Tissue-specific nonheritable influences drive endometrial immune system variation.

Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific.

Surgically treated degenerative disk disease in twins.

PURPOSE: Previous studies have suggested that genetic factors are important in the development of degenerative disk disease (DDD). However, the concordance rates for the phenotypes requiring surgery are unknown. The purpose of this study was to determine the concordance rates for DDD requiring surgery by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. METHODS: Patients, aged between 18 and 85 years, operated for DDD between 1996 and 2022 were identified in the national Swedish spine register (Swespine) and matched with the Swedish twin registry (STR) to identify MZ and DZ twins. Pairwise and probandwise concordance rates were calculated. RESULTS: We identified 11,207 patients, 53% women, operated for DDD. By matching the Swespine patients with the STR, we identified 121 twin pairs (37 MZ and 84 DZ) where one or both twins were surgically treated for DDD. The total twin incidence for operated DDD was 1.1%. For DDD requiring surgery, we found no concordant MZ pair and no concordant DZ pair where both twins were operated for DDD. When we evaluated pairs where at least one twin was operated for DDD, we found two concordant MZ pairs (the co-twins were operated for spinal stenosis) and two  concordant DZ pairs (one co-twin operated for spinal stenosis and one (co-twin operated for disk herniation). CONCLUSIONS: Our findings suggest that genetic factors are probably not a major etiologic component in most cases of DDD requiring surgery. The findings of this study can be used for counseling patients about the risk for requiring DDD surgery.

Surgically Treated Degenerative Lumbar Spine Diseases in Twins.

BACKGROUND: There is growing evidence to suggest a potential genetic component underlying the development and progression of lumbar spine diseases. However, the heritability and the concordance rates for the phenotypes requiring surgery for the common spine diseases lumbar spinal stenosis (LSS) and lumbar disc herniation (LDH) are unknown. The aim of this study was to determine the heritability and the concordance rates for LSS and LDH requiring surgery by studying monozygotic (MZ) and dizygotic (DZ) twin pairs. METHODS: Patients between 18 and 85 years of age who underwent surgery for LSS or LDH between 1996 and 2022 were identified in the national Swedish spine registry (LSS: 45,110 patients; LDH: 39,272 patients), and matched with the Swedish Twin Registry to identify MZ and DZ twins. Pairwise and probandwise concordance rates, heritability estimates, and MZ/DZ concordance ratios were calculated. RESULTS: We identified 414 twin pairs (92 MZ and 322 DZ pairs) of whom 1 or both twins underwent surgery for LSS. The corresponding number for LDH was 387 twin pairs (118 MZ and 269 DZ pairs). The probandwise concordance rate for LSS requiring surgery was 0.25 (26 of 105) (95% confidence interval [CI], 0.14 to 0.34) for MZ twins and 0.04 (12 of 328) (95% CI, 0.01 to 0.07) for DZ twins. The corresponding values for LDH requiring surgery were 0.03 (4 of 120) (95% CI, 0 to 0.08) and 0.01 (4 of 271) (95% CI, 0 to 0.04), respectively. The probandwise MZ/DZ concordance ratio was 6.8 (95% CI, 2.9 to 21.5) for LSS and 2.3 (95% CI, 0 to 8.9) for LDH. The heritability was significantly higher in LSS compared with LDH (0.64 [95% CI, 0.50 to 0.74] versus 0.19 [95% CI, 0.08 to 0.35]). CONCLUSIONS: Our findings suggest that genetic factors may play an important role in the risk of developing LSS requiring surgery, whereas heredity seems to be of less importance in LDH requiring surgery. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Twin studies as an innovative approach to address research questions in cancer care within primary care settings.

This paper proposes the utilisation of twin studies as a novel and powerful methodological approach to investigate critical research questions pertaining to cancer prevention, screening, diagnosis, treatment and survivorship within primary care contexts. The inherent genetic similarity between monozygotic (MZ) (identical) twins provides a unique opportunity to disentangle genetic and environmental influences on cancer-related outcomes. MZ twins share virtually identical genetic makeup, offering a unique opportunity to discern the relative contributions of genetic and environmental factors to cancer-related outcomes. In contrast, dizygotic (DZ) twins, also known as fraternal twins, develop from two separate eggs fertilised by two different sperm and share on average 50% of their genetic material, the same level of genetic similarity found in non-twin siblings. Comparisons between MZ and DZ twins enable researchers to disentangle hereditary factors from shared environmental influences. This methodology has the potential to advance our understanding of the multifaceted interplay between genetic predisposition, lifestyle factors and healthcare interventions in the context of cancer care. This paper outlines the rationale, design considerations and potential applications of twin studies in primary care-based cancer research.

