Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes.
Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes.
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DOI：
10.1038/s41366-021-00761-1
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发表时间：
2021-05
影响因子：
4.9
通讯作者：
Tarazona-Santos, Eduardo
中科院分区：
文献类型：
--
作者：
Scliar, Marilia O.;Sant'Anna, Hanaisa P.;Santolalla, Meddly L.;Leal, Thiago P.;Araujo, Nathalia M.;Alvim, Isabela;Borda, Victor;Magalhaes, Wagner C. S.;Gouveia, Mateus H.;Lyra, Ricardo;Machado, Moara;Michelin, Lucas;Rodrigues, Maira R.;Araujo, Gilderlanio S.;Kehdy, Fernanda S. G.;Zolini, Camila;Peixoto, Sergio V.;Luizon, Marcelo R.;Lobo, Francisco;Naslavsky, Michel S.;Yamamoto, Guilherme L.;Duarte, Yeda A. O.;Hansen, Matthew E. B.;Norris, Shane A.;Gilman, Robert H.;Guio, Heinner;Hsing, Ann W.;Mbulaiteye, Sam M.;Mensah, James;Dutil, Julie;Yeager, Meredith;Yeboah, Edward;Tishkoff, Sarah A.;Choudhury, Ananyo;Ramsay, Michele;Passos-Bueno, Maria Rita;Zatz, Mayana;O'Connor, Timothy D.;Pereira, Alexandre C.;Barreto, Mauricio L.;Lima-Costa, Maria Fernanda;Horta, Bernardo L.;Tarazona-Santos, Eduardo
混合种群是研究复杂表型的全球遗传结构的一种资源，考虑到非欧洲种群在基因组研究中的代表性严重不足，这一点至关重要。在这里，我们研究了巴西混合人群中儿童、青年和老年人BMI的遗传结构。利用巴西人的混合物，其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来自东北部（萨尔瓦多），东南部（班布伊）和南部（佩尔松）的三个巴西人群队列中进行混合物映射/体重指数（BMI）的精细映射。我们在来自萨尔瓦多的儿童（PALD 1和ZMIZ 1基因）和来自佩尔蒂的年轻人（NOD 2和MTUS 2基因）中发现了与非洲相关等位基因的显著关联。更重要的是，在骨盆，rs 114066381，映射在一个潜在的调控区域，是显着相关的，只有在女性（p = 2.76e-06）。这种变异在欧洲人中很少见，但在西非的频率约为3%，并且具有很强的女性特异性效应（95% CI：每个A等位基因2.32-5.65 kg/m2）。我们证实了这种性别特异性的关联，并在同一个Pelanmar队列中复制了其对调整后的脂肪质量指数的强烈影响，以及在另一个来自圣保罗（巴西东南部）的巴西队列中复制了其对BMI的强烈影响。一项荟萃分析证实了这一显著关联。值得注意的是，我们观察到，虽然rs 114066381-A等位基因的频率在研究人群中的范围为0.8%至2.1%，但在来自Peleton，圣保罗和Bambuí的病态肥胖女性中达到约9%。rs 114066381的效应量至少是FTO SNPs rs 9939609和rs 1558902的5倍，这已经是其高效应的象征。我们确定了6个与BMI相关的候选SNP。rs 114066381因其在病态肥胖女性中重复的高效应和高频率而脱颖而出。我们展示了混合人群是如何产生新的相关表型相关遗传变异的。
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. 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). 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/m2 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. 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.
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影响因子：
6.9
作者：
Basu, Analabha;Tang, Hua;Arnett, Donna;Gu, C. Charles;Mosley, Tom;Kardia, Sharon;Luke, Amy;Tayo, Bamidele;Cooper, Richard;Zhu, Xiaofeng;Risch, Neil
通讯作者：
Risch, Neil
影响因子：
3.7
作者：
Comuzzie AG;Cole SA;Laston SL;Voruganti VS;Haack K;Gibbs RA;Butte NF
通讯作者：
Butte NF
影响因子：
5.4
作者：
HILL W G;ROBERTSON A
通讯作者：
ROBERTSON A
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
9.8
作者：
Lasky-Su, Jessica;Lyon, Helen N.;Lange, Christoph
通讯作者：
Lange, Christoph