Two identical twin pairs discordant for longstanding anorexia nervosa and OSFED: lived experience accounts of eating disorder and recovery processes.

Research into the risk of anorexia nervosa (AN) has examined twin pairs to further the understanding of the contributions of genetics, trait inheritance, and environmental factors to eating disorder (ED) development. Investigations of twin experiences of EDs have been biologically-based and have not considered the qualitative, phenomenological aspects of twin experiences. A gap in the literature exists regarding understanding of discordant twins with EDs. This research was developed in response, with the aim to deepen understanding of AN in discordant twins and to create novel ideas for further research and testing. The case studies presented in this article provide lived experience insights of two identical discordant twin pairs: one twin pair discordant for longstanding AN and one twin pair discordant for 'atypical' AN (the twin with AN has recovered). The perspectives and experiences of each co-twin (one with AN and one without) explore a number of factors that may have contributed to twin discordance in these cases, and how each twin has responded to the impact of AN in their lives. Through use of first-person accounts in case study presentation, this article centres social justice values of lived experience leadership and involvement in research. This article aims to extend current knowledge and understanding of EDs in discordant twins, particularly regarding risk for ED development, ED duration, diagnosis and treatment, and recovery processes.

Inconsistent patterns of twin growth and their relationship with obstetric adverse outcomes / 中国现代医生

@#Objective To determine different patterns of fetal growth dissonance in twin pregnancies and their predictive role in obstetric adverse outcomes.Methods The medical records of 531cases of twin-pregnancy women who underwent labor examination and delivery in our hospital from January 2014 to december 2021 were retrospectively analyzed.According to the ultrasound parameters during the prenatal examination,the inconsistencies between twins were divided into four modes:mode 1:no significant inconsistencies group(268cases),Mode 2:early progressive inconsistencies(23cases),mode 3:early inconsistencies with plinosis(91cases)and mode 4:late inconsistencies(149cases).The dynamic changes of each model and its correlation with adverse outcomes were investigated.Results Pattern 2 and Pattern 3 inconsistencies>10%(20.5 and 20.7 weeks of gestation)and>20%(27.7 and 26.3weeks of gestation)occurred at similar times.Mode 2 had the highest rate of inconsistent progression(0.92%/week),which peaked at 23.7%at 36weeks of gestation.Mode 3 progressed at a slower rate(0.49%/week),with a smaller variance after 20weeks(from 13.3%at 20weeks to 16%at 36weeks).The onset time of pattern 4 inconsistencies was>10%at 29.8weeks of gestation,and the peak inconsistencies(14.8%)were lower than pattern 2 and pattern Using mode 1(no significant inconsistency)as a reference,after adjusting for relevant covariates,mode 2 and 3 were risk factors for preterm birth and preeclampsia at 34 and 32weeks of gestation,mode 2 was a risk factor for 5-minute Apgar score<7,and mode 2,3,and 4 were risk factors for newborn birth weight<10th percentile.Conclusion According to the occurrence,development and intensity of neonatal growth dissonance,four different dissonance patterns were identified to be associated with different obstetric outcomes.These models provide more predictive information than the single point in time when measurements of fetal size are inconsistent,which is commonly used.

Effects of smoking on genome-wide DNA methylation profiles: A study of discordant and concordant monozygotic twin pairs.

