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Background and aims Gonadal hormones are mainly thought to account for sex and gender differences in the incidence, clinical manifestation and therapy of many cardiovascular diseases. However, intrinsic sex differences at the cellular level are mostly overlooked. Here, we assessed sex-specific metabolic and functional differences between male and female human umbilical vein endothelial cells (HUVECs). Methods Cellular metabolism was investigated by bioenergetic studies (Seahorse Analyser) and a metabolomic approach. Protein levels were determined by Western blots and proteome analysis. Vascular endothelial growth factor (VEGF)-stimulated cellular migration was assessed by gap closure. HUVECs from dizygotic twin pairs were used for most experiments. Results No sex differences were observed in untreated cells. However, sexual dimorphisms appeared after stressing the cells by serum starvation and treatment with VEGF. Under both conditions, female cells had higher intracellular ATP and metabolite levels. A significant decline in ATP levels was observed in male cells after serum starvation. After VEGF, the ratio of glycolysis/mitochondrial respiration was higher in female cells and migration was more pronounced. Conclusions These results point to an increased stress tolerance of female cells. We therefore propose that female cells have an energetic advantage over male cells under conditions of diminished nutrient supply. A more favourable energy balance of female HUVECs after serum starvation and VEGF could potentially explain their stronger migratory capacity.

Meckel-Gruber syndrome in one twin of a naturally conceived dizygotic twin pregnancy is largely unknown and has not been reported till date. This report illustrates the sonographic features in a case of 20-week twin pregnancy where one twin had an occipital encephalocele, bilateral enlarged and cystic kidneys, hepatic cyst and oligohydramnios but the other twin was normal. The affected twin succumbed within few days after normal vaginal delivery while the normal twin survived and is healthy.

X-chromosome inactivation (XCI) silences one X-chromosome in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it varies across tissues and in a population is as yet unclear. In order to characterize the incidence and variability of escape across individuals and tissues, we conducted a large scale transcriptomic study of XCI escape in adipose, skin, lymphoblastoid cell lines (LCLs) and immune cells in 248 twins drawn from a healthy population cohort. We identify 159 X-linked genes with detectable escape, of which 54 genes, including 19 lncRNAs, were not previously known to escape XCI. Across tissues we find a range of tissue-specificity, with 11% of genes escaping XCI constitutively across tissues and 24% demonstrating tissue-restricted escape, including genes with cell-type specific escape between immune cell types (B, T-CD4+, T-CD8+ and NK cells) of the same individual. Escape genes interact with autosomal-encoded proteins and are involved in varied biological processes such as gene regulation. We find substantial variability in escape between individuals. 49% of genes show inter-individual variability in escape, indicating escape from XCI is an under-appreciated source of gene expression differences. We utilized twin models to investigate the role of genetics in variable escape. Overall, monozygotic (MZ) twin pairs share more similar escape than dizygotic twin pairs, indicating that genetic factors underlie differences in escape across individuals. However, we also identify instances of discordant XCI within MZ co-twin pairs, suggesting that environmental factors also influence escape. Thus, XCI escape may be shaped by an interplay of genetic factors with tissue- and cell type-specificity, and environment. These results illuminate an intricate phenotype whose characterization aids understanding the basis of variable trait expressivity in females.

How much pleasure we take in eating is more than just how much we enjoy the taste of food. Food involvement – the amount of time we spend on food beyond the immediate act of eating and tasting – is key to the human food experience. We took a biological approach to test whether food-related behaviors, together capturing food involvement, have genetic components and are partly due to inherited variation. We collected data via an internet survey from a genetically informative sample of 419 adult twins (114 monozygotic twin pairs, 31 dizygotic twin pairs, and 129 singletons). Because we conducted this research during the pandemic, we also ascertained how many participants had experienced COVID-19-associated loss of taste and smell. Since these respondents had previously participated in research in person, we measured their level of engagement to evaluate the quality of their online responses. Additive genetics explained 16-44% of the variation in some measures of food involvement, most prominently various aspects of cooking, suggesting some features of the human food experience may be inborn. Other features reflected shared (early) environment, captured by respondents’ twin status. About 6% of participants had a history of COVID-19 infection, many with transitory taste and smell loss, but all but one had recovered before the survey. Overall, these results suggest that people may have inborn as well as learned variations in their involvement with food. We also learned to adapt to research during a pandemic by considering COVID-19 status and measuring engagement in online studies of human eating behavior.

Depression and cardiovascular disease (ischemic heart disease and stroke) are associated in a bidirectional manner. Their relatively high heritability has led to the hypothesis that this co-occurrence is related to shared familial and genetic factors; this study aims to test this hypothesis. We included 23,498 monozygotic and 39,540 same-sex dizygotic twins from the Danish Twin Registry followed from January 1977 until December 2011 in nationwide Danish registries. We used survival analyses accounting for censoring and competing risk of death to estimate cumulative incidence, casewise concordance, relative recurrence risk, and heritability of the co-occurrence of depression and cardiovascular disease by age using monozygotic and same-sex dizygotic twin pairs. The casewise concordance of ischemic heart disease or stroke in twins whose co-twin was diagnosed with depression was at all ages similar for the monozygotic and dizygotic twin pairs and to the cumulative incidence of ischemic heart disease or stroke, respectively, in the entire twin population. A similar pattern was seen in analyses of depression risk given the co-twin being diagnosed with ischemic heart disease or stroke. Relative recurrence risk and heritability estimates were also of modest size and with confidence intervals including unity. Results were similar after stratification by gender as well as when redefining depression to include the use of antidepressant medication from 1995. Our findings do not support that co-occurrence between depression and cardiovascular disease is explainable by shared genetic factors, nor did we find strong evidence of a familial effect.

