Biology subjects

Bakermans-Kranenburg, M.

Publications and source records attributed to Bakermans-Kranenburg, M..

6 recordsLinked to original sources

bioRxiv2025

Epigenome-wide association study meta-analysis of wellbeing

Wellbeing is associated with both behavioral phenotypes as well as several key life outcomes, such as health, employment, and coping with stressful events. These phenotypes associated with wellbeing could be potential indicators of differential epigenetic patterns between individuals that differ in their levels of wellbeing. We performed the largest epigenome-wide (EWAS) meta-analysis of wellbeing to date by combining whole blood DNA methylation data (Illumina 450k array) from 13 cohorts from Europe, Australia, and the USA (N = 10,757 participants). After correcting for smoking and BMI, no epigenome-wide significant methylation sites were identified. We tested whether a weighted methylation score (MS) based on leave-one-cohort-out EWAS meta-analysis summary statistics predicted wellbeing in an independent cohort, and whether prediction was significant over and above the polygenic score (PGS) for wellbeing. The MS was associated with wellbeing (variance explained=0.22%, p=0.03) and was no longer significant after adding the polygenic score (PGS; variance explained=0.43%, p=0.0046, MS; variance explained=0.07%, p=0.2842). We further compared DNA methylation levels in 16 pairs of monozygotic twins discordant for wellbeing. These analyses revealed no significant within-pair DNA methylation differences at the top-sites from the meta-analysis or in MS. Our results suggest that larger EWAS meta-analyses with uniform phenotype assessment are required to identify methylation sites associated with wellbeing.

genomics↗

bioRxiv2025

Interdependency between oxytocin and dopamine in trust-based learning in mice

Oxytocin (OT) is a neuropeptide implicated in complex social behaviors including trust and attachment, yet the neural mechanisms underlying its effects remain unclear. OT is thought to modulate behavior by enhancing the salience of social cues and attenuating prediction error (PE) processing, the discrepancy between expected and actual outcomes that drives learning. Since both salience coding and PE processing involve dopamine (DA) neurons as well, the current study investigated the putative interdependence between OT and DA in social safety learning using the social transmission of food preference (STFP) paradigm. STFP is based on the observation that mice (observers) display neophobia toward novel food, but develop a preference for it after a conspecific demonstrator signals its safety. We interpreted STFP acquisition as a functional parallel to human trust-based learning and found that OT enhanced learning in a trust acquisition condition, but only when DA signaling was intact. In a trust violation condition, where demonstrated food was later paired with lithium chloride (LiCl)-induced food aversion, both OT and DA depletion blocked learning, resulting in retained preference for demonstrated food, but not when OT was administered under DA depletion. These findings reveal a functional interaction between the OT and DA systems to modulate social safety learning, which may have important implications for OTs potential in treating disorders involving DA dysfunction.

neuroscience↗

bioRxiv2024

Oxytocin enhances acquisition in a social trust task in mice, whereas both oxytocin and its antagonist block trust violation learning

The complex effects of the neurohormone oxytocin (OT) on socio-cognitive phenomena have recently been proposed to be complementary with safety learning, where a stimulus acquires safety-predicting properties when it predicts non-occurrence of an aversive event. OT may enhance saliency of safety stimuli and promote positive social behavior, such as trust, by reducing anxiety and stress. Complementary, OT may reduce the ability to modulate previously learned behaviors based on new, contradicting information. This occurs through its attenuation of prediction error (PE)--the discrepancy between expectations and actual outcomes. In the current study, we stimulated or inhibited (with antagonist cligosiban, CL) the OT system and subjected male and female mice to our social transmission of food preference (STFP) protocol to assess social safety learning. STFP is based on the observation that food neophobia of rodents is attenuated when a conspecific signals the safety of the food. We used safe food preference as putative murine homologue of human trust acquisition, and modeled trust violation (PE) using lithium chloride (LiCl)-induced food aversion after social interaction. In males, results revealed that OT enhanced trust acquisition, whereas both OT and its antagonist CL similarly blocked trust violation learning. None of the manipulations affected female behavior. Our findings highlight the complexities of OTs role in social behavior, emphasizing caution in therapeutic manipulations of this system.

neuroscience↗

bioRxiv2020

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2x10-7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

genetics↗

bioRxiv2019

Association between DNA methylation and ADHD symptoms from birth to school age: A prospective meta-analysis

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is not known. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school-age. We examined associations of DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age range 4-15 years) in 2477 children from five cohorts and DNA methylation at school-age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from ten cohorts. CpGs identified with nominal significance (p<0.05) in either of the EWAS were correlated between timepoints ({rho}=0.30), suggesting overlap in associations, however, top signals were very different. At birth, we identified nine CpGs that were associated with later ADHD symptoms (P<1*10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 located in the promotor region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which was associated with neurite outgrowth and an ADHD diagnosis in previous studies. In contrast, at school-age, no CpGs were associated with ADHD with P<1*10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

genetics↗

bioRxiv2019

Maternal care of heterozygous Dopamine Receptor D4 knockout mice: Differential susceptibility to early-life rearing conditions

The differential susceptibility hypothesis proposes that individuals who are more susceptible to the negative effects of adverse rearing conditions may also benefit more from enriched environments. Evidence derived from human experiments suggests the lower efficacy dopamine receptor D4 (DRD4) 7-repeat as a main factor in exhibiting these for better and for worse characteristics. However, human studies lack the genetic and environmental control offered by animal experiments, complicating assessment of causal relations. To study differential susceptibility in an animal model, we exposed Drd4+/- mice and control litter mates to a limited nesting/bedding (LN), standard nesting (SN) or communal nesting (CN) rearing environment from postnatal day (P) 2-14. Puberty onset was examined from P24-P36 and adult females were assessed on maternal care towards their own offspring. In both males and females, LN reared mice showed a delay in puberty onset that was partly mediated by a reduction in body weight at weaning, irrespective of Drd4 genotype. During adulthood, LN reared females exhibited characteristics of poor maternal care, whereas dams reared in CN environments showed lower rates of unpredictability towards their own offspring. Differential susceptibility was observed only for licking/grooming levels of female offspring towards their litter; LN reared Drd4+/- mice exhibited the lowest and CN reared Drd4+/- mice the highest levels of licking/grooming. These results indicate that both genetic and early-environmental factors play an important role in shaping maternal care of the offspring for better and for worse.

developmental biology↗