Background: Smoking-associated DNA methylation levels identified through epigenome-wide association studies (EWASs) are generally ascribed to smoking-reactive mechanisms, but the contribution of a shared genetic predisposition to smoking and DNA methylation levels is typically not accounted for. Methods: We exploited a strong within-family design, that is, the discordant monozygotic twin design, to study reactiveness of DNA methylation in blood cells to smoking and reversibility of methylation patterns upon quitting smoking. Illumina HumanMethylation450 BeadChip data were available for 769 monozygotic twin pairs (mean age = 36 years, range = 18-78, 70% female), including pairs discordant or concordant for current or former smoking. Results: In pairs discordant for current smoking, 13 differentially methylated CpGs were found between current smoking twins and their genetically identical co-twin who never smoked. Top sites include multiple CpGs in CACNA1D and GNG12, which encode subunits of a calcium voltage-gated channel and G protein, respectively. These proteins interact with the nicotinic acetylcholine receptor, suggesting that methylation levels at these CpGs might be reactive to nicotine exposure. All 13 CpGs have been previously associated with smoking in unrelated individuals and data from monozygotic pairs discordant for former smoking indicated that methylation patterns are to a large extent reversible upon smoking cessation. We further showed that differences in smoking level exposure for monozygotic twins who are both current smokers but differ in the number of cigarettes they smoke are reflected in their DNA methylation profiles. Conclusions: In conclusion, by analysing data from monozygotic twins, we robustly demonstrate that DNA methylation level in human blood cells is reactive to cigarette smoking. Funding: We acknowledge funding from the National Institute on Drug Abuse grant DA049867, the Netherlands Organization for Scientific Research (NWO): Biobanking and Biomolecular Research Infrastructure (BBMRI-NL, NWO 184.033.111) and the BBRMI-NL-financed BIOS Consortium (NWO 184.021.007), NWO Large Scale infrastructures X-Omics (184.034.019), Genotype/phenotype database for behaviour genetic and genetic epidemiological studies (ZonMw Middelgroot 911-09-032); Netherlands Twin Registry Repository: researching the interplay between genome and environment (NWO-Groot 480-15-001/674); the Avera Institute, Sioux Falls (USA), and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995); epigenetic data were generated at the Human Genomics Facility (HuGe-F) at ErasmusMC Rotterdam. Cotinine assaying was sponsored by the Neuroscience Campus Amsterdam. DIB acknowledges the Royal Netherlands Academy of Science Professor Award (PAH/6635).

The genetic information of people who smoke present distinctive characteristics. In particular, previous research has revealed differences in patterns of DNA methylation, a type of chemical modification that helps cells switch certain genes on or off. However, most of these studies could not establish for sure whether these changes were caused by smoking, predisposed individuals to smoke, or were driven by underlying genetic variation in the DNA sequence itself. To investigate this question, van Dongen et al. examined DNA methylation data from the blood cells of over 700 pairs of identical twins. These individuals share the exact same genetic information, making it possible to better evaluate the impact of lifestyle on DNA modifications. The analyses identified differences in methylation at 13 DNA locations in pairs of twins where one was a current smoker and their sibling had never smoked. Two of the genes code for proteins involved in the response to nicotine, the primary addictive chemical in cigarette smoke. The differences were smaller if one of the twins had stopped smoking, suggesting that quitting can help to reverse some of these changes. These findings confirm that DNA methylation in blood cells is influenced by cigarette smoke, which could help to better understand smoking-associated diseases. They also demonstrate how useful identical twins studies can be to identify methylation changes that are markers of lifestyle.

In search of environmental risk factors for obsessive-compulsive disorder: study protocol for the OCDTWIN project.

BACKGROUND: The causes of obsessive-compulsive disorder (OCD) remain unknown. Gene-searching efforts are well underway, but the identification of environmental risk factors is at least as important and should be a priority because some of them may be amenable to prevention or early intervention strategies. Genetically informative studies, particularly those employing the discordant monozygotic (MZ) twin design, are ideally suited to study environmental risk factors. This protocol paper describes the study rationale, aims, and methods of OCDTWIN, an open cohort of MZ twin pairs who are discordant for the diagnosis of OCD. METHODS: OCDTWIN has two broad aims. In Aim 1, we are recruiting MZ twin pairs from across Sweden, conducting thorough clinical assessments, and building a biobank of biological specimens, including blood, saliva, urine, stool, hair, nails, and multimodal brain imaging. A wealth of early life exposures (e.g., perinatal variables, health-related information, psychosocial stressors) are available through linkage with the nationwide registers and the Swedish Twin Registry. Blood spots stored in the Swedish phenylketonuria (PKU) biobank will be available to extract DNA, proteins, and metabolites, providing an invaluable source of biomaterial taken at birth. In Aim 2, we will perform within-pair comparisons of discordant MZ twins, which will allow us to isolate unique environmental risk factors that are in the causal pathway to OCD, while strictly controlling for genetic and early shared environmental influences. To date (May 2023), 43 pairs of twins (21 discordant for OCD) have been recruited. DISCUSSION: OCDTWIN hopes to generate unique insights into environmental risk factors that are in the causal pathway to OCD, some of which have the potential of being actionable targets.

Genome Sequencing and Transcriptome Profiling in Twins Discordant for Mayer-Rokitansky-Küster-Hauser Syndrome.

