Maternal Characteristics in Natural and Medically Assisted Reproduction Dizygotic Twin Pregnancies.

Previous studies have shown that mothers of naturally conceived dizygotic (DZ) twins tend to be taller, older, and smoke more than mothers of naturally conceived monozygotic (MZ) twin and mothers of singletons. Here, we investigate whether mothers of naturally conceived DZ twins differ from mothers who conceived their DZ twins after medically assisted reproduction (MAR) in eight maternal traits related to fertility based on observational survey data. We include data from 33,648 mothers from the Netherlands Twin Register (NTR) and 1660 mothers of twins from the Norwegian Mother, Father and Child Cohort Study (MoBA). We contrast mothers of naturally conceived DZ twins with mothers of MAR DZ twins. Next, we further segment the MAR group into mothers who underwent hormonal induction of ovulation but not in vitro fertilization (IVF) and those who IVF twins, comparing them both to each other and against the mothers of naturally conceived DZ twins. Mothers of naturally conceived DZ twins smoke more often, differ in body composition, have a higher maternal age and have more offspring before the twins than mothers of MZ twins. Compared to MAR DZ twin mothers, mothers of naturally conceived DZ twins have fewer miscarriages, lower maternal age and increased height, more offspring and are more often smokers. BMI before the twin pregnancy is similar in both natural and MAR DZ twin mothers. Mothers who received hormonal induction of ovulation (OI) have a lower maternal age, fewer miscarriages, and a higher number of offspring before their twin pregnancy than twin mothers who received IVF and/or intracytoplasmic sperm injection (ICSI) treatments. Our study shows that twin mothers are a heterogenous group and the differences between twin mothers should be taken into account in epidemiological and genetic research that includes twins.

Epigenetic Signatures of Asthma: A Comprehensive Study of DNA Methylation and Clinical Markers.

Background: Asthma, a complex respiratory disease, presents with inflammatory symptoms in the lungs, blood, and other tissues. We investigated the relationship between DNA methylation and 35 clinical markers of asthma. The Illumina Infinium EPIC v1 methylation array was used to evaluate 742,442 CpGs in whole blood samples from 319 participants. They were part of the Netherlands Twin Register from families with at least one member suffering from severe asthma. Repeat blood samples were taken after 10 years from 182 of these individuals. Principal component analysis (PCA) on the clinical markers yielded ten principal components (PCs) that explained 92.8% of the total variance. We performed epigenome-wide association studies (EWAS) for each of the ten PCs correcting for familial structure and other covariates. Results: 221 unique CpGs reached genome-wide significance at timepoint 1 (T1) after Bonferroni correction. PC7 accounted for the majority of associations (204), which correlated with loadings of eosinophil counts and immunoglobulin levels. Enrichment analysis via the EWAS Atlas identified 190 of these CpGs to be previously identified in EWASs of asthma and asthma-related traits. Proximity assessment to previously identified SNPs associated with asthma identified 17 unique SNPs within 1 MB of two of the 221 CpGs. EWAS in 182 individuals with epigenetic data at a second timepoint (T2) identified 49 significant CpGs. EWAS Atlas enrichment analysis indicated that 4 of the 49 were previously associated with asthma or asthma-related traits. Comparing the estimates of all the significant associations identified across the two time points (271 in total) yielded a correlation of 0.81. Conclusion: We identified 270 unique CpGs that were associated with PC scores generated from 35 clinical markers of asthma, either cross-sectionally or 10 years later. A strong correlation was present between effect sizes at the 2 timepoints. Most associations were identified for PC7, which captured blood eosinophil counts and immunoglobulin levels and many of these CpGs have previous associations in earlier studies of asthma and asthma-related traits. The results point to using this robust DNA methylation profile as a new, stable biomarker for asthma.

No gene by stressful life events interaction on individual differences in adults' self-control.

Background: Difficulty with self-control, or the ability to alter impulses and behavior in a goal-directed way, predicts interpersonal conflict, lower socioeconomic attainments, and more adverse health outcomes. Etiological understanding, and intervention for low self-control is, therefore, a public health goal. A prominent developmental theory proposes that individuals with high genetic propensity for low self-control that are also exposed to stressful environments may be most at-risk of low levels of self-control. Here we examine if polygenic measures associated with behaviors marked by low self-control interact with stressful life events in predicting self-control. Methods: Leveraging molecular data from a large population-based Dutch sample (N = 7,090, Mage = 41.2) to test for effects of genetics (i.e., polygenic scores for ADHD and aggression), stressful life events (e.g., traffic accident, violent assault, financial problems), and a gene-by-stress interaction on self-control (measured with the ASEBA Self-Control Scale). Results: Both genetics (ß =.03 -.04, p <.001) and stressful life events (ß = .11 -.14, p <.001) were associated with individual differences in self-control. We find no evidence of a gene-by-stressful life events interaction on individual differences in adults' self-control. Conclusion: Our findings are consistent with the notion that genetic influences and stressful life events exert largely independent effects on adult self-control. However, the small effect sizes of polygenic scores increases the likelihood of null results. Genetically-informed longitudinal research in large samples can further inform the etiology of individual differences in self-control from early childhood into later adulthood and its downstream implications for public health.