Objectives: To develop a multivariate model for risk factors specific to early onset preeclampsia (EOP) and late onset preeclampsia (LOP) in our entire population (singleton and twin pregnancies). Material and methods: 20 year-observational population-based historical cohort study (2001–2020). All consecutive births delivered at the Centre Hospitalier Universitaire Hospitalier Sud Reunion’s maternity ward. A standardized validated epidemiological perinatal database was used. Results: During the 20-year period, there were 81,834 pregnancies and 83,497 infants born, 1232 dichorionic and 350 monochorionic twin pregnancies. There were 2120 cases of preeclampsia, of which 2001 were preeclamptic singleton pregnancies and 119 twin pregnancies (incidence 7.5% in twin pregnancies vs. 2.5% singletons, OR 3.0, p &lt, 0.001). Independent risk factors for EOP and LOP in a multivariate model (controlling for the two major confounders: maternal ages—both risks for EOP and LOP, and maternal pre-pregnancy BMI—specific risk factor for LOP) were: history of preeclampsia (adjusted OR (aOR) 11.7 for EOP, 7.8 for LOP, p &lt, 0.0001), chronic hypertension (aOR 7.3 for EOP, 3.9 for LOP, p &lt, 0.0001), history of perinatal death (aOR 2.2 for EOP, p &lt, 0.0001 and 1.48 for LOP, p = 0.007), primipaternity (aOR 3.0 for EOP and 3.6 for LOP, p = 0.001), dizygotic twin pregnancies (aOR 3.7 for EOP, p &lt, 0.0001 and 2.1 for LOP, p = 0.003), monozygotic twin pregnancies (aOR 3.98 for EOP, p = 0.003 and non-significant (NS) for LOP), ovulation induction (aOR 5.6 for EOP, p = 0.004 and NS for LOP), and in vitro fertilization (aOR 2.8 for EOP, p = 0.05 and NS for LOP). Specific to LOP and NS for EOP: renal diseases (aOR for LOP 2.9, p = 0.007) and gestational diabetes mellitus (aOR 1.2, p = 0.04). Conclusions: Maternal ages over 35 years, chronic hypertension, history of preeclampsia, ovulation induction, in vitro fertilizations, history of perinatal deaths and twin pregnancy (in our experience, especially mono zygotic twin pregnancies) are significant risk factors for EOP. New paternity is an independent factor for both EOP and LOP.

ObjectiveThe objectives are to estimate the vertical transmission rate in twins relative to singleton pregnancies, to evaluate whether discordance within twin pairs is rare, and to characterize concordance within monozygotic and dizygotic twin pairs in relation to hereditability.MethodsWe first sought to estimate the vertical transmission rate of congenital CMV infection in twins by gathering cohort-based studies of congenital CMV in which vertical transmission in both singleton and twin pregnancies was reported. This also allowed us to compare singleton and twin infection rates. From the above studies and other large cohorts of congenitally infected infants, the percentage of discordantly infected twin pairs determined whether this is a rare phenomenon. Theorizing discordance is not rare, we then analyzed data from cases with twin outcomes for congenital CMV infection, according to whether the twins were monozygotic or dizygotic, and calculated their corresponding concordance rates to estimate the broad-sense heritability. Lastly, we described other factors that might affect vertical transmission.ResultsFrom five articles following at-risk pregnancies, the rate of vertical transmission in twin pregnancies is 58.7% (95% CI 43.3-72.3%) whereas in singleton pregnancies it is 31.4% (95% CI: 29.0-34.0%) p = 0.0002. Of ten studies of larger cohorts of infants with congenital CMV infection, 21 of 42 twin pairs with at least one twin infected were discordant for congenital CMV (50.0%, 95% CI: 34.4–65.6%) indicating discordance of congenital CMV infection in twin pairs is not rare. Of 28 studies covering 37 twin pairs where at least one twin had congenital CMV, and zygosity was known, eleven of thirteen monozygotic twin pairs (84.6%; 95% CI: 53.7-97.3%) were concordant for CMV infection, and nine of twenty-four dizygotic twin pairs (37.5%; 95% CI: 19.6-59.2%) were concordant for infection giving an estimated hereditability of 94.2%. Within these 37 twin pairs, factors such as primary or recurrent maternal infection, prematurity, growth discordance, and sex are described; however, in many of these cases these factors are unknown.ConclusionThe rate of vertical transmission of congenital CMV is higher for twins than singletons. Discordance of congenital CMV in twins is not rare and suggests a possible genetic susceptibility to congenital CMV.

Over the previous decades, twinning rates worldwide have increased remarkably. This study aimed to describe changes in multiple birth rates and related demographic characteristics, such as maternal age and the level of education of parents in South Korea from 1981 to 2019. This study analyzed birth data obtained from the Korean Statistical Information Service. From 1981 to 2019, the total twinning rate increased from 5 to 22.5 pairs per 1000 births. This rapid increase was due to an increase in dizygotic twin births, which mainly occurred in mothers aged between 30 and 39 years. The average maternal age of multiples increased from 26.06 years in 1981 to 33.98 years in 2019, suggesting that a delay in childbearing contributed to the increase in the twinning rate. The percentage of mothers of multiples who completed a college or higher degree (CHD) increased by 1000% from 1981 to 2019, indicating that a sharp increase in the level of education of females in part explains the delay in childbearing. The percentages of individuals who completed a CHD were higher among parents of multiples than among those of singletons in recent years when public funding arrangements for fertility treatments were available. This result suggested that completion of higher education may be associated with increased use of assisted reproductive technology (ART) independent of the financial status of couples. Taken together, the analysis suggested that increased maternal age, ART and the increased number of females who completed CHD may be responsible for the remarkable increase in the rates of multiple births in South Korea in the last four decades.