Genetic and Environmental Causes of Variation in an Automated Breast Cancer Risk Factor Based on Mammographic Textures.

BACKGROUND: Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus. METHODS: We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants. RESULTS: There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%). CONCLUSION: Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins. IMPACT: Early-life factors, shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognized as a critical window of vulnerability to breast carcinogens.

Inference on the Genetic Architecture of Breast Cancer Risk.

BACKGROUND: What are the major determinants of women's breast cancer risk? Rare mutations such as those in the BRCA1/2 genes, polygenic scores of common alleles identified by genome-wide association studies, or nongenetic factors? METHODS: The population-based Nordic Twin Study of Cancer, with 3,933 breast cancer cases among 21,054 monozygotic (MZ) and 30,939 dizygotic (DZ) female twin pairs, provides three key clues to this question: (i) the average lifetime risk, approximately 8%, does not differ by twin zygosity; (ii) the mean time interval between diagnoses when both twins develop disease (i.e., disease concordance) also does not differ by zygosity; but, (iii) conditioning on one twin having developed disease, the incidence rate in the co-twin is approximately 1% per year if the pair is MZ and 0.5% per year if DZ. RESULTS: Assuming that nongenetic risk factors are shared similarly between twins regardless of zygosity, we can draw two conclusions from (i) to (iii). CONCLUSIONS: First, (i) and (iii) imply that the chief determinant of risk is in the germline DNA, because the conditional incidence rate is several-fold higher than the average risk (8% lifetime) in MZ twins but only half as much in DZ twins. Second, the seeming inconsistency between the two-fold conditional incidence rate (iii) and the equality of the mean inter-twin disease intervals in disease concordance (ii) can be resolved if the risk factors in the germline DNA are rare variants, not common variants. IMPACT: This paper details simple deductive reasoning for these conclusions and draws a critical inference regarding breast cancer etiology. See related In the Spotlight, p. 1477.

Does lower educational attainment increase the risk of osteoarthritis surgery? a Swedish twin study.

BACKGROUND: Previous studies have reported an inverse association between educational attainment and different osteoarthritis (OA) outcomes. However, none of the previous studies have accounted for potential confounding by early-life environment and genetics. Thus, we aimed to examine the association between educational attainment and knee and hip OA surgery using twin data. METHODS: From the Swedish Twin Registry (STR), we identified dizygotic (DZ) and monozygotic (MZ) twins. All twins in the STR aged 35 to 64 years were followed from January the 1st 1987 or the date they turned 35 years until OA surgery, relocation outside Sweden, death or the end of 2016 (18,784 DZ and 8,657 MZ complete twin pairs). Associations between educational attainment and knee and hip OA surgery were estimated in models matched on twin pairs, using Weibull within-between (WB) shared frailty model. RESULTS: For knee OA surgery, the analysis matched on MZ twins yielded a within-estimate hazard ratio (HR) per 3 years of education, of 1.06 (95% CI: 0.81, 1.32), suggesting no association between the outcome and the individual´s education. Rather, there seemed to be a so called familial effect of education, with a between-pair estimate of HR = 0.71 (95% CI: 0.41, 1.01). For hip OA surgery, the within- and between-pair estimates for MZ twins were 0.92 (95% CI: 0.69, 1.14) and 1.15 (95% CI: 0.87, 1.42), respectively. CONCLUSIONS: Our results suggest that the inverse associations between education and knee/hip OA surgery observed in cohort studies are potentially confounded by unobserved familial factors like genetics and/or early life exposures.

The relative and interactive impact of multiple risk factors in schizophrenia spectrum disorders: a combined register-based and clinical twin study.

