Sex differences in DNA methylation across gestation: a large scale, cross-cohort, multi-tissue analysis.

Biological sex is a key variable influencing many physiological systems. Disease prevalence as well as treatment success can be modified by sex. Differences emerge already early in life and include pregnancy complications and adverse birth outcomes. The placenta is a critical organ for fetal development and shows sex-based differences in the expression of hormones and cytokines. Epigenetic regulation, such as DNA methylation (DNAm), may underlie the previously reported placental sexual dimorphism. We associated placental DNAm with fetal sex in three cohorts. Individual cohort results were meta-analyzed with random-effects modelling. CpG-sites differentially methylated with sex were further investigated regarding pathway enrichment, overlap with methylation quantitative trait loci (meQTLs), and hits from phenome-wide association studies (PheWAS). We evaluated the consistency of findings across tissues (CVS, i.e. chorionic villus sampling from early placenta, and cord blood) as well as with gene expression. We identified 10,320 epigenome-wide significant sex-differentially methylated probes (DMPs) spread throughout the epigenome of the placenta at birth. Most DMPs presented with lower DNAm levels in females. DMPs mapped to genes upregulated in brain, were enriched for neurodevelopmental pathways and significantly overlapped with meQTLs and PheWAS hits. Effect sizes were moderately correlated between CVS and placenta at birth, but only weakly correlated between birth placenta and cord blood. Sex differential gene expression in birth placenta was less pronounced and implicated genetic regions only marginally overlapped with those associated with differential DNAm. Our study provides an integrative perspective on sex-differential DNAm in perinatal tissues underscoring the possible link between placenta and brain.

Epigenetic signature of very low birth weight in young adult life.

BACKGROUND: Globally, one in ten babies is born preterm (<37 weeks), and 1-2% preterm at very low birth weight (VLBW, <1500 g). As adults, they are at increased risk for a plethora of health conditions, e.g., cardiometabolic disease, which may partly be mediated by epigenetic regulation. We compared blood DNA methylation between young adults born at VLBW and controls. METHODS: 157 subjects born at VLBW and 161 controls born at term, from the Helsinki Study of Very Low Birth Weight Adults, were assessed for peripheral venous blood DNA methylation levels at mean age of 22 years. Significant CpG-sites (5'-C-phosphate-G-3') were meta-analyzed against continuous birth weight in four independent cohorts (pooled n = 2235) with cohort mean ages varying from 0 to 31 years. RESULTS: In the discovery cohort, 66 CpG-sites were differentially methylated between VLBW adults and controls. Top hits were located in HIF3A, EBF4, and an intergenic region nearest to GLI2 (distance 57,533 bp). Five CpG-sites, all in proximity to GLI2, were hypermethylated in VLBW and associated with lower birth weight in the meta-analysis. CONCLUSION: We identified differentially methylated CpG-sites suggesting an epigenetic signature of preterm birth at VLBW present in adult life. IMPACT: Being born preterm at very low birth weight has major implications for later health and chronic disease risk factors. The mechanism linking preterm birth to later outcomes remains unknown. Our cohort study of 157 very low birth weight adults and 161 controls found 66 differentially methylated sites at mean age of 22 years. Our findings suggest an epigenetic mark of preterm birth present in adulthood, which opens up opportunities for mechanistic studies.

The brain insulin receptor gene network and associations with frailty index.

OBJECTIVE: To investigate longitudinal associations between variations in the co-expression-based brain insulin receptor polygenic risk score and frailty, as well as change in frailty across follow-up. METHODS: This longitudinal study included 1605 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network, which measure genetic variation in the function of the insulin receptor, were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Frailty was assessed in at baseline in 2001-2004, 2011-2013 and 2017-2018 by applying a deficit accumulation-based frailty index. Analyses were carried out by applying linear mixed models and logistical regression models adjusted for adult socioeconomic status, birthweight, smoking and their interactions with age. RESULTS: The FI levels of women were 1.19%-points (95% CI 0.12-2.26, P = 0.029) higher than in men. Both categorical and continuous hePRS-IR in women were associated with higher FI levels than in men at baseline (P < 0.05). In women with high hePRS-IR, the rate of change was steeper with increasing age compared to those with low or moderate hePRS-IR (P < 0.05). No associations were detected between mePRS-IR and frailty at baseline, nor between mePRS-IR and the increase in mean FI levels per year in either sex (P > 0.43). CONCLUSIONS: Higher variation in the function of the insulin receptor gene network in the hippocampus is associated with increasing frailty in women. This could potentially offer novel targets for future drug development aimed at frailty and ageing.

Genetic risk of type 2 diabetes modifies the association between lifestyle and glycemic health at 5 years postpartum among high-risk women.

INTRODUCTION: Lifestyle interventions are effective in preventing type 2 diabetes, but genetic background may influence the individual response. In the Finnish gestational diabetes prevention study, RADIEL, lifestyle intervention during pregnancy and first postpartum year was effective in preventing gestational diabetes (GDM) and postpartum glycemic abnormalities only among women at highest genetic risk of type 2 diabetes. This study aimed to assess whether still 5 years postpartum the genetic risk modifies the association between lifestyle and glycemic health. RESEARCH DESIGN AND METHODS: The RADIEL study (randomized controlled trial) aimed to prevent GDM with a lifestyle intervention among high-risk women (body mass index ≥30 kg/m2 and/or prior GDM). The follow-up study 5 years postpartum included anthropometric measurements, laboratory assessments, device-measured physical activity (PA), and questionnaires. A Healthy Lifestyle Score (HLS) indicated adherence to lifestyle goals (PA, diet, smoking) and a polygenic risk score (PRS) based on 50 type 2 diabetes risk alleles depicted the genetic risk. RESULTS: Altogether 314 women provided genetic and glycemic data 5 years postpartum. The PRS for type 2 diabetes was not associated with glycemic abnormalities, nor was HLS in the total study sample. There was, however, an interaction between HLS and type 2 diabetes PRS on glycemic abnormalities (p=0.03). When assessing the association between HLS and glycemic abnormalities in PRS tertiles, HLS was associated with reduced risk of glycemic abnormalities only among women at the highest genetic risk (p=0.008). CONCLUSIONS: These results extend our previous findings from pregnancy and first postpartum year demonstrating that still at 5 years postpartum, healthy lifestyle is associated with a lower risk of prediabetes/diabetes only among women at the highest genetic risk of type 2 diabetes.