Handedness and 23 Early Life Characteristics in 37,495 Dutch Twins.

In studies of singletons, a range of early-life characteristics have been reported to be associated with handedness, but some of these associations have failed to replicate. We examined associations between 23 early life characteristics with handedness in a large sample of 37,495 5-year-old twins. We considered three definitions of handedness: left-handedness (LH), mixed-handedness (MH), and non-right-handedness (NRH). Our main aim was to test whether the associations with sex, birth weight, gestational age, and season of birth - as reported in singletons - replicate in twins, and to examine twin-specific variables, including zygosity, chorionicity, birth order, and intertwin delivery time. Compared to previously published data from adults born as singletons (7.23%), the prevalence of NRH was higher in both twins (16.19%) and their parents (15.09%). In the twins, LH and NRH were associated with parents' LH. Male sex and lower gestational age were associated with NRH, and LH was associated with not being breastfed. MH was related to neurodevelopmental delays and higher externalizing problems later in childhood. Other previously reported associations were not replicated, and no twin-specific characteristics were related to handedness. These results emphasize the importance of considering multiple definitions of handedness and indicate a small number of replicated associations across studies.

Self-rated health when population health is challenged by the COVID-19 pandemic; a longitudinal study.

RATIONALE: The coronavirus disease 2019 (COVID-19) pandemic and consequent lockdown measures have had a large impact on people's lives. Recent evidence suggests that self-rated health (SRH) scores remained relatively stable or increased during the pandemic. OBJECTIVE: For the current project, we examine potential changes in the variance decomposition of SRH before and during the COVID-19 pandemic in the Netherlands. METHODS: We analyse data from the Netherlands Twin Register to examine pre-pandemic SRH scores (N = 16,127), pandemic SRH scores (N = 17,451), and SRH difference scores (N = 7464). Additionally, we perform bivariate genetic analyses to estimate genetic and environmental variance components in pre-pandemic and pandemic SRH, and estimate the genetic correlation to assess potential gene-environment interaction. RESULTS: The majority of the sample (66.7%) reported the same SRH before and during the pandemic, while 10.8% reported a decrease, and 22.5% an increase. Individuals who reported good/excellent SRH before the pandemic were most likely to report unchanged SRH during the pandemic, and individuals with bad/mediocre/reasonable SRH more often reported increased SRH. The bivariate longitudinal genetic model reveals no significant change in variance decomposition of SRH from before to during the pandemic, with a heritability estimate of 45% (CI 36%-52%). We found that the genetic correlation could be constrained to 1, and a moderate unique environmental correlation (rE = 0.49, CI = 0.37 to 0.60). CONCLUSIONS: We theorize that the increases in SRH are explained by uninfected individuals evaluating their health more positively than under normal circumstances (partly through social comparison with infected individuals), rather than actual improvements. As the same genes are expressed under different environmental exposures, these results imply no evidence for gene-environment interaction. While different environmental factors might influence SRH at the two time-points, the influence of environmental factors does not become relatively more important during the pandemic.

DNA methylation in peripheral tissues and left-handedness.

Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355-0.578]), but inconsistent across tissues (correlation range [- 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain.

Genetic and environmental influences on quality of life: The COVID-19 pandemic as a natural experiment.

By treating the coronavirus disease 2019 (COVID-19) pandemic as a natural experiment, we examine the influence of substantial environmental change (i.e., lockdown measures) on individual differences in quality of life (QoL) in the Netherlands. We compare QoL scores before the pandemic (N = 25,772) to QoL scores during the pandemic (N = 17,222) in a sample of twins and their family members. On a 10-point scale, we find a significant decrease in mean QoL from 7.73 (SD = 1.06) before the pandemic to 7.02 (SD = 1.36) during the pandemic (Cohen's d = 0.49). Additionally, variance decomposition shows an increase in unique environmental variance during the pandemic (0.30-1.08), and a decrease in the heritability estimate from 30.9% to 15.5%. We hypothesize that the increased environmental variance is the result of lockdown measures not impacting everybody equally. Whether these effects persist over longer periods and how they impact health inequalities remain topics for future investigation.

Gene-by-Crisis Interaction for Optimism and Meaning in Life: The Effects of the COVID-19 Pandemic.

