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A new study published in Nature provides evidence that some genetic traits are shaped not just by which variant a person inherits, but by which parent they inherit it from. By analyzing genetic data from over 100,000 individuals in the UK Biobank, researchers identified more than 30 instances in which the effects of a genetic variant depended on whether it came from the mother or the father. These “parent-of-origin effects” were especially common for traits related to growth and metabolism, including height, fat distribution, and risk for type 2 diabetes.
The study was motivated by a longstanding hypothesis in evolutionary biology known as the parental conflict theory, which proposes that mothers and fathers may have different evolutionary incentives when it comes to how much biological investment is made in their offspring.
For example, paternally inherited genes may favor greater offspring growth to enhance survival and reproductive success, while maternally inherited genes may promote more conservative energy use to preserve resources for future pregnancies. This evolutionary tension is thought to give rise to “genomic imprinting,” in which certain genes are expressed only when inherited from a specific parent.
While earlier studies have uncovered a handful of parent-specific effects, many were constrained by the requirement to have genetic information from both parents. This limitation sharply reduced sample sizes and made it difficult to detect more subtle but widespread effects across the genome. To overcome this, the researchers developed a new method that can infer the parental origin of a gene without direct access to parental genomes.
“We still remember how fascinated we were when we first read the groundbreaking study by Kong and colleagues from Iceland in 2009, which had shown that parent-of-origin effects (POEs) exist on complex traits and diseases,” explained study authors Zoltán Kutalik, an associate professor, and Robin Hofmeister, a postdoctoral researcher.
“However, those studies were limited by small sample sizes due to the requirement of parental genomes or genealogy being available. In 2014, our group (the Statistical Genetics Group at the University of Lausanne and Unisanté) developed a new approach to indirectly infer parent-of-origin effects without parents, by examining phenotypic variance in people with various constellations of genetic variants.”
“Then in 2022, Robin Hofmeister, during his PhD with Olivier Delaneau, came up with the idea to leverage shared DNA segments between relatives to infer ‘surrogate parents,’ which allowed the identification of the parental origin of certain DNA variations. When Robin joined the Statistical Genetics Group, we expanded on this approach by incorporating new biobank data and massively improving the method.”
The researchers combined several strategies—such as tracking shared DNA segments between siblings, analyzing sex chromosomes, and using mitochondrial DNA—to estimate whether a given allele came from the mother or the father. These methods enabled them to assign parental origin to genetic variants for over 109,000 white British participants in the UK Biobank, increasing the usable sample size more than fourfold compared to earlier efforts.
They also applied their approach to two other large cohorts: 85,050 individuals from the Estonian Biobank and 42,346 children from the Norwegian Mother, Father and Child Cohort Study. These replication datasets helped validate their findings and assess how these effects might manifest across development.
Their analysis uncovered more than 30 parent-of-origin effects across a range of complex traits. In many instances, the same genetic variant had opposite effects depending on its parental origin. For example, one variant on chromosome 7 increased triglyceride levels when inherited from the father but decreased them when inherited from the mother. These opposite-direction effects—called “bipolar” effects—were especially common for traits related to energy regulation, such as fat percentage, glucose levels, and cholesterol.
One striking example was found in a well-known region on chromosome 11 that includes the IGF2 gene, which is involved in growth. A variant in this region showed that the paternal copy was associated with shorter height, while the maternal copy had no significant effect. Another nearby variant exhibited a maternal-specific influence on standing height and also affected traits such as fat-free mass and basal metabolic rate. These findings indicate that parent-specific genetic influences may help shape body size and composition across the lifespan.
In another case, a variant on chromosome 11 was associated with type 2 diabetes in a parent-specific manner: the paternal version increased risk, while the maternal version was protective. While this had been suggested in earlier research, the new study provided the strongest confirmation yet.
The presence of multiple bipolar effects in traits related to energy use and growth lends support to the parental conflict hypothesis. Across the identified cases, paternal alleles tended to promote growth and energy expenditure, while maternal alleles were more likely to limit these traits. This pattern was especially apparent for traits such as birth weight, height, and metabolic biomarkers, echoing predictions from evolutionary theory.
To ensure these findings were robust and not the result of random variation or imbalanced datasets, the researchers introduced a new statistical framework that formally tests whether maternal and paternal effects differ significantly. Their use of rigorous thresholds and independent replication helped provide greater confidence in the results.
By analyzing longitudinal data from the Norwegian cohort, the team was also able to track how these effects emerge over time. In one case, a variant associated with height showed parent-of-origin effects from infancy into early childhood. Another variant linked to body mass index showed a maternal-specific effect during infancy that reversed direction in adulthood, suggesting that the impact of parental origin may shift over developmental stages.
“What is key in our findings is that it is not only the DNA sequence that we inherit from our parents, but small attached chemical structures (so-called methylation marks or imprints), which also have an impact on human characteristics,” Kutalik and Hofmeister told PsyPost. “Because of this, we have to consider not only the actual genomic sequence that we inherited, but also from which parent we inherited it, as the effects can differ substantially.”
“Our study identified 30 such examples where the parent of origin of DNA variants matters, and 19 of these had conflicting effects: when inherited from one parent, a variant may predispose us to a cardiometabolic disease, but when the same DNA sequence is inherited from the other parent, it can be protective against that same disease,” they explained. “What surprised us most was how often we observed opposing parental effects—suggesting that this is more the rule than the exception.”
“This last observation was the most surprising: how often we observe opposing parental effects, which is consistent with the parental conflict hypothesis—whereby mothers aim to preserve resources for their own survival and future reproduction, while fathers may prioritize enhancing the fitness of the current offspring, even at the cost of maternal resources.”
Despite the scale and innovation of the study, there are limitations. The researchers focused on individuals of white European ancestry, which limits generalizability to more diverse populations. The traits examined were mainly physical and metabolic; psychiatric and behavioral traits were not analyzed in detail, though the authors note that their methods could be applied in future studies.
Another limitation is that their approach identifies only the transmitted allele, making it difficult to disentangle true genetic effects from potential environmental influences tied to parenting. For instance, a maternal allele linked to lower body mass index might reflect a biological effect, a behavioral influence, or a combination of both.
The team now plans to explore the molecular mechanisms behind these effects. Many of the observed patterns suggest differences in gene expression depending on the parental source, possibly due to regulatory elements that respond to imprinting marks. Future work may involve transcriptomic and epigenetic studies to understand these mechanisms more deeply.
They also hope to extend this line of research to psychiatric traits, which are harder to study due to complex environmental influences and smaller datasets. As access to diverse and multi-generational biobanks grows, the possibility of uncovering parent-specific effects on cognition, emotion, and mental health may soon become more feasible.
“Collaboration was really essential—not only to boost sample size but to assess whether these effects are generalizable across populations, thanks to the Estonian Biobank, and to track whether these patterns emerge in early life, thanks to the Mother, Father and Child Cohort Study,” Kutalik and Hofmeister added.
The study, “Parent-of-origin effects on complex traits in up to 236,781 individuals,” was authored by Robin J. Hofmeister, Théo Cavinato, Roya Karimi, Adriaan van der Graaf, Fanny-Dhelia Pajuste, Jaanika Kronberg, Nele Taba, the Estonian Biobank research team, Reedik Mägi, Marc Vaudel, Simone Rubinacci, Stefan Johansson, Lili Milani, Olivier Delaneau, and Zoltán Kutalik.
