Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Human Genome and Stem Cell Research Center, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brazil.
Int J Obes (Lond). 2021 May;45(5):1017-1029. doi: 10.1038/s41366-021-00761-1. Epub 2021 Feb 26.
BACKGROUND/OBJECTIVES: Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil. SUBJECTS/METHODS: Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European, and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of body mass index (BMI) in three Brazilian population-based cohorts from Northeast (Salvador), Southeast (Bambuí), and South (Pelotas). RESULTS: We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p = 2.76e-06). This variant is rare in Europeans but with frequencies of ~3% in West Africa and has a strong female-specific effect (95% CI: 2.32-5.65 kg/m per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from São Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains ~9% among women with morbid obesity from Pelotas, São Paulo, and Bambuí. The effect size of rs114066381 is at least five times higher than the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects. CONCLUSIONS: We identified six candidate SNPs associated with BMI. rs114066381 stands out for its high effect that was replicated and its high frequency in women with morbid obesity. We demonstrate how admixed populations are a source of new relevant phenotype-associated genetic variants.
背景/目的：混合人群是研究复杂表型全球遗传结构的资源，这是至关重要的，因为非欧洲人群在基因组研究中严重代表性不足。在这里，我们研究了巴西混合人群中儿童、年轻人和老年人的 BMI 遗传结构。 研究对象/方法：利用巴西人的混合遗传，他们的染色体是美洲原住民、欧洲和非洲起源的片段的马赛克，我们使用全基因组数据在三个巴西基于人群的队列中进行 BMI 的混合映射/精细映射：东北部的萨尔瓦多（Salvador）、东南部的班布伊（Bambuí）和南部的佩洛塔斯（Pelotas）。 结果：我们发现，在萨尔瓦多的儿童中，与非洲相关的等位基因（PALD1 和 ZMIZ1 基因）以及在佩洛塔斯的年轻人中（NOD2 和 MTUS2 基因）与非洲相关的等位基因存在显著关联。更重要的是，在佩洛塔斯，位于潜在调控区域的 rs114066381 仅在女性中显著相关（p=2.76e-06）。这种变体在欧洲人中很少见，但在西非的频率约为 3%，并且具有强烈的女性特异性效应（每个 A 等位基因的 95%置信区间为 2.32-5.65kg/m）。我们证实了这种性别特异性关联，并在同一佩洛塔斯队列中复制了其对调整后的脂肪质量指数的强烈影响，以及在巴西另一个来自圣保罗（巴西东南部）的队列中的 BMI。荟萃分析证实了这种显著的关联。值得注意的是，我们观察到，虽然在研究人群中，rs114066381-A 等位基因的频率在 0.8%至 2.1%之间，但在来自佩洛塔斯、圣保罗和班布伊的病态肥胖女性中，其频率达到约 9%。rs114066381 的效应大小至少是 FTO SNPs rs9939609 和 rs1558902 的五倍，它们已经因其高效应而闻名。 结论：我们确定了六个与 BMI 相关的候选 SNP。rs114066381 因其高效应、复制性和在病态肥胖女性中的高频率而引人注目。我们展示了混合人群如何成为新的与表型相关的遗传变异的来源。
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