Vicuna, L., Barrientos, E., Norambuena, T., Alvares, D., Gana, J. C., Leiva-Yamaguchi, V., et al. (2023). New insights from GWAS on BMI-related growth traits in a longitudinal cohort of admixed children with Native American and European ancestry. iScience, 26(2), 106091.
Abstract: Body-mass index (BMI) is a hallmark of adiposity. In contrast with adulthood, the genetic architecture of BMI during childhood is poorly understood. The few genome-wide association studies (GWAS) on children have been performed almost exclusively in Europeans and at single ages. We performed cross-sectional and longitudinal GWAS for BMI-related traits on 904 admixed children with mostly Mapuche Native American and European ancestries. We found regulatory variants of the immune gene HLA-DQB3 strongly associated with BMI at 1.5 – 2.5 years old. A variant in the sex-determining gene DMRT1 was associated with the age at adiposity rebound (Age-AR) in girls (P = 9.8 x 10(-9)). BMI was significantly higher in Mapuche than in Europeans between 5.5 and 16.5 years old. Finally, Ag
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Vicuna, L., Fernandez, M. I., Vial, C., Valdebenito, P., Chaparro, E., Espinoza, K., et al. (2019). Adaptation to Extreme Environments in an Admixed Human Population from the Atacama Desert. Genome Biol. Evol., 11(9), 2468–2479.
Abstract: Inorganic arsenic (As) is a toxic xenobiotic and carcinogen associated with severe health conditions. The urban population from the Atacama Desert in northern Chile was exposed to extremely high As levels (up to 600 μmg/l) in drinking water between 1958 and 1971, leading to increased incidence of urinary bladder cancer (BC), skin cancer, kidney cancer, and coronary thrombosis decades later. Besides, the Andean Native-American ancestors of the Atacama population were previously exposed for millennia to elevated As levels in water (similar to 120 μg/l) for at least 5,000 years, suggesting adaptation to this selective pressure. Here, we performed two genome-wide selection tests-PBSn1 and an ancestry-enrichment test-in an admixed population from Atacama, to identify adaptation signatures to As exposure acquired before and after admixture with Europeans, respectively. The top second variant selected by PBSn1 was associated with LCE4A-C1orf68, a gene that may be involved in the immune barrier of the epithelium during BC. We performed association tests between the top PBSn1 hits and BC occurrence in our population. The strongest association (P = 0.012) was achieved by the LCE4A-C1orf68 variant. The ancestry-enrichment test detected highly significant signals (P = 1.3 x 10(-9)) mapping MAK16, a gene with important roles in ribosome biogenesis during the G1 phase of the cell cycle. Our results contribute to a better understanding of the genetic factors involved in adaptation to the pathophysiological consequences of As exposure.
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Vicuna, L., Klimenkova, O., Norambuena, T., Martinez, F. I., Fernandez, M. I., Shchur, V., et al. (2020). Postadmixture Selection on Chileans Targets Haplotype Involved in Pigmentation, Thermogenesis and Immune Defense against Pathogens. Genome Biol. Evol., 12(8), 1459–1470.
Abstract: Detection of positive selection signatures in populations around the world is helping to uncover recent human evolutionary history as well as the genetic basis of diseases. Most human evolutionary genomic studies have been performed in European, African, and Asian populations. However, populations with Native American ancestry have been largely underrepresented. Here, we used a genome-wide local ancestry enrichment approach complemented with neutral simulations to identify postadmixture adaptations underwent by admixed Chileans through gene flow from Europeans into local Native Americans. The top significant hits (P=2.4x10(-7)) are variants in a region on chromosome 12 comprising multiple regulatory elements. This region includes rs12821256, which regulates the expression of KITLG, a well-known gene involved in lighter hair and skin pigmentation in Europeans as well as in thermogenesis. Another variant from that region is associated with the long noncoding RNA RP11-13A1.1, which has been specifically involved in the innate immune response against infectious pathogens. Our results suggest that these genes were relevant for adaptation in Chileans following the Columbian exchange.
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Vicuna, L., Norambuena, T., Miranda, J. P., Pereira, A., Mericq, V., Ongaro, L., et al. (2021). Novel loci and mapuche genetic ancestry are associated with pubertal growth traits in Chilean boys. Hum. Genet., 140(12), 1651–1661.
Abstract: Puberty is a complex developmental process that varies considerably among individuals and populations. Genetic factors explain a large proportion of the variability of several pubertal traits. Recent genome-wide association studies (GWAS) have identified hundreds of variants involved in traits that result from body growth, like adult height. However, they do not capture many genetic loci involved in growth changes over distinct growth phases. Further, such GWAS have been mostly performed in Europeans, but we do not know how these findings relate to other continental populations. In this study, we analyzed the genetic basis of three pubertal traits; namely, peak height velocity (PV), age at PV (APV) and height at APV (HAPV). We analyzed a cohort of 904 admixed Chilean children and adolescents with European and Mapuche Native American ancestries. Height was measured on roughly a 6-month basis from childhood to adolescence between 2006 and 2019. We predict that the difference in HAPV between an European and a Mapuche adolescent is 4.3 cm higher in the European (P = 0.042) and APV is 0.73 years later for the European compared with the Mapuche adolescent on average (P = 0.023). Further, by performing a GWAS on 774, 433 single-nucleotide polymorphisms, we identified a genetic signal harboring 3 linked variants significantly associated with PV in boys (P < 5 x 10(-8)). This signal has never been associated with growth-related traits.
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