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 × 10-4) 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: βpaternal = -0.023, p value = 1.5 × 10-8 and rs1431403: βpaternal = -0.011, p value = 5.4 × 10-6). The corresponding maternally-derived effects were statistically nonsignificant. The variant rs9332053, located on chr13 in RCBTB2 gene, demonstrated a maternal effect on hip circumference (βmaternal = -4.24, p value = 9.6 × 10-6; βpaternal = 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.

中文翻译：

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寻找亲本对印记基因组区域心脏代谢特征的影响。

心脏代谢特征构成了全球主要的公共卫生负担。大规模全基因组关联研究 (GWAS) 已确定多个位点可解释心脏代谢性状等复杂性状遗传变异的高达 30%。然而，GWAS 中很大程度上忽略了亲本效应（POE）对复杂性状的贡献。基于家庭的研究能够在遗传关联分析中评估 POE。我们在 3 项基于家庭的研究中调查了 POE 的一系列复杂特征。发现阶段是在基布兹家庭研究的大型谱系（n = 901 个体）和耶路撒冷围产期研究的 872 个亲子三人组中进行的。我们以印记基因组区域为重点，研究了父母特异性与 12 种复杂性状（即体型、血压、血脂）的关联，其中大部分是心脏代谢风险性状。最初发现具有 POE 的 11,967 个 SNP 中的 45 个在弗雷明汉心脏研究家族（最多 n = 8000 人）中进行了复制评估（p 值 < 1 × 10-4）。在荟萃分析中，三种常见变体提供了 POE 的证据。位于 HLA 区域的 chr6 上的两个变异显示出对身高的父系影响（rs1042136：βpaternal = -0.023，p 值 = 1.5 × 10-8 和 rs1431403：βpaternal = -0.011，p 值 = 5.4 × 10-6） 。相应的母源效应在统计上不显着。位于 RCBTB2 基因的 chr13 上的变体 rs9332053 表现出对臀围的母体影响（β母体 = -4.24，p 值 = 9.6 × 10-6；β父体 = 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）的关联研究中的效用提供了证据。该研究强调了使用基于家庭的数据来破译复杂性状的遗传结构的好处。