To identify potential genetic causes for Mayer-Rokitansky-Küster-Hauser syndrome (MRKH), we analyzed blood and rudimentary uterine tissue of 5 MRKH discordant monozygotic twin pairs. Assuming that a variant solely identified in the affected twin or affected tissue could cause the phenotype, we identified a mosaic variant in ACTR3B with high allele frequency in the affected tissue, low allele frequency in the blood of the affected twin, and almost absent in blood of the unaffected twin. Focusing on MRKH candidate genes, we detected a pathogenic variant in GREB1L in one twin pair and their unaffected mother showing a reduced phenotypic penetrance. Furthermore, two variants of unknown clinical significance in PAX8 and WNT9B were identified. In addition, we conducted transcriptome analysis of affected tissue and observed perturbations largely similar to those in sporadic cases. These shared transcriptional changes were enriched for terms associated with estrogen and its receptors pointing at a role of estrogen in MRKH pathology. Our genome sequencing approach of blood and uterine tissue of discordant twins is the most extensive study performed on twins discordant for MRKH so far. As no clear pathogenic differences were detected, research to evaluate other regulatory layers are required to better understand the complex etiology of MRKH.

An Epidemiologic, Longitudinal, and Discordant-Twin Study of the Association Between Gambling Disorder and Suicidal Behaviors.

Gambling disorder is associated with suicidal behaviors, but it is not clear whether the association is due to common etiologic factors or to gambling disorder being causally related to suicidality. This question was examined from epidemiologic, longitudinal, and discordant twin study perspectives. The results suggested that the causes of the association with disordered gambling differed for suicidal ideation, plan, and attempt, and differed for men and women. The association of suicidal thoughts with disordered gambling was non-causally explained by common genetic influences among women (but not men). Conversely, there was evidence consistent with a potentially causal influence of disordered gambling on suicide attempt among men (but not women), which might have been related to gambling-related financial problems. The use of monetary data to identify individuals experiencing financial harms associated with their gambling may represent a more practicable target for screening, intervention, and prevention and may reduce gambling-related financial crises, thereby warding off a potential gambling-related suicide attempt.

NAD+ deficiency in human congenital malformations and miscarriage: A new model of pleiotropy.

Pleiotropy is defined as the phenomenon of a single gene locus influencing two or more distinct phenotypic traits. However, nicotinamide adenine dinucleotide (NAD+) deficiency through diet alone can cause multiple or single malformations in mice. Additionally, humans with decreased NAD+ production due to changes in pathway genes display similar malformations. Here, I hypothesize NAD+ deficiency as a pleiotropic mechanism for multiple malformation conditions, including limb-body wall complex (LBWC), pentalogy of Cantrell (POC), omphalocele-exstrophy-imperforate anus-spinal defects (OEIS) complex, vertebral-anal-cardiac-tracheoesophageal fistula-renal-limb (VACTERL) association (hereafter VACTERL), oculoauriculovertebral spectrum (OAVS), Mullerian duct aplasia-renal anomalies-cervicothoracic somite dysplasia (MURCS), sirenomelia, and urorectal septum malformation (URSM) sequence, along with miscarriages and other forms of congenital malformation. The term Congenital NAD Deficiency Disorder (CNDD) could be considered for patients with these malformations; however, it is important to emphasize there have been no confirmatory experimental studies in humans to prove this hypothesis. In addition, these multiple malformation conditions should not be considered individual entities for the following reasons: First, there is no uniform consensus of clinical diagnostic criteria and all of them fail to capture cases with partial expression of the phenotype. Second, reports of individuals consistently show overlapping features with other reported conditions in this group. Finally, what is currently defined as VACTERL is what I would refer to as a default label when more striking features such as body wall defects, caudal dysgenesis, or cloacal exstrophy are not present.

Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia.

