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利用基因组学和流行病学进行人群结构研究(PAGE)中不同祖先群体的体重指数遗传位点跨种族精细定位揭示了既定位点存在多个信号的证据。

Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.

作者信息

Fernández-Rhodes Lindsay, Gong Jian, Haessler Jeffrey, Franceschini Nora, Graff Mariaelisa, Nishimura Katherine K, Wang Yujie, Highland Heather M, Yoneyama Sachiko, Bush William S, Goodloe Robert, Ritchie Marylyn D, Crawford Dana, Gross Myron, Fornage Myriam, Buzkova Petra, Tao Ran, Isasi Carmen, Avilés-Santa Larissa, Daviglus Martha, Mackey Rachel H, Houston Denise, Gu C Charles, Ehret Georg, Nguyen Khanh-Dung H, Lewis Cora E, Leppert Mark, Irvin Marguerite R, Lim Unhee, Haiman Christopher A, Le Marchand Loic, Schumacher Fredrick, Wilkens Lynne, Lu Yingchang, Bottinger Erwin P, Loos Ruth J L, Sheu Wayne H-H, Guo Xiuqing, Lee Wen-Jane, Hai Yang, Hung Yi-Jen, Absher Devin, Wu I-Chien, Taylor Kent D, Lee I-Te, Liu Yeheng, Wang Tzung-Dau, Quertermous Thomas, Juang Jyh-Ming J, Rotter Jerome I, Assimes Themistocles, Hsiung Chao A, Chen Yii-Der Ida, Prentice Ross, Kuller Lewis H, Manson JoAnn E, Kooperberg Charles, Smokowski Paul, Robinson Whitney R, Gordon-Larsen Penny, Li Rongling, Hindorff Lucia, Buyske Steven, Matise Tara C, Peters Ulrike, North Kari E

机构信息

Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

出版信息

Hum Genet. 2017 Jun;136(6):771-800. doi: 10.1007/s00439-017-1787-6. Epub 2017 Apr 8.

Abstract

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

摘要

大多数体重指数(BMI)基因位点是在主要针对欧洲血统人群的研究中确定的。这些位点在其他种族/族裔群体中的作用尚不清楚。因此,我们旨在利用来自“利用基因组学和流行病学研究构建人群结构”(Population Architecture using Genomics and Epidemiology Study)中超过102,000名非洲、西班牙裔/拉丁裔、亚洲、欧洲以及美洲印第安/阿拉斯加原住民后裔的成年人样本,来描述170个已确定的BMI变异体或其代理在不同美国人群中的可推广性,并跨种族精细定位36个BMI基因位点。我们对代谢芯片(Illumina公司)上BMI基因位点的加性单核苷酸多态性(SNP)进行BMI(18.5 - 70kg/m²)自然对数的线性回归,并对年龄、性别、人群分层、研究地点或亲缘关系进行校正。然后,我们进行固定效应荟萃分析和贝叶斯跨种族荟萃分析,以根据等位基因频率差异进行实证聚类。最后,我们近似估计条件关联和联合关联,以检验是否存在次要信号。我们注意到与先前报道的风险等位基因在方向上具有一致性,超出了偶然预期的范围(二项式p < 0.05)。在跨种族分析中,近四分之一先前描述的BMI指数SNP以及代谢芯片上36个密集基因分型的BMI基因位点中的29个得以复制/推广。我们在9个基因位点观察到多个信号,包括对7个具有新型多个信号的基因位点的描述。这项研究支持将大多数常见基因位点推广到不同祖先群体,并强调了密集多民族基因组数据在细化感兴趣基因位点的功能变异以及描述具有多个潜在遗传变异的几个基因位点方面的重要性。

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