Introduction DSTYK encodes dual serine/threonine and tyrosine protein kinase. DSTYK has been associated with autosomal-dominant congenital anomalies of the kidney and urinary tract and with autosomal-recessive hereditary spastic paraplegia type 23. Here, we report a father and his two dizygotic twin sons carrying a novel heterozygous missense variant in DSTYK, presenting with early onset lower urinary tract dysfunction due to dysfunctional voiding. Moreover, in the later course of the disease, both sons presented with bilateral spasticity in their lower limbs, brisk reflexes, and absence seizures. Materials and methods Exome sequencing in the affected father and his affected sons was performed. The sons presented clinically with urinary hesitancy, dysfunctional voiding, and night incontinence till adolescence, while the father reported difficulty in voiding. In the sons, cystoscopy excluded urethral valves and revealed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with absence epilepsy in early childhood. Filtering of exome data focused on rare (MAF < 0.01%), autosomal-dominant variants, predicted to be deleterious, residing in highly conserved regions of the exome. Results Exome analysis identified a novel, heterozygous missense variant (c.271C>A (p.Leu91Met)) in DSTYK segregating with the disease. In silico prediction analyses uniformly rated the variant to be deleterious suggesting the variant to be disease-causing in the family. Conclusion To the best of our knowledge, this is the first report of early onset dysfunctional voiding, seizures, and bilateral spasticity of the lower limbs associated with a novel heterozygous dominant missense variant in DSTYK.

Aim: Alcohol intake alters DNA methylation profiles and methylation might mediate the association between alcohol and disease, but limited number of positive CpG sites repeatedly replicated. Materials & methods: In total, 57 monozygotic (MZ) twin pairs discordant for alcohol drinking from the Chinese National Twin Registry and 158 MZ and dizygotic twin pairs in the Swedish Adoption/Twin Study of Aging were evaluated. DNA methylation was detected using the Infinium HumanMethylation450 BeadChip. Results: Among candidate CpG sites, cg07326074 was significantly correlated with drinking after adjusting for covariates in MZ twins in both datasets but not in the entire sample or dizygotic twins. Conclusion: The hypermethylation of cg07326074, located in the tumor-promoting gene C16orf59, was associated with alcohol consumption.

Gait analysis and gait indices are frequently used to evaluate gait pathologies and outcomes. The aim of this study is to investigate the differences in gait parameters of dizygotic twin athletes according to each other and athletes group who are similar age but non-twin. Eighty-four athletes without any disease that could cause gait pathology were included the study. Time-distance measurements, kinematic – kinetic variables, and gait deviation index (GDI) of the gait functions of twin athletes (17 boys and 25 girls, height: 153.9 ± 15 cm, weight: 45.9 ± 12 kg, leg length 80.5 ± 11 cm) were compared with each other and with 42 sex and age matched non-twins athletes (height: 155 ± 15 cm, weight: 47 ± 14 kg, leg length 80.6 ± 9.8 cm, mean age 11.8 ± 2.29, range 6–15 years). No statistically significant difference was found about the time, distance parameters and GDIs in comparison of twin athletes with each other and the non-twin group. Additionally, kinetic and kinematic variables were similar in between twins. We measured lower adduction angles and higher abduction angles in non-twin athletes in comparison to the twin athletes ( p = 0.01, 0.04). Additionally, the angle of knee flexion at the first contact was higher in non-twins ( p = 0.003). Being dizygotic twin seems to have no clinical effect on gait function in athletes.

Similarities between parent and offspring are widespread in psychology; however, shared genetic variants often confound causal inference for offspring outcomes. A polygenic score (PGS) derived from genome-wide association studies (GWAS) can be used to test for the presence of parental influence that controls for genetic variants shared across generations. We use a PGS for educational attainment (EA3; N ≈ 750 thousand) to predict offspring years of education in a sample of 2517 twins and both parents. We find that within families, the dizygotic twin with the higher PGS is more likely to attain higher education (unstandardized β = 0.32; p < 0.001). Additionally, however, we find an effect of parental genotype on offspring outcome that is independent of the offspring’s own genotype; this raises the variance explained in offspring years of education from 9.3 to 11.1% (ΔR(2) = 0.018, p < 0.001). Controlling for parental IQ or socioeconomic status substantially attenuated or eliminated this effect of parental genotype. These findings suggest a role of environmental factors affected by heritable characteristics of the parents in fostering offspring years of education.

Background Longitudinal studies enhance understanding of the complex reciprocal relationship between smoking and depression from adolescence to young adulthood. Examining bi-directional associations between cigarette smoking and depressive symptoms in a genetically informative twin design can help to understand whether the associations are independent of shared genetic and environmental factors. Methods We analyzed longitudinal data on smoking and depressive symptoms in twins participating in the adolescent (mean age 17.5) and young adult (mean age 21.9) surveys of the FinnTwin12 study (maximum N = 2,954 individuals; 1,154 twin pairs). At both waves, self-reported depressive symptoms, assessed with the 10-item version of the General Behavior Inventory (GBI), and smoking status were analyzed. The bi-directional associations were first studied among individuals and then within monozygotic and dizygotic twin pairs. Results When adjusted for multiple covariates and baseline depressive symptoms, daily smokers at age 17 had higher depressive symptom scores at age 22 than never smokers (Incidence Rate Ratio = 1.17, 95% CI: 1.03–1.33). Similarly, when adjusted for covariates and baseline smoking, higher score in GBI at age 17 was associated with an increased likelihood of being a non-daily (Relative Risk Ratio (RRR) = 1.06, 95% CI: 1.01–1.11) or daily (RRR = 1.05, 95% CI: 1.00–1.10) smoker at age 22. No associations were found in within-pair analyses, suggesting that the individual-level association is explained by shared familial liabilities. Conclusion During the developmental period from adolescence to adulthood, cigarette smoking and depressive symptoms are reciprocally associated. However, these associations are confounded by shared genetic and other familial liabilities.