OBJECTIVE: We used data from twins and their families to probe the genetic factors contributing to microtia-atresia, in particular, early post-twinning variations that potentially account for the discordant phenotypes of monozygotic twin pairs. METHODS: Six families of monozygotic twins discordant for congenital microtia-atresia were recruited for study. The six patients shared a consistent clinical phenotype of unilateral microtia-atresia. Whole-exome sequencing (WES) was performed for all six twin pairs and their parents. Family segregation and multiple bioinformatics methods were applied to identify suspicious mutations in all families. Recurring mutations commonly detected in at least two families were highlighted. All variants were validated via Sanger sequencing. Gene Ontology (GO) analysis was performed to identify candidate gene sets and related pathways. Copy number variation (CNV), linkage analysis, association analysis and machine learning methods were additionally applied to isolate candidate mutations, and comparative genomics and structural modeling tools used to evaluate their potential roles in onset of microtia-atresia. RESULTS: Our analyses revealed 61 genes with suspected mutations associated with microtia-atresia. Five (HOXA4, MUC6, CHST15, TBX10, and AMER1) contained 7 de novo mutations that appeared in at least two families, which have been previously reported as pathogenic for other diseases. Among these, HOXA4 (c.920A>C, p.H307P) was determined as the most likely pathogenic variant for microtia-atresia. GO analysis revealed four gene sets involving 11 pathways potentially related to underlying pathogenesis of the disease. CNVs in three genes (UGT2B17, OVOS, and KATNAL2) were detected in at least two families. Linkage analysis disclosed 13 extra markers for the disease, of which two (FGFR1 and EYA1) were validated via machine learning analysis as plausible candidate genes for the disease. CONCLUSION: Based on comprehensive genetic and bioinformatic analyses of WES data from six families of discordant monozygotic twins with microtia-atresia, we identified multiple candidate genes that may function in post-twinning onset of the disease. The collective findings provide novel insights into the pathogenesis of congenital microtia-atresia.

Retinopathy of prematurity in discordant twins: is the small twin at increased risk?

PURPOSE: To examine the effect of birth weight (BW) independent of gestational age (GA) on Retinopathy of prematurity (ROP) in preterm discordant twins. METHODS: A retrospective cohort study of 45 preterm twin pairs born at < 34 weeks of gestation with BW discordance of ≥ 20%. The twin pairs were divided into two groups based on BW - small or large. Rates of ROP, stage, treatment, and prognosis were compared between the two groups. Other neonatal outcomes related to prematurity were also compared between groups. RESULTS: The mean gestation age at delivery was 31.1 weeks of gestation. The rate of ROP was significantly higher among the smaller twins compared to the larger twins (8.9% vs 0% respectively, p = 0.04). All smaller twins with ROP had stage 2 disease, and all cases of ROP had resolved without treatment. Regarding neonatal morbidities, the smaller twins had longer hospitalization length (53.8 vs 39.4 days respectively, p < 0.01) and a higher rate of hypoglycemia (55.6% vs 24.4% respectively, p = 0.003), whereas the larger twins were more commonly affected by respiratory distress syndrome (59.1% vs 26.7% respectively, p = 0.002). CONCLUSION: The rate of ROP was higher among the small twins in preterm discordant twins. This may indicate that low BW rather than early GA is the main factor contributing to the development of ROP.

Disease-discordant twin structural MRI studies on affective disorders.

Magnetic resonance imaging (MRI) studies have identified neural structures implicated in the pathophysiology of mood disorders, especially bipolar disorder (BD) and major depressive disorder (MDD). However, the role of genetic and environmental influences on such brain deficits is still unclear. In this context, the present review summarizes the current evidence from structural MRI and Diffusion Tensor Imaging (DTI) studies on twin samples concordant or discordant for BD or MDD, with the aim of clarifying the role of genetic and environmental risk factors on brain alterations. Although the results showed a complex interplay between gene and environment in affective disorders, the evidence seem to underline that both genetic and environmental risk factors have an impact on brain areas and vulnerability to MDD and BD. However, the precise mechanism of action and the interaction between these factors still needs to be unveiled. Therefore, future larger studies on concordant or discordant twins should be encouraged, because this population provides a unique opportunity to probe separately genetic and environmental markers of disease vulnerability.

Neonatal morbidity and mortality among growth-discordant dichorionic twins, classified according to birth weight of the smaller twin: a population-based cohort study.

Objective: To examine the outcomes among discordant dichorionic (DC) twins, where the smaller twin is small for gestational age (SGA) or non-SGA.Materials and methods: We used the national perinatal registry to compare the relationship between selected maternal characteristics (age, parity, body mass index, gestational diabetes, hypertensive disorders, and gestational age at delivery) and neonatal outcomes in discordant >25% DC twins. Chorionicity was established by standard ultrasound criteria and confirmed postpartum. The smaller of the twins was further classified as SGA or non-SGA. The neonatal outcomes included 5-min Apgar score <7, admission to neonatal intensive care unit, early neonatal death and neonatal morbidities.Results: We identified 377 pairs of DC discordant twins >25% born during the 15 years study period, 270 (71.6%) of which included an SGA smaller twin and 107 (28.4%) were non-SGA smaller twin. Maternal characteristics and neonatal morbidities were unrelated to the smaller discordant twin being SGA. A significantly increased incidence of stillbirth was found in the SGA group. Early neonatal deaths were only found in the SGA group.Conclusion: When the smaller twin is SGA, the growth discordant DC twin pair is associated with increased incidence of perinatal deaths. These appear unrelated to maternal characteristics and neonatal morbidity.