BACKGROUND: Research has yielded evidence for genetic and environmental factors influencing the risk of schizophrenia. Numerous environmental factors have been identified; however, the individual effects are small. The additive and interactive effects of multiple risk factors are not well elucidated. Twin pairs discordant for schizophrenia offer a unique opportunity to identify factors that differ between patients and unaffected co-twins, who are perfectly matched for age, sex and genetic background. METHODS: Register data were combined with clinical data for 216 twins including monozygotic (MZ) and dizygotic (DZ) proband pairs (one or both twins having a schizophrenia spectrum diagnosis) and MZ/DZ healthy control (HC) pairs. Logistic regression models were applied to predict (1) illness vulnerability (being a proband v. HC pair) and (2) illness status (being the patient v. unaffected co-twin). Risk factors included: A polygenic risk score (PRS) for schizophrenia, birth complications, birth weight, Apgar scores, paternal age, maternal smoking, season of birth, parental socioeconomic status, urbanicity, childhood trauma, estimated premorbid intelligence and cannabis. RESULTS: The PRS [odds ratio (OR) 1.6 (1.1-2.3)], childhood trauma [OR 4.5 (2.3-8.8)], and regular cannabis use [OR 8.3 (2.1-32.7)] independently predicted illness vulnerability as did an interaction between childhood trauma and cannabis use [OR 0.17 (0.03-0.9)]. Only regular cannabis use predicted having a schizophrenia spectrum diagnosis between patients and unaffected co-twins [OR 3.3 (1.1-10.4)]. CONCLUSION: The findings suggest that several risk factors contribute to increasing schizophrenia spectrum vulnerability. Moreover, cannabis, a potentially completely avoidable environmental risk factor, seems to play a substantial role in schizophrenia pathology.

Intersexual Twins due to Tetragametic Chimerism.

Disorders of or differences in sexual development (DSD) are defined by congenital conditions in which development of chromosomal, gonadal, or anatomic sex are atypical. Here, we report on monochorionic diamniotic twins delivered by caesarean section in the 36th week of pregnancy. Monochorionic twins are usually monozygous and thus should have the same sexual differentiation. In this case, one twin had female external genitalia, while the other showed ambiguous genitalia. At first, a diagnosis of mixed gonadal dysgenesis was proposed because of the obvious sexual discrepancy between the supposedly monozygous twins. Cytogenetic analyses were performed to assure the sex chromosome status for both children. Male and female cells were found subsequently in both children. While hematopoietic chimerism of monochorionic dizygous twins as a result of twin-to-twin blood transfusion is a rare but already well-documented phenomenon, to our knowledge this is the first case description of tetragametic chimerism that led to intersexuality.

An Italian Twin Study of Non-Cancer Chronic Pain as a Wide Phenotype and Its Intensity.

Background and Objectives: Non-cancer chronic pain (CP) results from the interaction between genetic and environmental factors. Twin studies help to estimate genetic and environmental contributions to complex traits such as CP. To date, twin studies on the heritability of pain phenotypes have relied almost exclusively on specific diagnoses, neglecting pain intensity. This study aims to estimate the genetic and environmental contributions to CP occurrence as a wide phenotype and its intensity among a non-clinical population. Materials and Methods: A nationwide online survey was conducted in February 2020 on 6000 adult twins enrolled in the Italian Twin Registry. A five-item questionnaire, designed and validated by our study group, was administered to detect the CP condition along with its intensity, underlying causes or triggers, treatments, and self-perceived efficacy. The twin study design was used to infer the relative weight of genes and environment on CP occurrence and intensity, and biometrical modelling was applied to these phenotypes. Results: A total of 3258 twins, aged ≥18, replied to the online survey (response rate 54%). These included 762 intact pairs (mean age: 39 years; age range: 18-82 years; 34% male; CP prevalence: 24%), of whom 750 pairs were subjected to biometrical modelling after the exclusion of pairs with either unknown zygosity or cancer-associated CP. Broad-sense heritability estimates were driven by non-additive genetic effects and were 0.36 (0.19-0.51) for CP occurrence and 0.31 (0.16-0.44) for CP intensity. No evidence emerged for either sex differences in genetic and environmental variance components or interactions of these components with age. Conclusions: Moderate non-additive genetic components were suggested for non-cancer CP occurrence and its intensity. These results encourage further research on the gene-gene interactions underlying CP liability and associated phenotypes, and also strengthen the need for prevention strategies to avoid CP occurrence or to decrease pain intensity.

Comparison of Concordance of Peptic Ulcer Disease, Non-Adenomatous Intestinal Polyp, and Gallstone Disease in Korean Monozygotic and Dizygotic Twins: A Cross-Sectional Study.