BackgroundThe phenotypic and aetiological architecture of depression symptomatology has been mostly studied in Western samples. In this study, we conducted a genetically informed factor analysis to elucidate both the phenotypic and aetiological architectures of self-reported depression among a Japanese adult twin sample.MethodsDepressive symptoms assessed by Zung's Self-rating Depression Scale were self-rated by 425 twin pairs (301 monozygotic and 124 dizygotic twin pairs) in a community sample in Japan.ResultsAn exploratory factor analysis extracted three symptom domains representing cognitive, affective and somatic symptomatology. A confirmatory factor analysis demonstrated that a bi-factor solution fitted better than the alternative solutions, implying that depression may be defined as a combination of a single general construct and three factors specific to each of the three symptom domains. A multivariate genetic analysis with the bi-factor solution showed that the general factor was substantially heritable (47%), and that only the affective symptom domain was significantly heritable (29%) among the three specific factors, their remaining variance being explained by non-shared environmental influences.ConclusionsDepression symptomatology appears to be adequately captured by a substantially heritable general factor. The heritability of this factor (47%) in a Japanese adult sample is in line with commonly reported heritability estimates for depression. The three specific factors – cognitive, affective and somatic – are mostly explained by non-shared environmental factors, which include measurement error. The extent to which these specific factors are uniquely associated with correlates of depression when the general factor is accounted for should be investigated in future studies.

Evidence suggests that Disgust Sensitivity (DS) is a personality trait that may confer risk for the development of some anxiety-related disorders. To examine the origins of this trait we administered the DS subscale of the Disgust Propensity and Sensitivity Scale-Revised to 90 monozygotic and 90 dizygotic twin pairs, of which 55% were women. The DS subscale consists of two dimensions; Somatic Disgust and Ruminative Disgust. Biometrical modeling techniques were used to estimate heritability of the DS dimensions by sex. For women, each dimension was influenced by a combination of genetic and environmental factors. More specifically, 40.1% of the variance in DS was observed to be due to additive genetic factors and the remaining variance due to non-shared environment. Correlations among DS dimensions for women could be explained by genetic and environmental factors influencing the two dimensions. For men, the two dimensions were influenced by environmental but not genetic factors. These findings suggest that the etiology of DS is complex and arises as a function of dimension-specific and non-specific etiologic factors that vary as a function of sex. The implication of these findings for the sex differences in the etiology of some anxiety-related disorders are discussed.

Differences in concordance rates between monozygotic and dizygotic twin pairs with Parkinson's disease (PD) have been used to estimate genetic influences in PD pathogenesis. We hypothesized that “discordance” may not in all cases adequately reflect the multifaceted disease manifestation of PD that involves a continuum from prodromal to definite PD. Deep clinical phenotyping, combining motor, nonmotor, and imaging modalities in five monozygotic, seemingly discordant twin pairs revealed motor and/or nonmotor features and/or nigral hyperechogenicity in all of the five putatively unaffected twins. In conclusion, our data suggest that concordance rates in monozygotic twins may be higher than previously appreciated.

Background: Dizygotic twin pregnancies with discordant manifestation of abnormalities with unclear etiology are of interest because they arise in the same environment. Case report: We present a dizygotic third trimester twin placenta with discordant villous maturation, one placenta lacking developed syncytiocapillary membranes. The twins were eutrophic with no perinatal or postnatal complications. Conclusions: Discordant manifestation of villous maturation in dizygotic twin placentas could be a hint for a genetic rather than an environmental etiology. Villous maturation defect may be underrecognized and has been associated with perinatal morbidity and stillbirth in the late third trimester. Proper recognition is important because of the increased recurrence risk of villous dysmaturity.

Several studies on twins in recent years have revealed both genetic and environmental contributions to personality stability and change in adulthood. However, knowledge on such contributions during adolescence is limited. The present study examined sources of the variances of intra-individual absolute change in personality during adolescent years in 347 pairs of Japanese twins (270 monozygotic and 77 dizygotic twin pairs). Phenotypic analyses with the difference score model showed statistically significant mean-level increases in neuroticism-related traits. Then we applied the Cholesky decomposition model to the difference score model to examine heritability and environmentality of intra-individual change in personality traits. Biometric analyses revealed that the best-fitting model for adolescent personality included additive genetic and nonshared environmental influences. Heritability estimates of intra-individual personality change ranged approximately from 0.00 to 0.27. These findings suggest that both genetic and environmental effects have substantial roles in the etiology of mean-level personality change in adolescence.

Sesquizygotic multiple pregnancy is an exceptional intermediate between monozygotic and dizygotic twinning. We report a monochorionic twin pregnancy with fetal sex discordance. Genotyping of amniotic fluid from each sac showed that the twins were maternally identical but chimerically shared 78% of their paternal genome, which makes them genetically in between monozygotic and dizygotic; they are sesquizygotic. We observed no evidence of sesquizygosis in 968 dizygotic twin pairs whom we screened by means of pangenome single-nucleotide polymorphism genotyping. Data from published repositories also show that sesquizygosis is a rare event. Detailed genotyping implicates chimerism arising at the juncture of zygotic division, termed heterogonesis, as the likely initial step in the causation of sesquizygosis.

