Concordance In Monozygotic Twins Research Articles

Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission.

Schizophrenia affects approximately 1% of the world population. Genetics, epigenetics, and environmental factors are known to play a role in this psychiatric disorder. While there is a high concordance in monozygotic twins, about half of twin pairs are discordant for schizophrenia. To address the question of how and when concordance in monozygotic twins occur, we have obtained fibroblasts from two pairs of schizophrenia discordant twins (one sibling with schizophrenia while the second one is unaffected by schizophrenia) and three pairs of healthy twins (both of the siblings are healthy). We have prepared iPSC models for these 3 groups of patients with schizophrenia, unaffected co-twins, and the healthy twins. When the study started the co-twins were considered healthy and unaffected but both the co-twins were later diagnosed with a depressive disorder. The reprogrammed iPSCs were differentiated into hippocampal neurons to measure the neurophysiological abnormalities in the patients. We found that the neurons derived from the schizophrenia patients were less arborized, were hypoexcitable with immature spike features, and exhibited a significant reduction in synaptic activity with dysregulation in synapse-related genes. Interestingly, the neurons derived from the co-twin siblings who did not have schizophrenia formed another distinct group that was different from the neurons in the group of the affected twin siblings but also different from the neurons in the group of the control twins. Importantly, their synaptic activity was not affected. Our measurements that were obtained from schizophrenia patients and their monozygotic twin and compared also to control healthy twins point to hippocampal synaptic deficits as a central mechanism in schizophrenia.

Concordance factors in craniosynostosis twins: a meta-analysis and case report

Introductions: Craniosynostosis is a condition where the cranial sutures close prematurely. It is influenced by both genetics and environment. This paper focuses on craniosynostosis in twins, which is an understudied area. It presents a case report of male identical twins and conducts a meta-analysis based on 34 articles to understand the factors affecting concordance in twins who have craniosynostosis. The study considers factors such as zygosity, gender, genetic syndromes, and the type of synostosis. Material and methods: A meta-analysis was conducted on 105 twin pairs (210 patients) identified from studies carried out between 1963 to 2023. The eligible studies, based on PICO criteria, included case reports and case series focusing on twins with craniosynostosis. A systematic literature search was conducted on PUBMED and Mendeley platforms to gather data on gestational age, zygosity, genetic syndromes, affected sutures, and concordance. Results: The report is about two identical twin brothers who had sagittal and metopic suture synostosis. They were treated successfully with cranial remodeling surgery. In a meta-analysis of 105 twin pairs (210 patients) , a total of 25.9% showed concordance. The study found a significant difference in concordance between monozygotic (45.3%) and dizygotic (7.3%) twins. The analysis also revealed that twins with scaphocephaly had a higher degree of concordance than those with trigonocephaly (46.7% vs. 18.9%, respectively). The study did not find any significant correlation between gender, the presence of genetic syndromes, and concordance. Conclusion: This investigation highlights the complex interplay of genetic and environmental factors in craniosynostosis in twins. The higher concordance in monozygotic twins emphasizes the genetic basis. These findings validate existing literature and provide new insights.

Comparison of the Concordance of Cardiometabolic Diseases and Physical and Laboratory Examination Findings between Monozygotic and Dizygotic Korean Adult Twins: A Cross-Sectional Study Using KoGES HTS Data.

This study investigated the contribution of genetic and environmental factors to cardiometabolic diseases (CMDs) by comparing disease concordance in monozygotic and dizygotic twins. This cross-sectional study analyzed 1294 (1040 monozygotic and 254 dizygotic) twin pairs (>20 years) based on the Korean Genome and Epidemiology Study data (2005-2014). The odds ratios of disease concordance were calculated using binomial and multinomial logistic regression models. The occurrence of CMDs (hypertension, hyperlipidemia, type 2 diabetes, cerebral stroke, transient ischemic attack, and ischemic heart disease) and related physical and laboratory levels did not differ between the monozygotic and dizygotic twin groups. The odds for concordance of the presence/absence of CMDs and the likelihood of incident CMD within monozygotic twins were comparable to that of dizygotic twins. The absolute differences in hemoglobin A1c, insulin, low- and high-density lipoprotein cholesterol, total cholesterol, triglycerides, and systolic blood pressure were lower in monozygotic twins than in dizygotic twins. Absolute differences in fasting glucose and diastolic blood pressure did not differ between groups. Although baseline levels of several laboratory parameters related to CMD showed a strong likelihood of heritability in monozygotic twins, CMD phenotype appears to be largely affected by environmental factors.

Comparison of the Coincidence of Osteoporosis, Fracture, Arthritis Histories, and DEXA T-Score between Monozygotic and Dizygotic Twins: A Cross-Sectional Study Using KoGES HTS Data.

We explored the genetic and environmental inter-relationships among osteoporosis, fracture, arthritis, and bone mineral density concordance in monozygotic twins compared to those in dizygotic twins. This cross-sectional research assessed data of 1032 monozygotic and 242 dizygotic twin pairs aged >20 years included in the Healthy Twin Study data of the Korean Genome and Epidemiology Study between 2005 and 2014. Outcomes of interest included illness concordance and absolute differences in dual-energy X-ray absorptiometry (DEXA) T-scores. We found comparable concordances of osteoporosis, fractures, osteoarthritis, and rheumatoid arthritis between monozygotic and dizygotic twins. Medical histories of osteoporosis, fractures caused by accident or falling, osteoarthritis, and rheumatoid arthritis were not distinct between monozygotic and dizygotic twins. Accidental fracture occurrence in both monozygotic twins showed significantly lower odds than that in dizygotic twins. Genetic influence on liability to fracture risk might thus be maintained. DEXA T-scores for bone mineral density indicated more comparable tendencies within monozygotic twin pairs than within dizygotic ones, suggesting the relative importance of genetic contribution to bone mineral density. The relative importance of genetic factors in bone mineral density is sustained between monozygotic twins; overt disease expression of osteoporosis, fractures, or arthritis may be affected by environmental factors.

