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