Background Nemaline myopathy 8 is a severe autosomal recessive muscle disorder characterized by fetal akinesia or hypokinesia, contractures, fractures, respiratory failure and swallowing difficulties apparent at birth. Methods An affected dizygotic twin pair from a non‐consanguineous Chinese family presented with severe asphyxia, lethargy and no response to stimuli. The dysmorphic features included prominent nasal bridge, telecanthus, excessive hip abduction, limb edema, absent palmar and sole creases, acromelia, bilateral clubfoot, appendicular hypertonia and cryptorchidism. Both infants died in the first week of life. Whole‐exome sequencing was used to identify the causative gene. Results Whole‐exome sequencing identified a recurrent missense variant c.1516A>C and a novel splice‐acceptor variant c.1153‐1G>C in KLHL40 gene in both siblings. We estimated the disease incidence in Southern Chinese population to be 2.47/100,000 based on the cumulative allele frequency of pathogenic and likely pathogenic variants in our internal database. Conclusion Our study expanded the mutation spectrum of KLHL40 and the condition could have been underdiagnosed before. We identified a recurrent missense variant c.1516A>C and provided evidence further supporting the founder effect of this variant in Southern Chinese population. Given the severity of the condition and the relative high incidence, this not‐so‐rare disorder should be included in expanded carrier screening panel for Chinese population., Two male babies with nemaline myopathy‐8 also showed appendicular hypertonia exome sequencing identified a recurrent missense variant and a novel splice‐acceptor variant in KLHL40 Four additional novel pathogenic variants of KLHL40 were identified and it is speculated that nemaline myopathy‐8 is not‐so‐rare in Chinese population.

Metamizole is a widely prescribed NSAID with excellent analgesic and antipyretic properties. Although very effective, it is banned in some countries because of the risk for severe agranulocytosis. We here describe three patients with metamizole-associated agranulocytosis. Patient #1 suffered from agranulocytosis and tonsillitis followed by severe sepsis by Streptococcus pneumoniae and Epstein-Barr virus reactivation. Her dizygotic twin sister (patient #2) also suffered from agranulocytosis after a surgical intervention. Patient #3 initially had a tonsillitis and also developed neutropenia after metamizole intake. For all patients, pharmacogenetic diagnostic for the genes CYP2C9, CYP2C19 and NAT2, which are involved in metamizole metabolism and degradation of toxic metabolites, was initiated. Pharmacogenetic analysis revealed NAT2 slow acetylator phenotype in all three patients. Additionally, patient #2 is an intermediate metabolizer for CYP2C19 and patient #3 is a poor metabolizer for CYP2C9. Impairment of these enzymes causes a reduced degradation of toxic metabolites, for example, 4-methylaminoantipyrine (4-MAA) or 4-aminoantipyrine. The metabolite 4-MAA can complex with hemin, which is an early breakdown product during hemolysis. Hemolysis is often observed during invasive infections or after surgical procedures. It is known that the 4-MAA/hemin complex can induce cytotoxicity in the bone marrow and interrupt granulocyte maturation. In conclusion, metamizole-induced agranulocytosis most likely was a consequence of the underlying genetical predisposition, that is, polymorphisms in the genes NAT2, CYP2C9 and CYP2C19. Hemolysis may have increased the toxicity of metamizole metabolites.

Hydatidiform mole with coexisting live foetus presents a management enigma. It can happen either as a consequence of dizygotic twin gestation in which complete hydatidiform mole is associated with coexisting live foetus (CHMCF) or partial mole with live foetus. Differentiation between these two entities is important because treatment for partial mole with live foetus is termination of pregnancy while in cases with CHMCF, pregnancy can be continued but only under strict maternal and foetal surveillance.

Aim: To identify whether periodontal traits derived from electronic dental records are biologically informative and heritable.Materials and methods: The study included 11,974 adult twins (aged 30-92 years) in the Swedish Twin Registry. Periodontal records from dental examinations were retrieved from a national register and used to derive continuous measures of periodontal health. A latent class approach was used to derive categorial measures of periodontal status. The correlation patterns in these traits were contrasted in monozygotic and dizygotic twin pairs using quantitative genetic models to estimate the heritability of the traits. Results: For continuous traits, heritability estimates ranged between 41.5% and 48.3% with the highest estimates for number of missing tooth surfaces and rate of change in number of deep periodontal pockets ( 6 mm). For categorial traits the latent class approach identified 3 classes (good periodontal health, mild periodontitis signs, severe signs of periodontitis) and there was a clear difference in the hazard for subsequent tooth loss between these 3 classes. Despite this, the class allocations were only slightly more heritable than a conventional dichotomous disease definition (45.2% versus 42.6%).Conclusions: Periodontitis is a moderately heritable disease. Quantitative periodontal traits derived from electronic records are an attractive target for future genetic association studies.

The number of de novo mutations (DNMs) in the human germline is correlated with parental age at conception, but this explains only part of the observed variation. We investigated whether there is a family-specific contribution to the number of DNMs in offspring. The analysis of DNMs in 111 dizygotic twin pairs did not identify a substantial family-specific contribution. This result was corroborated by comparing DNMs of 1669 siblings to those of age-matched unrelated offspring following correction for parental age. In addition, by modeling DNM data from 1714 multi-offspring families, we estimated that the family-specific contribution explains ∼5.2% of the variation in DNM number. Furthermore, we found no substantial difference between the observed number of DNMs and those predicted by a stochastic Poisson process. We conclude that there is a small family-specific contribution to DNM number and that stochasticity explains a large proportion of variation in DNM counts.

