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寻找印记基因组区域中心血管代谢特征的亲本来源效应。

Searching for parent-of-origin effects on cardiometabolic traits in imprinted genomic regions.

机构信息

Braun School of Public Health, The Hebrew University of Jerusalem, 99112102, Jerusalem, Israel.

Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.

出版信息

Eur J Hum Genet. 2020 May;28(5):646-655. doi: 10.1038/s41431-019-0568-1. Epub 2020 Jan 2.

Abstract

Cardiometabolic traits pose a major global public health burden. Large-scale genome-wide association studies (GWAS) have identified multiple loci accounting for up to 30% of the genetic variance in complex traits such as cardiometabolic traits. However, the contribution of parent-of-origin effects (POEs) to complex traits has been largely ignored in GWAS. Family-based studies enable the assessment of POEs in genetic association analyses. We investigated POEs on a range of complex traits in 3 family-based studies. The discovery phase was carried out in large pedigrees from the Kibbutzim Family Study (n = 901 individuals) and in 872 parent-offspring trios from the Jerusalem Perinatal Study. Focusing on imprinted genomic regions, we examined parent-specific associations with 12 complex traits (i.e., body-size, blood pressure, lipids), mostly cardiometabolic risk traits. Forty five of the 11,967 SNPs initially found to have POE were evaluated for replication (p value < 1 × 10) in Framingham Heart Study families (max n = 8000 individuals). Three common variants yielded evidence of POE in the meta-analysis. Two variants, located on chr6 in the HLA region, showed a paternal effect on height (rs1042136: β = -0.023, p value = 1.5 × 10 and rs1431403: β = -0.011, p value = 5.4 × 10). The corresponding maternally-derived effects were statistically nonsignificant. The variant rs9332053, located on chr13 in RCBTB2 gene, demonstrated a maternal effect on hip circumference (β = -4.24, p value = 9.6 × 10; β = 1.29, p value = 0.23). These findings provide evidence for the utility of incorporating POEs into association studies of cardiometabolic traits, especially anthropometric traits. The study highlights the benefits of using family-based data for deciphering the genetic architecture of complex traits.

摘要

心脏代谢特征是全球主要的公共卫生负担。大规模全基因组关联研究(GWAS)已经确定了多个基因座,这些基因座占心脏代谢等复杂特征遗传变异的 30%。然而,GWAS 中很大程度上忽略了亲本来源效应(POE)对复杂特征的贡献。基于家庭的研究可以评估遗传关联分析中的 POE。我们在 3 个基于家庭的研究中研究了一系列复杂特征的 POE。发现阶段在 Kibbutzim 家庭研究(n=901 人)的大型家系和耶路撒冷围产期研究的 872 个父母-子女三体型中进行。我们专注于印迹基因组区域,检查了 12 种复杂特征(即体型、血压、血脂)的特定于亲本的关联,这些特征主要是心脏代谢风险特征。在最初发现具有 POE 的 11967 个 SNP 中,有 45 个在 Framingham Heart Study 家族中进行了复制评估(p 值<1×10)(最大 n=8000 人)。在荟萃分析中,有 3 个常见变体显示出 POE 的证据。两个变体位于 chr6 的 HLA 区域,对身高表现出父系效应(rs1042136:β=-0.023,p 值=1.5×10;rs1431403:β=-0.011,p 值=5.4×10)。相应的母系衍生效应在统计学上不显著。位于 chr13 的 RCBTB2 基因中的变体 rs9332053 显示出对臀围的母系效应(β=-4.24,p 值=9.6×10;β=1.29,p 值=0.23)。这些发现为将 POE 纳入心脏代谢特征,尤其是人体测量特征的关联研究提供了证据。该研究强调了使用基于家庭的数据来解析复杂特征遗传结构的好处。

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