Epidemiological studies have suggested the role of multiple genetic and environmental factors in the development of non-neoplastic gastrointestinal (GI) diseases; however, little information is available on these factors in the Korean population. Therefore, this cross-sectional study explored the effect of these factors by analyzing the concordance of several benign GI disorders in 525 monozygotic twins compared to that in 122 dizygotic twins aged >20 years from the Healthy Twin Study data of the Korean Genome and Epidemiology Study (2005-2014). Chi-square test, Wilcoxon rank-sum, and binomial and multinomial logistic regression models were used for statistical analysis. There was lack of concordance of gastric/duodenal ulcers and cholelithiasis/cholangitis between monozygotic twins compared to that in dizygotic twins, suggesting that environmental factors may mediate those concordant disease expressions in monozygotic twins. The concordance of intestinal polyps in monozygotic twins was 32% lower than that in dizygotic twins (p = 0.028), indicating that the effect of genetic factors on the risk for intestinal polyp development may be low. In conclusion, the lack or low concordance of several benign GI diseases between monozygotic and dizygotic twin groups suggests the relative importance of environmental factors, indicating that these are preventable diseases.

Concordance for Gender Dysphoria in Genetic Female Monozygotic (Identical) Triplets.

The biopsychosocial etiology of gender dysphoria is poorly understood, but current thought suggests a complex interaction of genetic, hormonal, environmental, and differences in brain development and physiology. Twin studies have implicated a genetic role in the formation of gender identity. Congruence for gender dysphoria is more common among monozygotic twins compared to dizygotic twins. We present a case of monozygotic (identical) triplets who have each transitioned from female to male under the care of a university transgender health service. Each triplet experienced gender dysphoria from childhood and has undergone transitional endocrine care and various aspects of gender-affirming surgery. Although a pure genetic or biological component cannot be attributed as a cause of their gender dysphoria with absolute certainty since the triplets were raised together, this unusual case of gender dysphoria among a set of monozygotic triplets adds support for a heritable role in gender identity formation.

Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts.

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

Cancer-Related Reductions in Survival: Extent and Duration Evaluated Using a Large Cohort Study of Twins, 1943-2011.

BACKGROUND: The time during which there is an increased risk of death for cancer survivors was evaluated in a large twin study, which allows for matching on shared components such as age, genes, and socioeconomic factors in childhood. METHODS: By use of data from Danish registers, time to death from initial cancer was studied prospectively in twins in two different settings. The twins were diagnosed with at least one cancer in the period 1943 to 2011. Setting I included 5,680 same-sex twin pairs aged 6 and over, while Setting II included 3,218 twin individuals from age 70 and over. The study provides comparisons within twin pairs and across birth cohorts, age at diagnoses, and time at diagnosis. RESULTS: In 2001 to 2011, the 5-year mortality risk for a twin surviving cancer after the age of 70 was twofold that of the co-twin, regardless of sex and zygosity, and it was 1.5-fold if the twin survived the initial 9 months. After 5 to 6 years, the mortality risk corresponded to that of the co-twin. In previous decades, the excess hazard risk was considerably higher for both older and younger cohorts. There were no indications of change in relative survival across old birth cohorts. CONCLUSIONS: This large twin study suggested that for a cancer-treatment survivor diagnosed at age 70 or later, the additional mortality risk was largely absent 5 years later, by which time the survival relative to the co-twin was 60%. IMPACT: Elevated mortality risk after cancer is offset after 5 to 6 years.

Alcohol consumption at age 18-25 and number of children at a 33-year follow-up: Individual and within-pair analyses of Finnish twins.

BACKGROUND: Do drinking patterns in late adolescence/early adulthood predict lifetime childlessness and number of children? Research on this question has been only tangentially relevant and the results inconsistent. The designs used to date have been compromised by genetic and environmental confounds that are poorly controlled; covariate effects of smoking and education that are often ignored; males being understudied; population-based sampling rare, and long-term prospective studies with genetically informative designs yet to be reported. METHOD: In a 33-year follow-up, we linked the drinking patterns of >3500 Finnish twin pairs, assessed at ages 18-25, to registry data on their eventual number of children. Analyses distinguished associations of early drinking patterns with lifetime childlessness from those predictive of family size. Within-twin pair analyses used fixed-effects regression models to account for shared familial confounds and genetic liabilities. Childlessness was analyzed with Cox proportional hazards models and family size with Poisson regression. Analyses within-pairs and of twins as individuals were run before and after adjustment for smoking and education, and for oral contraceptive (OC) use in individual-level analyses of female twins. RESULTS: Baseline abstinence and heavier drinking both significantly predicted lifetime childlessness in individual-level analyses. Few abstinent women used OCs, but they were nonetheless more often eventually childless; adjusting for smoking and education did not affect this finding. Excluding childless twins, Poisson models of family size showed heavier drinking at 18-25 to be predictive of fewer children in both men and women. Those associations were replicated in within-pair analyses of dizygotic twins, each level of heavier drinking being associated with smaller families. Among monozygotic twins, associations of drinking with completed family size yielded effects of similar magnitude, reaching significance at the highest levels of consumption, ruling out familial confounds. CONCLUSIONS: Compared to moderate levels of drinking, both abstinence and heavier drinking in late adolescence/early adulthood predicted a greater likelihood of lifetime childlessness and eventual number of children. Familial confounds do not fully explain these associations.