Objective: Familial and genetic factors seem to contribute to the development of depression but whether this varies with age at diagnosis remains unclear. We examined the influence of familial factors on the risk of depression by age at first diagnosis. Methods: We included 23 498 monozygotic and 39 540 same-sex dizygotic twins from the population-based Danish Twin Registry, followed from 1977 through 2011 in nationwide registers. We used time-to-event analyses accounting for censoring and competing risk of death to estimate cumulative incidence, casewise concordance, relative recurrence risk, and heritability of first depression by age using monozygotic and same-sex dizygotic twin pairs. Results: During follow-up, a total of 1545 twins were diagnosed with depression. For twins at age 35 or younger at first depression, heritability was estimated to be 24.8% (95% confidence interval [CI], 4.6–43.1%), whereas at age 90 it was 14.7% (95% CI, 3.1–26.3%). The relative recurrence risk was higher at younger ages: At age 35, the risk was 27.7-fold (95% CI, 20.0–35.5) and 6.9-fold (95% CI, 3.9–9.8) higher than the population risk for monozygotic and same-sex dizygotic twins, respectively, while the corresponding numbers were 3.0 (95% CI, 2.3–3.6) and 1.8 (95% CI, 1.3–2.2) at age 90. Heritability seemed similar for male and female twins. Conclusion: Familial risk of depression, caused either by genes or shared environment, seemed to slightly decrease with age at diagnosis and an elevated concordance risk for monozygotic over same-sex dizygotic pairs suggested a genetic contribution to the development of depression.

The number of de novo mutations (DNMs) in the human germline is correlated with parental age at conception, but this explains only part of the observed variation. We investigated whether there is a family-specific contribution to the number of DNMs in offspring. The analysis of DNMs in 111 dizygotic twin pairs did not identify a significant family-specific contribution. This result was corroborated by comparing DNMs of 1669 siblings to those of age-matched unrelated offspring. In addition, by modeling DNM data from 1714 multi-offspring families we estimated that the family specific contribution explains approximately 5.2% of the variation in DNM number. Furthermore, we found no significant difference between the observed number of DNMs and those based on a stochastic Poisson process. We conclude that a family-specific contribution to DNMs is small and that stochasticity explains a large proportion of variation in DNM counts.

The aim of the study was to examine the Family and School Psychosocial Environment (FSPE) questionnaire in relation to a possible genotype–environment correlation and genetic mediation between the FSPE variables and personality variables, assessed by the Junior Eysenck Personality Questionnaire. A sample of 506 Swedish children aged 10–20 years from 253 families were recruited via the Swedish state population and address register and SchoolList.Eu. The children were divided into 253 pairs: 46 monozygotic twin pairs, 42 dizygotic twin pairs, 140 pairs of full siblings and 25 pairs of half-siblings. The behavioral genetic analysis showed that both FSPE factors, Warmth and Conflicts, may be partly influenced by genetic factors (suggesting genotype–environment correlation) and that nonadditive genetic factors may mediate the relationship between FSPE factors and psychoticism/antisocial personality (P). An indication of a special shared monozygotic twin environment was found for P and Lie/social desirability, but based on prior research findings this factor may have a minor influence on P and L. P and L were negatively correlated, and the relationship seems to be partly mediated by nonadditive genetic factors. Nonshared environment and measurement errors seem to be the most influential mediating factors, but none of the cross-twin cross-dimension correlations suggest a common shared environmental mediating factor.

The critical role of blood lipids in a broad range of health and disease states is well recognised, while an understanding of the complex genetic regulation of lipid homeostasis is emerging. Traditional blood lipids (LDL-C, HDL-C and triglycerides) are known to be substantially regulated by genetic variation. Less well explored is the interplay of genetics and environment within the broader blood lipidome. Here we use the twin model to examine heritability of the plasma lipidome among healthy older aged twins and explore gene expression and epigenetic (DNA methylation) associations of these lipids. Heritability of 209 plasma lipids quantified by liquid chromatography coupled mass spectrometry (LC-MS) was assessed in 75 monozygotic and 55 dizygotic twin pairs enrolled in the Older Australian Twins Study (OATS), aged 69-93 years. Only 27/209 lipids (13.3%) were significantly heritable under the classical ACE twin model (h2 = 0.28-0.59). Ceramides (Cer) and triglycerides (TG) were most heritable, while sphingomyelins (SM) and most phospholipids, especially lysophospholipids, were not significantly heritable. Lipid levels correlated with 3731 transcripts. Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, which were not directly associated with lipid metabolism, but with immune function, signalling and transcriptional regulation. Genome-wide average DNA methylation (GWAM) levels accounted for a proportion of variability in some non-heritable lipids, especially lysophosphatidylcholine (LPC). We found a complex interplay of genetic and environmental influences on the ageing plasma lipidome, with most of the variation controlled by unique environmental influences.

We estimated the genetic covariance matrix among four inattention (INATT) and four hyperactivity (HYP) measures in the classical twin design. Data on INATT and HYP symptom counts were obtained in mono- and dizygotic twin pairs (N = 1593) with an average age of 12.2 years (sd = .51). We analyzed maternal ratings of INATT and HYP based on the Conners’ Parent Rating Scale (CPRS), the Strengths and Weaknesses of ADHD-symptoms and Normal-behavior (SWAN), and teacher ratings based on the Conners' Teacher rating scale (CTRS) and the ASEBA Teacher Rating Form (TRF). Broad-sense heritabilities, corrected for the main effects of sex and for random teacher rater effects, were large (ranging from .658 to .912). The results reveal pervasive and strong broad-sense genetic effects on INATT and HYP phenotypes with the phenotypic covariance among the phenotypes largely due to correlated genetic effects. Specifically between 79.9 and 99.9% of the phenotypic covariance among the HYP measures, and between 81.0 and 93.5% of the INATT measures are attributable to broad-sense genetic effects. Overall, the present results, pertaining to the broad-sense heritabilities and shared genetic effects, support the current genome-wide association meta-analytic approach to identifying pleiotropic genetic variants.

