Hofmeister Robin J, Cavinato Théo, Karimi Roya, van der Graaf Adriaan, Pajuste Fanny-Dhelia, Kronberg Jaanika, Taba Nele, Mägi Reedik, Vaudel Marc, Rubinacci Simone, Johansson Stefan, Milani Lili, Delaneau Olivier, Kutalik Zoltán
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
Swiss Institute of Bioinformatic (SIB), University of Lausanne, Lausanne, Switzerland.
Nature. 2025 Aug 6. doi: 10.1038/s41586-025-09357-5.
Parent-of-origin effects (POEs) occur when the effect of a genetic variant depends on its parental origin. Traditionally linked to genomic imprinting, POEs are believed to occur due to parental conflict over resource allocation to offspring, resulting in opposing parental influences. Despite their importance, POEs remain underexplored in complex traits, owing to the lack of parental genomes. Here we present an approach to infer the parent of origin of alleles without parental genomes, leveraging interchromosomal phasing, mitochondrial and X chromosome data, and sex-specific crossover in siblings. Applied to the UK Biobank, this enabled parent-of-origin inference for up to 109,385 individuals. Genome-wide association study scans for 59 complex traits and over 14,000 protein quantitative trait loci contrasting maternal and paternal effects identified over 30 POEs and confirmed more than 50% of known associations. More than one third of these showed opposite parental influences, especially for traits related to growth (for example, IGF1 and height) and metabolism (for example, type 2 diabetes and triglyceride levels). Replication in up to 85,050 individuals from the Estonian Biobank and 42,346 offspring from the Norwegian Mother, Father and Child Cohort Study (MoBa) validated 87% of testable associations. Overall, our findings highlight the contribution of POEs to complex traits and support the parental conflict hypothesis, providing compelling evidence for this understudied evolutionary phenomenon.
亲本来源效应（POEs）是指基因变异的效应取决于其亲本来源时所发生的现象。传统上，POEs与基因组印记相关联，人们认为它是由于亲本在向后代分配资源时的冲突而产生的，从而导致亲本的影响相互对立。尽管POEs很重要，但由于缺乏亲本基因组，它们在复杂性状中仍未得到充分研究。在这里，我们提出了一种方法，无需亲本基因组即可推断等位基因的亲本来源，该方法利用染色体间定相、线粒体和X染色体数据以及兄弟姐妹中的性别特异性交叉。应用于英国生物银行，这使得能够对多达109,385个人进行亲本来源推断。对59种复杂性状和超过14,000个蛋白质数量性状位点进行全基因组关联研究扫描，对比母本和父本效应，识别出30多个POEs，并确认了超过50%的已知关联。其中超过三分之一显示出相反的亲本影响，特别是对于与生长相关的性状（例如，IGF1和身高）和代谢相关的性状（例如，2型糖尿病和甘油三酯水平）。在爱沙尼亚生物银行的多达85,050名个体以及挪威母亲、父亲和儿童队列研究（MoBa）的42,346名后代中进行的重复验证，证实了87%的可测试关联。总体而言，我们的研究结果突出了POEs对复杂性状的贡献，并支持亲本冲突假说，为这一研究不足的进化现象提供了令人信服的证据。