Clinical study on independent risk factors and neonatal complications in discordant twins / 中华实用儿科临床杂志

Objective To investigate the perinatal independent risk factors and neonatal complications of discordant twins.Methods Clinical data of 152 (76 pairs) discordant twins and 552 (276 pairs) concordant twins were enrolled at the Obstetrics of Peking University People's Hospital from November 1,2011 to October 31,2016.The perinatal characteristics and the neonatal complications in 2 groups were analyzed and compared.Binary Logistic regression analysis was used to identify the independent risk factors associated with the occurrence of discordant twins.Results (1) The gestational age,the incidence of term infants and birth weight of the discordant twins were significantly lower than those of the concordant twins[(35.8 ±2.5) weeks vs.(36.7 ± 1.8) weeks,48.7％ vs.60.2％,(2 277.1 ± 575.7) g vs.(2 545.0 ± 413.4) g],and the differences were statistically significant (all P ＜ 0.05).The incidence of premature infants,the incidence of infants small for gestational age and the rate of transferring discordant twins to pediatric department were significantly higher than that of concordant twins (51.3％ vs.39.9％,40.8％ vs.13.2％,46.1％ vs.26.8％),and the differences were statistically significant (all P ＜ 0.05).(2) The incidence of neonatal asphyxia,neonatal respiratory distress syndrome,neonatal pneumonia,neonatal apnea,bronchopulmonary dysplasia,neonatal sepsis and neonatal intracranial hemorrhage were significantly higher than those of concordant twins (6.6％ vs.2.5％,7.2％ vs.3.1％,5.3％ vs.1.3％,9.2％ vs.3.3％,3.9％ vs.0.9％,3.3％ vs.0.7％,4.6％ vs.O.7％),and the differences were statistically significant(all P ＜ 0.05).(3) The birth weight in the twins with low body weight group was significantly lower than that in the twins with high body weight group [(1 926.7 ± 414.1) g vs.(2 618.7 ± 504.6) g],and the differences were statistically significant (P ＜ 0.05).The incidence of small for gestational age,the rate of conversion to pediatrics and the incidence of neonatal intracranial hemorrhage in the twins with low body weight group were significantly higher than those in the twins with high body weight group (65.8％ vs.6.6％,56.6％ vs.35.5 ％,9.2％ vs.0),and the differences were statistically significant (all P ＜ 0.05).(4) Logistic regression analysis showed that hypertensive disorder during pregnancy (OR =2.127,95％ CI:1.392-3.253) and gestational diabetes mellitus (OR =1.684,95％ CI:1.112-2.552) were independent risk factors for the occurrence of discordant twins.Conclusions Hypertensive disorder during pregnancy and gestational diabetes mellitus are independent risk factors for the occurrence of discordant twins,who are much more likely to develop various neonatal complications,particularly low-birth-weight infants.Timely surveillance and treatment of short-term complications and long-time follow-up are essential to discordant twins.

Restricción de crecimiento aumenta el riesgo de displasia broncopulmonar, muerte y sepsis en gemelos de 30 o menos semanas de gestación / Growth restriction increases the risk of bronchopulmonary dysplasia, death, and sepsis in twins of 30 weeks or less of gestation

INTRODUCCIÓN: Múltiples factores influyen en el riesgo de morbimortalidad del prematuro con restricción del crecimiento intrauterino (RCIU). La comparación de gemelos con crecimiento intrauterino discordante permite evaluar su efecto, excluyendo factores maternos y manejo prenatal. Nuestro objetivo fue evaluar el efecto de la RCIU sobre la morbilidad aguda, crónica y mortalidad, en parejas de recién nacidos gemelares prematuros extremos. PACIENTES Y MÉTODO: Gemelos menores de 1500 g y 30 semanas de gestación, de la Red Neocosur. Se realizaron análisis separados de pares de gemelos concordantes, discordantes leves y severos, evaluando el efecto de la RCIU sobre morbi-mortalidad. Se realizó análisis multivariado para establecer magnitud del efecto. RESULTADOS: 459 pares de gemelos, 227 concordantes, 110 discordantes leves y 122 severos. Entre los concordantes solo hubo diferencia en uso de oxígeno a las 36 semanas. En discordantes leves, el menor tuvo menos enfermedad de membrana hialina y requirió menos dosis de surfactante, pero tuvo un mayor riesgo de Displasia broncopulmonar (DBP) o muerte. En discordantes severos, el menor presentó mayor mortalidad, sepsis, utilización y permanencia en ventilación mecánica, pese a menor frecuencia de enfermedad de membrana hialina. En regresión múltiple, el riesgo combinado de DBP o muerte fue mayor en gemelo menor y discordante severo. CONCLUSIÓN: En gemelos discordantes, la patología respiratoria aguda fue más frecuente en el gemelo mayor, aunque el riesgo de DBP o muerte fue mayor en el gemelo con RCIU.