The corona virus disease 2019 (COVID-19) pandemic and the restrictions to reduce the spread of the virus has had a large impact on daily life. We investigated the individual differences in the effect of the COVID-19 pandemic and first lockdown on optimism and meaning in life in a sample from the Netherlands Twin Register. Participants completed surveys before (N = 9964, Mean age: 48.2, SD = 14.4) and during the first months of the pandemic (i.e. April-May 2020, N = 17,464, Mean age: 44.6 SD = 14.8), with a subsample completing both surveys (N = 6461, Mean age T1: 48.8, SD = 14.5). We applied genetic covariance structure models to twin data to investigate changes in the genetic architecture of the outcome traits due to the pandemic and the interaction of genes with the environmental exposure. Although 56% and 35% of the sample was negatively affected by the pandemic in their optimism and meaning in life, many participants were stable (32% and 43%) or even showed increased optimism and meaning in life (11% and 22%). Subgroups, specifically women, higher educated people, and people with poorer health, experienced larger negative effects. During the first months of the pandemic, slightly lower heritability estimates for optimism and meaning in life (respectively 20% and 25%) were obtained compared to pre-pandemic (respectively 26% and 32%), although confidence intervals overlap. The lower than unity genetic correlations across time (.75 and .63) suggest gene-environment interactions, where the expression of genes that influence optimism and meaning in life differs before and during the pandemic. The COVID-19 pandemic is a strong exposure that leads to imbalanced effects on the well-being of individuals. Some people decrease in well-being, while others get more optimistic and consider their lives as more meaningful during the pandemic. These differences are partly explained by individual differences in genetic sensitivity to extreme environmental change. More knowledge on the person-specific response to specific environmental variables underlying these individual differences is urgently needed to prevent further inequality.

Predicting Complex Traits and Exposures From Polygenic Scores and Blood and Buccal DNA Methylation Profiles.

We examined the performance of methylation scores (MS) and polygenic scores (PGS) for birth weight, BMI, prenatal maternal smoking exposure, and smoking status to assess the extent to which MS could predict these traits and exposures over and above the PGS in a multi-omics prediction model. MS may be seen as the epigenetic equivalent of PGS, but because of their dynamic nature and sensitivity of non-genetic exposures may add to complex trait prediction independently of PGS. MS and PGS were calculated based on genotype data and DNA-methylation data in blood samples from adults (Illumina 450 K; N = 2,431; mean age 35.6) and in buccal samples from children (Illumina EPIC; N = 1,128; mean age 9.6) from the Netherlands Twin Register. Weights to construct the scores were obtained from results of large epigenome-wide association studies (EWASs) based on whole blood or cord blood methylation data and genome-wide association studies (GWASs). In adults, MSs in blood predicted independently from PGSs, and outperformed PGSs for BMI, prenatal maternal smoking, and smoking status, but not for birth weight. The largest amount of variance explained by the multi-omics prediction model was for current vs. never smoking (54.6%) of which 54.4% was captured by the MS. The two predictors captured 16% of former vs. never smoking initiation variance (MS:15.5%, PGS: 0.5%), 17.7% of prenatal maternal smoking variance (MS:16.9%, PGS: 0.8%), 11.9% of BMI variance (MS: 6.4%, PGS 5.5%), and 1.9% of birth weight variance (MS: 0.4%, PGS: 1.5%). In children, MSs in buccal samples did not show independent predictive value. The largest amount of variance explained by the two predictors was for prenatal maternal smoking (2.6%), where the MSs contributed 1.5%. These results demonstrate that blood DNA MS in adults explain substantial variance in current smoking, large variance in former smoking, prenatal smoking, and BMI, but not in birth weight. Buccal cell DNA methylation scores have lower predictive value, which could be due to different tissues in the EWAS discovery studies and target sample, as well as to different ages. This study illustrates the value of combining polygenic scores with information from methylation data for complex traits and exposure prediction.

Genetic and Environmental Causes of Individual Differences in Borderline Personality Disorder Features and Loneliness are Partially Shared.

Loneliness is related to mental and somatic health outcomes, including borderline personality disorder. Here, we analyze the sources of variation that are responsible for the relationship between borderline personality features (including four dimensions, affective instability, identity disturbance, negative relationships, self-harm and a total score) and loneliness. Using genetically informative data from two large nonclinical samples of adult twin pairs from Australia and the Netherlands (N = 11,329), we estimate the phenotypic, genetic and environmental correlations between self-reported borderline personality features and loneliness. Individual differences in borderline personality and loneliness were best explained by additive genetic factors with heritability estimates h2 = 41% for the borderline personality total score and h2 = 36% for loneliness, with the remaining variation explained by environmental influences that were not shared by twins from the same pair. Genetic and environmental factors influencing borderline personality (total score and four subscales separately) were also partial causes of loneliness. The correlation between loneliness and the borderline personality total score was rph = .51. The genetic correlation was estimated at rg = .64 and the environmental correlation at re = .40. Our study suggests common etiological factors in loneliness and borderline personality features.