腹部和臀部脂肪组织的共表达网络分析揭示了代谢综合征及相关表型的调节遗传位点。

Coexpression network analysis in abdominal and gluteal adipose tissue reveals regulatory genetic loci for metabolic syndrome and related phenotypes.

机构信息

The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

出版信息

PLoS Genet. 2012;8(2):e1002505. doi: 10.1371/journal.pgen.1002505. Epub 2012 Feb 23.

DOI:10.1371/journal.pgen.1002505

PMID:22383892

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3285582/

Abstract

Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue, and whole blood (WB), from 29 MetS cases and 44 controls. Co-expression network analysis for each tissue independently identified nine, six, and zero MetS-associated modules of coexpressed genes in ABD, GLU, and WB, respectively. Of 8,992 probesets expressed in ABD or GLU, 685 (7.6%) were expressed in ABD and 51 (0.6%) in GLU only. Differential eigengene network analysis of 8,256 shared probesets detected 22 shared modules with high preservation across adipose depots (D(ABD-GLU) = 0.89), seven of which were associated with MetS (FDR P<0.01). The strongest associated module, significantly enriched for immune response-related processes, contained 94/620 (15%) genes with inter-depot differences. In an independent cohort of 145/141 twins with ABD and WB longitudinal expression data, median variability in ABD due to familiality was greater for MetS-associated versus un-associated modules (ABD: 0.48 versus 0.18, P = 0.08; GLU: 0.54 versus 0.20, P = 7.8×10(-4)). Cis-eQTL analysis of probesets associated with MetS (FDR P<0.01) and/or inter-depot differences (FDR P<0.01) provided evidence for 32 eQTLs. Corresponding eSNPs were tested for association with MetS-related phenotypes in two GWAS of >100,000 individuals; rs10282458, affecting expression of RARRES2 (encoding chemerin), was associated with body mass index (BMI) (P = 6.0×10(-4)); and rs2395185, affecting inter-depot differences of HLA-DRB1 expression, was associated with high-density lipoprotein (P = 8.7×10(-4)) and BMI-adjusted waist-to-hip ratio (P = 2.4×10(-4)). Since many genes and their interactions influence complex traits such as MetS, integrated analysis of genotypes and coexpression networks across multiple tissues relevant to clinical traits is an efficient strategy to identify novel associations.

摘要

代谢综合征（MetS）患病率高，对公众健康有重大影响，但潜在的遗传因素仍不清楚。为了鉴定与 MetS 相关的基因网络，我们对 29 名 MetS 病例和 44 名对照的腹部（ABD）和臀（GLU）脂肪组织及全血（WB）进行了全基因组表达和基因型分析。每个组织的共表达网络分析分别鉴定了 ABD、GLU 和 WB 中与 MetS 相关的 9、6 和 0 个共表达基因模块。在 ABD 或 GLU 中表达的 8992 个探针中，有 685 个（7.6%）在 ABD 中表达，51 个（0.6%）仅在 GLU 中表达。对 8256 个共享探针的差异特征基因网络分析检测到 22 个共享模块，在脂肪组织中具有高度保存性（D（ABD-GLU）=0.89），其中 7 个与 MetS 相关（FDR P<0.01）。与 MetS 相关的最强相关模块，显著富集免疫反应相关过程，包含 94/620（15%）个基因具有脂肪组织间差异。在 145/141 对具有 ABD 和 WB 纵向表达数据的双胞胎的独立队列中，由于家族性导致 ABD 中 MetS 相关与非相关模块的变异中位数更大（ABD：0.48 与 0.18，P=0.08；GLU：0.54 与 0.20，P=7.8×10(-4)）。对与 MetS 相关（FDR P<0.01）和/或脂肪组织间差异（FDR P<0.01）相关的探针的顺式-eQTL 分析提供了 32 个 eQTL 的证据。与 MetS 相关表型的关联在两项超过 10 万人的 GWAS 中对相应的 eSNP 进行了检测；rs10282458 影响 RARRES2（编码 chemerin）的表达，与体重指数（BMI）相关（P=6.0×10(-4)）；rs2395185 影响 HLA-DRB1 表达的脂肪组织间差异，与高密度脂蛋白（P=8.7×10(-4)）和 BMI 校正的腰臀比（P=2.4×10(-4)）相关。由于许多基因及其相互作用影响 MetS 等复杂特征，因此跨多个与临床特征相关的组织对基因型和共表达网络进行综合分析是鉴定新关联的有效策略。