Miranda José P, Pereira Ana, Corvalán Camila, Miquel Juan F, Alberti Gigliola, Gana Juan C, Santos José L
Department of Nutrition, Diabetes, and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
School of Medicine, PhD in Epidemiology Program, Pontificia Universidad Católica de Chile, Santiago, Chile.
Front Genet. 2024 May 17;15:1382103. doi: 10.3389/fgene.2024.1382103. eCollection 2024.
Gene variants in the gene are strongly associated with circulating bilirubin levels in several populations, as well as other variants of modest effect across the genome. However, the effects of such variants are unknown regarding the Native American ancestry of the admixed Latino population. Our objective was to assess the Native American genetic determinants of serum bilirubin in Chilean admixed adolescents using the local ancestry deconvolution approach. We measured total serum bilirubin levels in 707 adolescents of the Chilean Growth and Obesity Cohort Study (GOCS) and performed high-density genotyping using the Illumina-MEGA array (>1.7 million genotypes). We constructed a local ancestry reference panel with participants from the 1000 Genomes Project, the Human Genome Diversity Project, and our GOCS cohort. Then, we inferred and isolated haplotype tracts of Native American, European, or African origin to perform genome-wide association studies. In the whole cohort, the rs887829 variant and others near were the unique signals achieving genome-wide statistical significance (b = 0.30; = 3.34 × 10). After applying deconvolution methods, we found that significance is also maintained in Native American (b = 0.35; = 3.29 × 10) and European (b = 0.28; = 1.14 × 10) ancestry components. The rs887829 variant explained a higher percentage of the variance of bilirubin in the Native American (37.6%) compared to European ancestry (28.4%). In Native American ancestry, carriers of the TT genotype of this variant averaged 4-fold higher bilirubinemia compared to the CC genotype ( = 2.82 × 10). We showed for the first time that variants are the primary determinant of bilirubin levels in Native American ancestry, confirming its pan-ethnic relevance. Our study illustrates the general value of the local ancestry deconvolution approach to assessing isolated ancestry effects in admixed populations.
该基因中的基因变异与多个群体的循环胆红素水平密切相关，以及基因组中其他具有中等效应的变异。然而，对于混合拉丁裔人群的美洲原住民血统而言，此类变异的影响尚不清楚。我们的目标是使用本地血统反卷积方法评估智利混合青少年血清胆红素的美洲原住民遗传决定因素。我们测量了智利生长与肥胖队列研究（GOCS）中707名青少年的血清总胆红素水平，并使用Illumina-MEGA芯片（>170万个基因型）进行了高密度基因分型。我们利用来自千人基因组计划、人类基因组多样性计划和我们的GOCS队列的参与者构建了一个本地血统参考面板。然后，我们推断并分离出美洲原住民、欧洲或非洲起源的单倍型片段，以进行全基因组关联研究。在整个队列中，rs887829变异及附近的其他变异是达到全基因组统计学显著性的唯一信号（b = 0.30；P = 3.34×10）。应用反卷积方法后，我们发现美洲原住民（b = 0.35；P = 3.29×10）和欧洲（b = 0.28；P = 1.14×10）血统成分中也保持着显著性。与欧洲血统（28.4%）相比，rs887829变异在美洲原住民中解释了更高比例的胆红素变异（37.6%）。在美洲原住民血统中，该变异TT基因型携带者的胆红素血症平均比CC基因型高4倍（P = 2.82×10）。我们首次表明，这些变异是美洲原住民血统中胆红素水平的主要决定因素，证实了其泛种族相关性。我们的研究说明了本地血统反卷积方法在评估混合人群中孤立血统效应方面的普遍价值。