Development and validation of the puppy blues scale measuring temporary affective disturbance resembling baby blues.

It has been described that many puppy owners experience a state called puppy blues involving stress, worry, anxiety, strain, frustration, or regret. While puppy blues is a commonly used term among dog owners, the term is nearly nonexistent in scientific literature. In turn, analogous phenomenon, postpartum affective disturbance of infant caregivers, is well described in the literature. This study aimed to develop and validate the first questionnaire to evaluate puppy blues. The methodology involved generating scale items based on a qualitative review of 135 pilot survey responses from people who had experienced distress during the puppy period, conducting exploratory factor analysis for the final scale items from a dataset of 1801 answers from Finnish dog owners (92% women), and collecting test-retest data from 265 individuals to assess the consistency of the measurement of items and factor structure across time. In addition, we collected an independent sample of 326 owners of 1-2-year-old dogs who answered the survey both regarding puppy period and current moment. The results indicate that the scale is a valid and reliable tool for measuring dog owners' negative experiences and feelings related to puppyhood. We discovered three factors that describe different aspects of puppy blues: Frustration, Anxiety, and Weariness, which accounted for a significant proportion of the variance in puppy blues. The study demonstrated good internal consistency and consistency across two independent samples for the three identified factors. The test-retest reliability of the factors was good. Responses for the current timeframe compared to puppyhood experiences revealed significantly lower current scores across all factors for the current period, validating that the scale captures distress during puppyhood that diminishes over time. Interestingly, we found a fading affect bias where recollections of the experiences in the puppy period became more positive with time. Our findings shed light on the characteristics of puppy blues and provide a useful retrospective tool for measuring it.

Affect dimensions and variability during major depressive episodes: Ecological momentary assessment of unipolar, bipolar, and borderline patients and healthy controls.

Differentiating major depressive episodes (MDEs) of major depressive disorder (MDD), bipolar disorder (MDE/BD) and the MDEs comorbid with borderline personality disorder (MDE/BPD) is crucial for appropriate treatment, and knowledge of phenomenological differences may aid this. However, studies comparing affect experiences of these three patient groups and healthy subjects are scarce. In our study, participants (N = 114), including patients with MDD (n = 34), MDE/BD (n = 27), and MDE/BPD (n = 24), and healthy controls (HC, n = 29) responded to ecological momentary assessment (EMA) with ten circumplex model affect items ten times daily for seven days (7709 recordings). Explorative factor analysis resulted in two affect dimensions. The positive dimension included active, excited, cheerful (high arousal), and content (low arousal) affects, and the negative dimension irritated, angry, and nervous (high arousal) affects. Relative to HC, patients reported 3.5-fold negative affects (mean MDD 1.36 (SD 0.92), MDE/BD 1.43 (0.76), MDE/BPD 1.81 (0.95) vs. HC 0.44 (0.49) (p < 0.01)) but 0.5-fold positive affects (2.01 (0.90), 1.95 (0.89), 2.24 (1.03), vs. 3.2 (0.95), respectively (p < 0.01)). We used multilevel modelling. Negative-affect within-individual stability was lowest in MDE/BPD and highest in MDD. Negative affect predicted concurrent positive affect more in MDE/BPD than in MDD. Moderate size of subcohorts and no inpatients were limitations. Despite apparently similar MDEs, affective experiences may differ between BPD, BD, and MDD patients. Clinical subgroups of patients with depression may vary in affective instability and concurrent presence of negative and positive affects during depression.

Biologically Informed Polygenic Scores for Brain Insulin Receptor Network Are Associated with Cardiometabolic Risk Markers and Diabetes in Women.

Background: To investigate associations between variations in the co-expression-based brain insulin receptor polygenic score and cardiometabolic risk factors and diabetes mellitus. Methods: This cross-sectional study included 1,573 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Cardiometabolic markers included body composition, waist circumference, circulating lipids, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 1 and 3 (IGFBP-1 and -3). Glucose and insulin levels were measured during a standardized 2-hour 75 g oral glucose tolerance test and impaired glucose regulation status was defined by the World Health Organization 2019 criteria. Analyzes were adjusted for population stratification, age, smoking, alcohol consumption, socioeconomic status, chronic diseases, birth weight, and leisure-time physical activity. Results: Multinomial logistic regression indicated that one standard deviation increase in hePRS-IR was associated with increased risk of diabetes mellitus in all participants (adjusted relative risk ratio, 1.17; 95% confidence interval, 1.01 to 1.35). In women, higher hePRS-IR was associated with greater waist circumference and higher body fat percentage, levels of glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, insulin, and IGFBP-1 (all P≤0.02). The mePRS-IR was associated with decreased IGF-1 level in women (P=0.02). No associations were detected in men and studied outcomes. Conclusion: hePRS-IR is associated with sex-specific differences in cardiometabolic risk factor profiles including impaired glucose regulation, abnormal metabolic markers, and unfavorable body composition in women.

Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance.

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.