Genetic analysis of APOE reveals distinct origins and distribution of ancestry-enrichment haplotypes in the Mexican Biobank
Artículo
Te invitamos a leer el artículo "Genetic analysis of APOE reveals distinct origins and distribution of ancestry-enrichment haplotypes in the Mexican Biobank" publicado en Genes & Diseases, a cargo del profesor investigador Dr. Andrés Moreno y su equipo de trabajo de la UGA.
Autores: Carmina Barberena-Jonas / Victor Flores-Ocampo / Natalia S. Ogonowski /Stefanie Danielle Piña-Escudero / Ignacio F. Mata / Jennifer S. Yokoyama / Lourdes García García / Carlos Alberto Aguilar Salinas / María Teresa Tusié Luna / Andrés Moreno-Estrada / Miguel E. Rentería
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Human Evolutionary and Population Genomics Lab, Unidad de Genómica Avanzada (UGA). México, Cinvestav, Mexico
Felicitamos al estudiantado y profesorado que contribuyeron en esta investigación por su arduo trabajo.
Summary:
The apolipoprotein E (APOE) gene, located on chromosome 19, remains the primary genetic factor associated with late-onset Alzheimer's disease.1 In European populations, the ε4 haplotype of APOE, present in approximately 14% of individuals, significantly increases Alzheimer's disease risk, while the less common ε2 haplotype (∼8%) appears to confer a protective effect.2 Despite its significance, APOE has not been genetically characterized in Latin American countries, where Alzheimer's disease-related dementia disproportionately affects individuals.3
APOE has three primary haplotypes (ε2, ε3, and ε4) defined by two single nucleotide polymorphisms, rs429358 (chr19:44908684:T:C) and rs7412 (chr19:44908822:C:T), which introduce amino acid changes resulting in the ε2 (Cys112, Cys158), ε3 (Cys112, Arg158), and ε4 (Arg112, Arg158) isoforms.1 The genetic burden for Alzheimer's disease associated with each APOE haplotype varies with the local ancestry of the APOE locus and demographic factors.1 Mexico's complex genetic architecture presents regional differences, with southern and central states exhibiting a higher percentage of Indigenous American ancestry compared with the north.4
Given recent efforts to investigate the genetic landscape of the Mexican population, we seized the opportunity to explore the genetic and epidemiological aspects of APOE in Mexico. In this study, we analyzed APOE haplotype frequencies in a large Mexican cohort (n = 6010) from the Mexican Biobank Project4 to investigate their regional variations and ancestry backgrounds across Mexico's 32 states.
APOE haplotype frequencies (ε2, ε3, and ε4) were calculated based on single nucleotide polymorphisms rs429358 and rs7412, with rs7412 imputed using TopMed. The single nucleotide polymorphism call rate of rs429358 was 99.53%, and after imputation, the r2 of rs7412 was 0.99111, reflecting a highly accurate imputation. The national haplotype frequencies were: ε3 at 0.876 (the most prevalent), ε4 at 0.1008, and ε2 at 0.024. Genotype analysis revealed that 4627 individuals were homozygous for ε3/ε3, 70 for ε4/ε4, and only 5 for ε2/ε2, the rarest genotype. Among heterozygotes, 1041 individuals carried the ε3/ε4 genotype, 236 had ε2/ε3, and 31 exhibited the ε2/ε4 combination.
The regional analysis found distinct patterns in haplotype distributions. ε4 frequencies ranged from 0.074 in Querétaro to 0.197 in Sonora, with the highest values observed in northern states, including Sinaloa, Tamaulipas, Durango, and Baja California. ε2 frequencies ranged from 0.0042 in Chiapas to 0.0586 in Aguascalientes, displaying a general north-to-south gradient. Across all regions, ε3 remained the predominant haplotype, with the lowest frequency in Sonora (76.97%) and the highest in Puebla (90.76%) (Fig. 1A).