with identity-by-descent and ancestry deconvolution analyses — the investigators were able to estimate the shifting historical ancestral population sizes present in different parts of Mesoamerica, for example.

"By leveraging the largest nationwide genomic biobank in Mexico, we find diverse sources of ancestries in Mexico in light of its unique history, and infer demographic and admixture histories and [runs of homozygosity] using ancestry-specific haplotype identity that reveal an elaborate fine-scale structure in the country," the authors wrote.

Members of that team also searched for ties to 22 complex traits and conditions, flagging genetic variants and environmental factors influencing traits ranging from BMI or blood triglyceride levels to height or blood glucose levels.

"Our work demonstrates the value of generating genotype-phenotype data on underrepresented groups to reveal lesser-known genetic histories and generate findings of biomedical relevance," the authors reported.