This article describes a 1930s case study series involving dizygotic female twin infants. The twins’ development was evaluated following periods of intentionally restricted practice and minimal social stimulation. In the opinion of the author of the current article, the study is very unsettling and unacceptable, despite the lack of institutional review boards at that time. This discussion is followed by twin research reviews of recent papers concerning twin and non-twin intracytoplasmic sperm injection conceptions, the Emory University Twin Study of cardiac and brain functions, labor trials in multiple pregnancies after previous C-section delivery and cell-free DNA fetal fraction in twin pregnancies. The article concludes with news items of a twin survivor of Auschwitz, a situation in which twins traded places, the rare birth of identical twin foals, the novel delivery of co-twins in different decades and the Twins Ambulette Service.

Moral judgments may be driven by both principled and opportunistic motivations. Being morally principled is to consistently adhere to a single set of rules about morality and justice. Opportunistic morality rather involves selectively enforcing rules when they are beneficial to one’s interests. These two kinds of motivations sometimes pull in the same direction, other times not. Prior studies on moral motivations have mostly focused on principled morality. Opportunistic morality, along with its phenotypic and genetic correlates, remains largely unexamined. Here, utilizing a sample from the Norwegian Twin Registry, consisting of 312 monozygotic-and 298 dizygotic twin pairs (N = 1220), we measure people’s propensity to react to injustice as victims, observers, beneficiaries, and perpetrators of injustice, using the Justice Sensitivity scale. Our genetically informative sample allows a biometric modeling approach that provides increased stringency in inferring latent psychological traits. We find evidence for two substantially heritable traits explaining correlations between Justice Sensitivity facets, which we interpret as aprincipled justice sensitivity(h2= .45) leading to increased sensitivity to injustices of all categories, and anopportunistic justice sensitivity(h2= .69) associated with increased victim sensitivity and a decreased propensity to feel guilt from being a perpetrator. These heritable justice traits share a genetic substrate with broad strategies for cooperation (as measured by altruism and trust) and for selectively benefitting oneself over the adaptive interests of others (as measured by social dominance orientation and support for monopolizing territory and resources), and differ genetically and phenotypically from Big Five personality traits.

Objective Exposure to adverse stressors has been associated with shortening of leukocyte telomere length (LTL). The present longitudinal study investigates the time course of exposure to life events and LTL to determine whether increases in exposure to life events are related to subsequent accelerated LTL shortening. Methods In the Swedish Adoption/Twin Study of Aging, we assessed late-life stressful events and LTL in 543 individual participants (mean age = 68.4 years, 40% men, including 48 complete monozygotic twin pairs and 167 complete dizygotic twin pairs) in up to five separate measurements over a period of 25 years. LTL was measured using quantitative polymerase chain reaction. Longitudinal analyses were conducted using time-varying mixed modeling, corrected for life-style factors and depressive symptoms. Results When adjusting for differences in genetic makeup by looking only in monozygotic twins, we found that an increase in life stressors within an individual was related to decreased LTL over time (B = -0.02; 95% confidence interval = -0.04 to 0.01; p = .002). None of the findings were significant when only looking at dizygotic twins (all, p > .05). Conclusions Our findings in an older population show a causal relation between increase in life stress and accelerated LTL shortening by using intraindividual time-varying analysis.

Dizygotic twin males, born at 34 weeks gestation, had prolonged jaundice, microcytic, hypochromic anemia, FABarts hemoglobin, elevated end-tidal CO, and blood films consistent with hereditary pyropoikilocytosis. DNA sequencing revealed both had a heterozygous alpha spectrin (SPTA1) mutation (c.460_462dup) inherited from their asymptomatic mother, plus a 3-base pair duplication in alpha globin (HBA2) (c.364_366dupGTG) inherited from their asymptomatic father.

Major obstetrics and gynecology societies offer inconsistent recommendation regarding optimal delivery timing in uncomplicated dizygotic twins. We sought to investigate the impact of delivery timing within term gestation, in dizygotic twins, on the short- and long-term offspring morbidity. A prospectively analyzed cohort of dizygotic twin deliveries was conducted. All women delivered at a regional tertiary medical center, at term (≥37 0/7), between the years 1991 and 2014, were included. The primary exposure was delivery at 37 0/7–37 + 6/7 weeks, while delivery at ≥38 0/7 weeks’ gestation was considered the reference. Neonatal short- and long-term outcomes according to hospitalizations of offspring up to 18 years of age due to cardiac, respiratory, hematological, neurological, and infectious morbidity were compared. Kaplan–Meier survival curves were used to compare cumulative incidences per each major-system hospitalization. Cox regression models were used to estimate the adjusted hazard ratios, while adjusting for variables with clinical importance. During the study period, 612 dizygotic twin deliveries met the inclusion criteria. Of them, 200 (31.3%) occurred at 37–37 6/7 weeks, and 412 (68.7%) occurred at ≥38 0/7 weeks’ gestation. In the long-term analysis, rates of hospitalizations involving several major morbidity categories exhibited comparable rates in both groups. The Cox regression models did not demonstrate an independent association between gestational age within term and later major pediatric morbidity in offspring (total long-term morbidity: adjusted hazard ratio 1.33, 95% confidence interval 0.77–2.29). Dizygotic twin deliveries occurring at different gestational ages within term do not appear to significantly impact on major short- and long-term outcomes.