INTRODUCTION: Multiple factors influence the risk of morbidity and mortality of premature infants with intrauterine growth restriction (IUGR). The comparison of twins with different intrauterine growth allows evaluating the effect of the restriction, excluding maternal factors and prenatal mana gement. Our objective was to assess the effect of IUGR on acute and chronic morbidity, and mortality of extreme preterm twins. PATIENTS AND METHOD: Twins weighing less than 1500 grams and gesta tion equal to or less than 30 weeks, of the Neocosur Network. Separate analyses were performed on concordant twin pairs, and on mild and severe discordant twins, evaluating the effect of IUGR on morbidity and mortality. A multivariate analysis was performed in order to establish the impact of this effect. RESULTS: 459 twin pairs, 227 concordant twins, 110 of mild discordance, and 122 of severe discordance. Among the concordant ones, there was only a difference in oxygen uptake at 36 weeks. In those of mild discordance, the smaller twin presented a lower frequency of hyaline membrane disease and required fewer doses of surfactant, but had a higher risk of bronchopulmonary dysplasia (BPD) or death. In severe discordant twins, the smaller one presented higher mortality, sepsis, use and permanence in mechanical ventilation, despite the lower frequency of hyaline membrane disease. In multiple regression analysis, the combined risk of BPD or death was higher in the smaller twin and of severe discordance. CONCLUSION: In discordant twins, the acute respiratory pathology was more frequent in the larger one, although the risk of BPD or death was higher in the one with IUGR.

Epigenome-wide analysis in newborn blood spots from monozygotic twins discordant for cerebral palsy reveals consistent regional differences in DNA methylation.

Background: Cerebral palsy (CP) is a clinical description for a group of motor disorders that are heterogeneous with respect to causes, symptoms and severity. A diagnosis of CP cannot usually be made at birth and in some cases may be delayed until 2-3 years of age. This limits opportunities for early intervention that could otherwise improve long-term outcomes. CP has been recorded in monozygotic twins discordant for the disorder, indicating a potential role of non-genetic factors such as intrauterine infection, hypoxia-ischaemia, haemorrhage and thrombosis. The aim of this exploratory study was to utilise the discordant monozygotic twin model to understand and measure epigenetic changes associated with the development of CP. Methods: We performed a genome-wide analysis of DNA methylation using the Illumina Infinium Human Methylation 450 BeadChip array with DNA from newborn blood spots of 15 monozygotic twin pairs who later became discordant for CP. Quality control and data preprocessing were undertaken using the minfi R package. Differential methylation analysis was performed using the remove unwanted variation (RUVm) method, taking twin pairing into account in order to identify CP-specific differentially methylated probes (DMPs), and bumphunter was performed to identify differentially methylated regions (DMRs). Results: We identified 33 top-ranked DMPs based on a nominal p value cut-off of p < 1 × 10-4 and two DMRs (p < 1 × 10-3) associated with CP. The top-ranked probes related to 25 genes including HNRNPL, RASSF5, CD3D and KALRN involved in immune signalling pathways, in addition to TBC1D24, FBXO9 and VIPR2 previously linked to epileptic encephalopathy. Gene ontology and pathway analysis of top-ranked DMP-associated genes revealed enrichment of inflammatory signalling pathways, regulation of cytokine secretion and regulation of leukocyte-mediated immunity. We also identified two top-ranked DMRs including one on chromosome 6 within the promoter region of LTA gene encoding tumour necrosis factor-beta (TNF-ß), an important regulator of inflammation and brain development. The second was within the transcription start site of the LIME1 gene, which plays a key role in inflammatory pathways such as MAPK signalling. CP-specific differential DNA methylation within one of our two top DMRs was validated using an independent platform, MassArray EpiTyper. Conclusions: Ours is the first epigenome-wide association study of CP in disease-discordant monozygotic twin pairs and suggests a potential role for immune dysfunction in this condition.

