Adiposity-Dependent Regulatory Effects on Multi-tissue Transcriptomes.
Adiposity-Dependent Regulatory Effects on Multi-tissue Transcriptomes.
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DOI：
10.1016/j.ajhg.2016.07.001
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发表时间：
2016-09-01
影响因子：
9.8
通讯作者：
Small KS
中科院分区：
文献类型：
--
作者：
Glastonbury CA;Viñuela A;Buil A;Halldorsson GH;Thorleifsson G;Helgason H;Thorsteinsdottir U;Stefansson K;Dermitzakis ET;Spector TD;Small KS
肥胖是一种全球流行病，在人口层面上与包括2型糖尿病和心血管疾病在内的一系列疾病有因果关系。然而，个体之间肥胖相关的结果存在明显的异质性。这可能反映了对肥胖的基因型依赖性反应。考虑到肥胖，通过BMI测量，与基因表达的广泛变化和调节变异介导大多数已知的复杂性状位点有关，我们试图在TwinsUK队列（n = 856）的多组织rna测序（RNA-seq）数据集中确定基因-by-BMI （G × BMI）相互作用对基因表达的调节。在5%的错误发现率下，我们在脂肪组织中发现了16个顺式G × BMI相互作用（最上面的顺式相互作用：CHURC1， rs7143432, p = 2.0 × 10−12）和一个调节53个反式基因的变异（最上面的反式相互作用：ZNF423， rs3851570, p = 8.2 × 10−13）。这种相互作用是脂肪特异性的，并且在重叠脂肪细胞增强子的变体中丰富，并且在代谢和炎症过程中丰富了调节基因。我们在一个独立的脂肪RNA-seq数据集中复制了一个相互作用的子集（deCODE genetics, n = 754）。我们还在TwinsUK个体的一个子集（n = 682）中证实了与肥胖的另一种测量方法的相互作用，即双能x射线吸收仪（DXA）衍生的内脏脂肪体积测量。所鉴定的G × BMI调节效应证明了基因调控的动态性，揭示了肥胖异质性反应的功能机制。此外，我们还提供了一个网络浏览器，允许对数据集进行交互式探索，包括四种组织中表达、BMI和G × BMI调节效应之间的关联。
Obesity is a global epidemic that is causally associated with a range of diseases, including type 2 diabetes and cardiovascular disease, at the population-level. However, there is marked heterogeneity in obesity-related outcomes among individuals. This might reflect genotype-dependent responses to adiposity. Given that adiposity, measured by BMI, is associated with widespread changes in gene expression and regulatory variants mediate the majority of known complex trait loci, we sought to identify gene-by-BMI (G × BMI) interactions on the regulation of gene expression in a multi-tissue RNA-sequencing (RNA-seq) dataset from the TwinsUK cohort (n = 856). At a false discovery rate of 5%, we identified 16 cis G × BMI interactions (top cis interaction: CHURC1, rs7143432, p = 2.0 × 10−12) and one variant regulating 53 genes in trans (top trans interaction: ZNF423, rs3851570, p = 8.2 × 10−13), all in adipose tissue. The interactions were adipose-specific and enriched for variants overlapping adipocyte enhancers, and regulated genes were enriched for metabolic and inflammatory processes. We replicated a subset of the interactions in an independent adipose RNA-seq dataset (deCODE genetics, n = 754). We also confirmed the interactions with an alternate measure of obesity, dual-energy X-ray absorptiometry (DXA)-derived visceral-fat-volume measurements, in a subset of TwinsUK individuals (n = 682). The identified G × BMI regulatory effects demonstrate the dynamic nature of gene regulation and reveal a functional mechanism underlying the heterogeneous response to obesity. Additionally, we have provided a web browser allowing interactive exploration of the dataset, including of association between expression, BMI, and G × BMI regulatory effects in four tissues.
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影响因子：
30.8
作者：
Cho, Yoon Shin;Chen, Chien-Hsiun;Hu, Cheng;Long, Jirong;Ong, Rick Twee Hee;Sim, Xueling;Takeuchi, Fumihiko;Wu, Ying;Go, Min Jin;Yamauchi, Toshimasa;Chang, Yi-Cheng;Kwak, Soo Heon;Ma, Ronald C. W.;Yamamoto, Ken;Adair, Linda S.;Aung, Tin;Cai, Qiuyin;Chang, Li-Ching;Chen, Yuan-Tsong;Gao, Yutang;Hu, Frank B.;Kim, Hyung-Lae;Kim, Sangsoo;Kim, Young Jin;Lee, Jeannette Jen-Mai;Lee, Nanette R.;Li, Yun;Liu, Jian Jun;Lu, Wei;Nakamura, Jiro;Nakashima, Eitaro;Ng, Daniel Peng-Keat;Tay, Wan Ting;Tsai, Fuu-Jen;Wong, Tien Yin;Yokota, Mitsuhiro;Zheng, Wei;Zhang, Rong;Wang, Congrong;So, Wing Yee;Ohnaka, Keizo;Ikegami, Hiroshi;Hara, Kazuo;Cho, Young Min;Cho, Nam H.;Chang, Tien-Jyun;Bao, Yuqian;Hedman, Asa K.;Morris, Andrew P.;McCarthy, Mark I.;Takayanagi, Ryoichi;Park, Kyong Soo;Jia, Weiping;Chuang, Lee-Ming;Chan, Juliana C. N.;Maeda, Shiro;Kadowaki, Takashi;Lee, Jong-Young;Wu, Jer-Yuarn;Teo, Yik Ying;Tai, E. Shyong;Shu, Xiao Ou;Mohlke, Karen L.;Kato, Norihiro;Han, Bok-Ghee;Seielstad, Mark
通讯作者：
Seielstad, Mark
影响因子：
9.9
作者：
Grishkevich, Vladislav;Ben-Elazar, Shay;Hashimshony, Tamar;Schott, Daniel H.;Hunter, Craig P.;Yanai, Itai
通讯作者：
Yanai, Itai
影响因子：
4.5
作者：
Gerrits A;Li Y;Tesson BM;Bystrykh LV;Weersing E;Ausema A;Dontje B;Wang X;Breitling R;Jansen RC;de Haan G
通讯作者：
de Haan G
影响因子：
3.3
作者：
Eng, Kevin H.;Kvitek, Daniel J.;Gasch, Audrey P.
通讯作者：
Gasch, Audrey P.
影响因子：
30.8
作者：
Gudbjartsson, Daniel F.;Helgason, Hannes;Stefansson, Kari
通讯作者：
Stefansson, Kari