Background A pair of dizygotic twins discordantly affected by heavy prenatal alcohol exposure (PAE) was reported previously by Riikonen, suggesting the role of genetic risk or protective factors in the etiology of alcohol‐induced developmental disorders. Now, we have re‐examined these 25‐year‐old twins and explored genetic origin of the phenotypic discordancy reminiscent with fetal alcohol syndrome (FAS). Furthermore, we explored alterations in DNA methylation profile of imprinting control region at growth‐related insulin‐like growth factor 2 (IGF2)/H19 locus in twins' white blood cells (WBC), which have been associated earlier with alcohol‐induced genotype‐specific changes in placental tissue. Methods Microarray‐based comparative genomic hybridization (aCGH) was used to detect potential submicroscopic chromosomal abnormalities, and developmental as well as phenotypic information about twins were collected. Traditional bisulfite sequencing was used for DNA methylation analysis. Results Microarray‐based comparative genomic hybridization revealed a microdeletion 18q12.3‐q21.1. in affected twin, residing in a known 18q deletion syndrome region. This syndrome has been associated with growth restriction, developmental delay or intellectual deficiency, and abnormal facial features in previous studies, and thus likely explains the phenotypic discordancy between the twins. We did not observe association between WBCs’ DNA methylation profile and PAE, but interestingly, a trend of decreased DNA methylation at the imprinting control region was seen in the twin with prenatal growth retardation at birth. Conclusions The microdeletion emphasizes the importance of adequate chromosomal testing in examining the etiology of complex alcohol‐induced developmental disorders. Furthermore, the genotype‐specific decreased DNA methylation at the IGF2/H19 locus cannot be considered as a biological mark for PAE in adult WBCs., Methylation profiles of imprinting control region at the IGF2/H19 locus in white blood cells of prenatally alcohol‐exposed adult twins and control women.

Insights into individual differences in gene expression and its heritability (h2) can help in understanding pathways from DNA to phenotype. We estimated the heritability of gene expression of 52,844 genes measured in whole blood in the largest twin RNA-Seq sample to date (1497 individuals including 459 monozygotic twin pairs and 150 dizygotic twin pairs) from classical twin modeling and identity-by-state-based approaches. We estimated for each gene h2total, composed of cis-heritability (h2cis, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h2res, the residual variance explained by all other genome-wide variants). Mean h2total was 0.26, which was significantly higher than heritability estimates earlier found in a microarray-based study using largely overlapping (>60%) RNA samples (mean h2 = 0.14, p = 6.15 × 10−258). Mean h2cis was 0.06 and strongly correlated with beta of the top cis expression quantitative loci (eQTL, ρ = 0.76, p −308) and with estimates from earlier RNA-Seq-based studies. Mean h2res was 0.20 and correlated with the beta of the corresponding trans-eQTL (ρ = 0.04, p −3) and was significantly higher for genes involved in cytokine-cytokine interactions (p = 4.22 × 10−15), many other immune system pathways, and genes identified in genome-wide association studies for various traits including behavioral disorders and cancer. This study provides a thorough characterization of cis- and trans-h2 estimates of gene expression, which is of value for interpretation of GWAS and gene expression studies.

PURPOSE: Binovular follicles including a pair of conjoined oocytes within a common zona pellucida or their fusion in the zonal region gained some attentions due to its possible role in dizygotic twins. Although some cases in the literature been reported in which two conjoined oocytes arising from binovular follicles were mature, and injected with two separated sperm, no available evidence reported for dizygotic twin pregnancies. METHODS: A case report of a 37-year-old female patient underwent embryo transfer cycle whereby a pair of conjoined blastocysts after ICSI of a pair of conjoined oocytes was transferred. RESULTS: The β-hCG level was positive 15 days after embryo transfer. The subsequent pregnancy scan revealed a dizygotic pregnancy. The woman gave birth to two healthy boys in the mid of 38 weeks of gestation by cesarean section. CONCLUSIONS: Given the insufficient evidence on how to handle conjoined oocytes, this report acknowledges the first occurrence of dizygotic twin delivery resulted from transfer of a pair of conjoined blastocysts after ICSI of a pair of conjoined oocytes. This also confirms that we should be extremely conservative in discarding any mature oocyte without sufficient data about its useless future to result in a healthy baby.

A triplet repeat expansion leading to transcriptional silencing of the FMR1 gene results in fragile X syndrome (FXS), which is a common cause of inherited intellectual disability and autism. Phenotypic variation requires personalized treatment approaches and hampers clinical trials in FXS. We searched for microRNA (miRNA) biomarkers for FXS using deep sequencing of urine and identified 28 differentially regulated miRNAs when 219 reliably identified miRNAs were compared in dizygotic twin boys who shared the same environment, but one had an FXS full mutation, and the other carried a premutation allele. The largest increase was found in miR-125a in the FXS sample, and the miR-125a levels were increased in two independent sets of urine samples from a total of 19 FXS children. Urine miR-125a levels appeared to increase with age in control subjects, but varied widely in FXS subjects. Should the results be generalized, it could suggest that two FXS subgroups existed. Predicted gene targets of the differentially regulated miRNAs are involved in molecular pathways that regulate developmental processes, homeostasis, and neuronal function. Regulation of miR-125a has been associated with type I metabotropic glutamate receptor signaling (mGluR), which has been explored as a treatment target for FXS, reinforcing the possibility that urine miR-125a may provide a novel biomarker for FXS.