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首页> 外文期刊>PLoS Genetics >Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium
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Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

机译：肥胖基因座的发现和精细映射利用非洲血统个体基因组关联研究的高密度归解：非洲血统人类学遗传联盟

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Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHR_(adjBMI)), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHR_(adjBMI)from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus ( TCF7L2/HABP2 ) for WHR_(adjBMI)and eight previously established loci at P < 5×10~(?8): seven for BMI, and one for WHR_(adjBMI)in African ancestry individuals. An additional novel locus ( SPRYD7/DLEU2 ) was identified for WHR_(adjBMI)when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI ( INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHR_(adjBMI)( SSX2IP , CASC8 , PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHR_(adjBMI)loci that were locus-wide significant ( P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHR_(adjBMI)loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHR_(adjBMI)including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations. Author summary Genome-wide association studies (GWAS) have identified >300 genetic regions that influence body size and shape as measured by body mass index (BMI) and waist-to-hip ratio (WHR), respectively, but few have been identified in populations of African ancestry. We conducted large scale high coverage GWAS and replication of these traits in 52,895 and 23,095 individuals of African ancestry, respectively, followed by additional replication in European populations. We identified 10 genome-wide significant loci in all individuals, and an additional seven loci by analyzing men and women separately. We combined African and European ancestry GWAS and were able to narrow down 43 out of 74 African ancestry associated genetic regions to contain small number of putative causal variants. Our results highlight the improvement of applying high density genome coverage and combining multiple ancestries in the identification and refinement of location of genetic regions associated with adiposity traits.
机译：基因组 - 宽协会研究（GWAs）已鉴定> 300基因座与肥胖措施相关，包括体重指数（BMI）和腰背率比（调节BMI，WHR_（ADJMI）），但是通过筛选鉴定了很少非洲祖先基因组。我们使用1000个基因组阶段1所需的GWA在非洲祖先人类学遗传联盟（AAAGC）的WHR_（ADAGBMI）上进行了大规模的Meta分析和复制，高达52,895人的BMI和最多23,095人，以改善普通和低频率变体在低互联性不平衡非洲血统基因组中。在性综合分析中，我们确定了一个新型基因座（TCF7L2 / HABP2）的WHR_（ADJBMI）和P <5×10〜（？8）的八个先前建立的基因座：BMI的七个，以及WHR_（ADJMI）在非洲祖先的个人。当与欧洲GWA相结合时，鉴定了另外的新型基因座（SPRyD7 / DLEU2），用于WHR_（ADDBMI）。在性分解分析中，我们确定了三种新的BMI（INTS10 / LPL和MLC1中的MLC1，女性IRX4 / IRX2中的MLC1）和FOR用于WHR_（ADJMI）（SSX2IP，CASC8，PDE3B和妇女中的ZDHHC1 / HSD11B2）非洲祖先或非洲和欧洲血统的个人。对于四种新型变体，次要等位基因频率低（<5％）。在47 BMI基因座和27个WHR_（ADJBMI）基因座的跨族裔精细映射中，从非洲血统性交和性分析分析中，源于轨迹宽的显着显着显着显着显着显着显着显着（P <0.05调整为有效数量的遗迹）， 26 BMI LOCI和17 WHR_（ADJBMI）LOCI包含≤20变体的可信集中，共同占驱动关联的99％后概率。这些基因座中的13中的铅变体具有很高的因果概率。与我们之前的HAPMAP电算GWAS相比，包括高达71,412和27,350个非洲祖先个体的BMI和WHR_（ADJBMI），我们的结果表明1000个基因组估算显示识别包括低频变体的GWAS基因座的适度改进。反族元分析进一步改善了非洲和欧洲祖先人群的基因座的推定因果变量的精细映射。作者概述基因组 - 范围协会研究（GWAs）已鉴定> 300个遗传区域，其分别影响体重指数（BMI）和腰背率（WHR）测量的体尺寸和形状，但少数已经识别非洲血统的人口。我们分别在52,895和23,095名非洲血统中进行了大规模的高覆盖GWA和这些特征的复制，然后在欧洲人口中进行了额外的复制。我们通过分别分析男性和女性，在所有个人中确定了10个基因组的重要基因座，以及额外的七个基因座。我们合并非洲和欧洲祖先GWAS，并能够缩小74个非洲祖先相关的遗传区域中的43个，以含有少量推定的因果变形。我们的结果突出了应用高密度基因组覆盖并将多种祖先识别和改进与肥胖性状相关的遗传区域的位置的改善。

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