Early life affects late-life health through determining DNA methylation across the lifespan: A twin study.

BACKGROUND: Previous findings for the genetic and environmental contributions to DNA methylation variation were for limited age ranges only. We investigated the lifespan contributions and their implications for human health for the first time. METHODS: 1,720 monozygotic twin (MZ) pairs and 1,107 dizygotic twin (DZ) pairs aged 0-92 years were included. Familial correlations (i.e., correlations between twins) for 353,681 methylation sites were estimated and modelled as a function of twin pair cohabitation history. FINDINGS: The methylome average familial correlation was around zero at birth (MZ pair: -0.01; DZ pair: -0.04), increased with the time of twins living together during childhood at rates of 0.16 (95%CI: 0.12-0.20) for MZ pairs and 0.13 (95%CI: 0.07-0.20) for DZ pairs per decade, and decreased with the time of living apart during adulthood at rates of 0.026 (95%CI: 0.019-0.033) for MZ pairs and 0.027 (95%CI: 0.011-0.043) for DZ pairs per decade. Neither the increasing nor decreasing rate differed by zygosity (both P>0.1), consistent with cohabitation environment shared by twins, rather than genetic factors, influencing the methylation familial correlation changes. Familial correlations for 6.6% (23,386/353,681) sites changed with twin pair cohabitation history. These sites were enriched for high heritability, proximal promoters, and epigenetic/genetic associations with various early-life factors and late-life health conditions. INTERPRETATION: Early life strongly influences DNA methylation variation across the lifespan, and the effects are stronger for heritable sites and sites biologically relevant to the regulation of gene expression. Early life could affect late-life health through influencing DNA methylation. FUNDING: Victorian Cancer Agency, Cancer Australia, Cure Cancer Foundation.

Genetic contribution to the etiology of Achilles tendon rupture. A Danish nationwide register study of twins.

BACKGROUND: It is unknown if genetics contribute to the etiology of acute Achilles tendon rupture (ATR). The aims of the present study were, 1) To calculate the concordance rate for monozygotic (MZ) twins and same-sex dizygotic (SSDZ) twins and 2) to estimate the heritability of ATR. METHODS: The study was performed as a registry study using the Danish Twin Registry and the Danish National Patient Registry. RESULTS: The study sample consisted of 85,534 twins born from 1895 to 1995. Of these, 572 (0.67%) were registered with ATR in the period from 1994 to 2014. The concordance rate was 8.1% (95% CI 1.4-14.7%) for MZ twins and 4.3% (95% CI 0.7-7.9%) for SSDZ twins. The heritability of ATR was 47% (95% CI 31-62%). CONCLUSION: This study found that genetics contribute substantially to the etiology of ATR with an estimated heritability of the liability to ATR of approximately 50%. The finding generates the hypothesis that genetics play a role in the pathological changes that occur in the Achilles tendon before a rupture. The risk of ATR for a twin within a 20 year period, if the co-twin has had an ATR, was 8% for MZ twins and 4% for SSDZ twins.

Twin study reveals non-heritable immune perturbations in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactions1,2. Here we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations. By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs, we estimated the variance in CD25 expression by helper T cells displaying a naive phenotype to be largely driven by genetic and shared early environmental influences. Nonetheless, the expanding helper T cells of twins with MS, which were also elevated in non-twin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25-IL-2 axis, and their proliferative capacity positively correlated with MS severity. Together, our matched-pair analysis of the extended twin approach allowed us to discern genetically and environmentally determined features of an MS-associated immune signature.

Examining the Vanishing Twin Hypothesis of Neural Tube Defects: Application of an Epigenetic Predictor for Monozygotic Twinning.

Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19). We see no difference in signature between cases and controls, providing no support for a common etiological role of MZ twinning in NTDs. The strong associations therefore continue to await elucidation.