Expression of Homeobox Gene HLX and its Downstream Target Genes are Altered in Placentae From Discordant Twin Pregnancies.

A discordant twin gestation, in which one fetus is significantly growth restricted, compared to the other normal twin, is a unique model that can be used to elucidate the mechanism(s) by which the intrauterine environment affects fetal growth. In many model systems, placental transcription factor genes regulate fetal growth. Transcription factors regulate growth through their activation or repression of downstream target genes that mediate important cell functions. The objective of this study was to determine the expression of the placental HLX homeobox gene transcription factor and its downstream target genes in dizygotic twins with growth discordance. In this cross-sectional study, HLX and its downstream target genes' retinoblastoma 1 (RB1) and cyclin kinase D (CDKN1C) expression levels were determined in placentae obtained from dichorionic diamniotic twin pregnancies (n = 23) where one of the twins was growth restricted. Fetal growth restriction (FGR) was defined as small for gestational age with abnormal umbilical artery Doppler indices when compared with the normal control co-twin. Homeobox gene HLX expression was significantly decreased at both the mRNA and protein levels in FGR twin placentae compared with the normal control co-twin placentae (p < .05). Downstream target genes CDKN1C and RB1 were also significantly decreased and increased, respectively, at both the mRNA and protein levels in FGR twin placentae compared with normal control co-twin placentae (p < .05). Together, these observations suggest an important association between HLX transcription factor expression and abnormal human placental development in discordant twin pregnancies.

Chronic prostatitis and comorbid non-urological overlapping pain conditions: A co-twin control study.

OBJECTIVES: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is characterized by pain and voiding symptoms in the absence of an obvious infection or other cause. CP/CPPS frequently occurs with non-urological chronic overlapping pain conditions (COPCs) of unknown etiology. We conducted a co-twin control study in men discordant for chronic prostatitis (CP), an overarching diagnosis of which approximately 90% is CP/CPPS. The primary aim was to investigate the contribution of familial factors, including shared genetic and common environmental factors, to the comorbidity of CP and COPCs. METHODS: Data from 6824 male twins in the Vietnam Era Twin Registry were examined to evaluate the association between self-reported lifetime physician diagnosis of CP with COPCs including fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, temporomandibular disorder, tension headaches, and migraine headaches. Random effects logistic regression models were used and within-pair analyses evaluated confounding effects of familial factors on the associations. RESULTS: There were significant associations between CP and all 6 examined COPCs. After adjusting for shared familial influences in within twin pair analyses, the associations for all COPCs diminished but remained significant. Familial confounding was strongest for the association of CP with fibromyalgia and temporomandibular disorder and smallest for irritable bowel syndrome. CONCLUSIONS: CP and COPCs are highly comorbid. These associations can be partially explained by familial factors. The mechanisms underlying these relationships are likely diverse and multifactorial. Future longitudinal research can help to further elucidate specific genetic and environmental mechanisms and determine potentially causal relationships between CP and its comorbidities.

Perceived stress is associated with increased rostral middle frontal gyrus cortical thickness: a family-based and discordant-sibling investigation.

Elevated stress perception and depression commonly co-occur, suggesting that they share a common neurobiology. Cortical thickness of the rostral middle frontal gyrus (RMFG), a region critical for executive function, has been associated with depression- and stress-related phenotypes. Here, we examined whether RMFG cortical thickness is associated with these phenotypes in a large family-based community sample. RMFG cortical thickness was estimated using FreeSurfer among participants (n = 879) who completed the ongoing Human Connectome Project. Depression-related phenotypes (i.e. sadness, positive affect) and perceived stress were assessed via self-report. After accounting for sex, age, ethnicity, average whole-brain cortical thickness, twin status and familial structure, RMFG thickness was positively associated with perceived stress and sadness and negatively associated with positive affect at small effect sizes (accounting for 0.2-2.4% of variance; p-fdr: 0.0051-0.1900). Perceived stress was uniquely associated with RMFG thickness after accounting for depression-related phenotypes. Further, among siblings discordant for perceived stress, those reporting higher perceived stress had increased RMFG thickness (P = 4 × 10-7 ). Lastly, RMFG thickness, perceived stress, depressive symptoms, and positive affect were all significantly heritable, with evidence of shared genetic and environmental contributions between self-report measures. Stress perception and depression share common genetic, environmental, and neural correlates. Variability in RMFG cortical thickness may play a role in stress-related depression, although effects may be small in magnitude. Prospective studies are required to examine whether variability in RMFG thickness may function as a risk factor for stress exposure and/or perception, and/or arises as a consequence of these phenotypes.

New developments in Silver-Russell syndrome and implications for clinical practice.

Silver-Russell syndrome is a clinically and genetically heterogeneous disorder, characterized by prenatal and postnatal growth restriction, relative macrocephaly, body asymmetry and characteristic facial features. It is one of the imprinting disorders, which results as a consequence of aberrant imprinted gene expressions. Currently, maternal uniparental disomy of chromosome 7 accounts for approximately 10% of Silver-Russell syndrome cases, while ~50% of patients have hypomethylation at imprinting control region 1 at chromosome 11p15.5 locus, leaving ~40% of cases with unknown etiologies. This review aims to provide a comprehensive list of molecular defects in Silver-Russell syndrome reported to date and to highlight the importance of multiple-loci/tissue testing and trio (both parents and proband) screening. The epigenetic and phenotypic overlaps with other imprinting disorders will also be discussed.

Neuro-developmental outcome of a large cohort of growth discordant twins.

UNLABELLED: Our aims were to study the effect of birthweight growth discordance (≥20%) on neuro-developmental outcome of monochorionic and dichorionic twins and to compare the relative effects of foetal growth discordance and prematurity on cognitive outcome. We performed a cross-sectional multicentre prospective follow-up study from a cohort of 948 twin pregnancies. One hundred nineteen birthweight-discordant twin pairs were examined (24 monochorionic pairs) and were matched for gestational age at delivery with 111 concordant control pairs. Participants were assessed with the Bayley Scales between 24 and 42 months of age. Analysis was by paired t test for intra-twin pair differences and by multiple linear regression. Compared to the larger twin of a discordant pair, the smaller twin performed significantly worse in cognition (mean composite cognitive score difference = -1.7, 95% confidence interval (CI) = 0.3-3.1, p = 0.01) and also in language and motor skills. Prematurity prior to 33 weeks' gestation, however, had a far greater impact on cognitive outcomes (mean cognitive composite score difference = -5.8, 95% CI = 1.2-10.5, p = 0.008). CONCLUSION: Birthweight growth discordance of ≥20% confers an independent adverse effect on long-term neuro-development of the smaller twin. However, prior to 33 weeks' gestation, gestational age at birth adversely affects cognitive development to a greater extent than foetal growth discordance.

The Concordance and Heritability of Type 2 Diabetes in 34,166 Twin Pairs From International Twin Registers: The Discordant Twin (DISCOTWIN) Consortium.

Twin pairs discordant for disease may help elucidate the epigenetic mechanisms and causal environmental factors in disease development and progression. To obtain the numbers of pairs, especially monozygotic (MZ) twin pairs, necessary for in-depth studies while also allowing for replication, twin studies worldwide need to pool their resources. The Discordant Twin (DISCOTWIN) consortium was established for this goal. Here, we describe the DISCOTWIN Consortium and present an analysis of type 2 diabetes (T2D) data in nearly 35,000 twin pairs. Seven twin cohorts from Europe (Denmark, Finland, Norway, the Netherlands, Spain, Sweden, and the United Kingdom) and one from Australia investigated the rate of discordance for T2D in same-sex twin pairs aged 45 years and older. Data were available for 34,166 same-sex twin pairs, of which 13,970 were MZ, with T2D diagnosis based on self-reported diagnosis and medication use, fasting glucose and insulin measures, or medical records. The prevalence of T2D ranged from 2.6% to 12.3% across the cohorts depending on age, body mass index (BMI), and national diabetes prevalence. T2D discordance rate was lower for MZ (5.1%, range 2.9-11.2%) than for same-sex dizygotic (DZ) (8.0%, range 4.9-13.5%) pairs. Across DISCOTWIN, 720 discordant MZ pairs were identified. Except for the oldest of the Danish cohorts (mean age 79), heritability estimates based on contingency tables were moderate to high (0.47-0.77). From a meta-analysis of all data, the heritability was estimated at 72% (95% confidence interval 61-78%). This study demonstrated high T2D prevalence and high heritability for T2D liability across twin cohorts. Therefore, the number of discordant MZ pairs for T2D is limited. By combining national resources, the DISCOTWIN Consortium maximizes the number of discordant MZ pairs needed for in-depth genotyping, multi-omics, and phenotyping studies, which may provide unique insights into the pathways linking genes to the development of many diseases.