Молекулярні механізми патогенезу автоімунного тиреоїдиту Хашимото (огляд літератури)

The purpose of the study was to systematize and analyze material of recent studies on molecular mechanisms of pathogenesis of autoimmune Hashimoto's thyroiditis. Materials and methods. Analytical and bibliosemantic methods were used in the study. Results and discussion. Autoimmune Hashimoto's thyroiditis is a chronic inflammatory disease of the thyroid gland of autoimmune genesis in which impaired tolerance to thyroid autoantigens results in chronic progressive lymphoid infiltration followed by gradual destruction of thyroid parenchyma. The disease is more often observed at the age of 45-65 years and is multifactorial – both genetic predisposition and environmental factors contribute to its development. The ratio of female to male patients is approximately 10-20:1, and in recent years, the prevalence of autoimmune Hashimoto's thyroiditis has increased more than tenfold. On morphological examination, the section of the thyroid is diffusely enlarged, the surface of the section is pale, yellow-brown in color, dense and nodular. Microscopic examination reveals numerous large mononuclear inflammatory infiltrates in the parenchyma, consisting of small lymphocytes and plasma cells, well-formed germinal centers. A twin method is used to assess the degree of contribution of genetic and environmental factors. Studies demonstrate significantly greater concordance in monozygotic twins than in dizygotic twins, confirming the important role of genetic factors in the etiology. Among the main immune mechanisms of damage are: direct action of CD8+ cytotoxic T cells on thyrocytes by binding through the Fas-receptor – Fas ligand system; the influence of cytokines, in particular – interferon γ, produced by TH1 cells and leading to macrophage activation with subsequent damage to follicles, antibody-dependent cell-mediated cytotoxicity, in which Fc fragments of antibodies previously bound to thyroid cells are binding sites to cells that commit killing, in particular – to the natural killer cells. In terms of thyroid cell damage, cytokines produced by the lymphocytic infiltrate play a key role. These include differentiation, signal transduction, and stimulation of other cells to release proinflammatory mediators or synthesize antibodies. Their ability to stimulate the thyroid cells themselves to release inflammatory mediators should be noted, thereby enhancing and perpetuating the autoimmune process. Researchers have identified other mechanisms, and the ratio of their contribution to the overall pathological process is a matter of debate and may vary from patient to patient. One explanation may be the multifactorial nature of the disease. In particular, different genetic mutations can lead to different disorders of intracellular and intercellular signaling, but the resulting factor will be one – immune autoaggression. Conclusion. The pathogenesis of autoimmune Hashimoto's thyroiditis is complex and multifaceted, involving both humoral and cellular immunity. The disease may be provoked both by mutations in the mechanisms of immune regulation, by mutations in the thyroid cells themselves, and by environmental factors

P703 Gut bacteria composition and familiality echo Inflammatory Bowel Disease type and pathological spectrum

Abstract Background Inflammatory bowel disease (IBD) aetiology encompasses genetic and environmental factors. Twin studies provide valuable insights to the familial degree (shared genetics and environment) of observed phenotypes. We characterised the gut bacterial composition of twins with IBD to find taxa associated with disease and estimate their familiality. Methods Faecal samples were collected from 88 monozygotic (MZ) and dizygotic (DZ) twin pairs concordant or discordant for Crohn’s disease (CD; 26 MZ; 19 DZ) or ulcerative colitis (UC; 16 MZ; 27 DZ). The 16S rRNA gene was sequenced and amplicon sequence variants (ASV) generated. ANCOM software was used to assess differences in IBD vs. non-IBD, stratifying by disease type (CD/UC) and adjusting for age, gender and smoking. Twin pair and zygosity were added as random effects to estimate familiality, defined as percentage of variation due to common environment and genetics. IBD-affected twins were used for differences in disease location or treatment. Participants reporting antibiotic/probiotic treatment within the last 3 months or with a stoma/pouch were not included. In UC, surgery-naive patients were compared to an excluded subset who underwent ileostomy or pouch surgery without any recent antibiotic courses. Results Disease concordance in MZ twins was higher in CD (54%) than UC (19%). Alpha diversity was lower in CD, but not UC, and in ileostomy and pouch vs. surgery-naive UC. Principal component analysis showed that CD-affected twins clustered apart from non-IBD ones (Figure 1A). Familiality was lower in CD, with 5% of ASVs having familiality > 50%, compared to 17% in UC (Figure 1B). Two Lachnospirales order ASVs were less abundant in UC, while 15 ASVs from Clostridia, Bacteroidia, Bacilli and Coriobacteriia classes differentiated CD from non-IBD. Firmicutes were higher in CD (β= 0.95; 95%CI [0.34,1.56]), while no phyla changed in UC. Veillonella, Barnesiella, Faecalimonas and Holdemania genera had opposite trends in ileocolonic or colonic CD vs. ileal, and two Clostridia ASVs were lower in extensive and left-sided UC. Gemmiger and Butyricicoccus_A genera were reduced in UC patients taking aminosalicylates compared to untreated. No treatment differences were found in CD. Patescibacteria was higher in ileostomy and Verrucomicrobiota in pouch, while Bacteroidota and Firmicutes_A were lower in both surgeries. Conclusion Despite higher disease concordance, gut bacteria familiality in CD was lower than UC, indicating that bacterial composition is an information-rich matrix which captures the heterogeneity of IBD clinical manifestations. Accordingly, we found taxonomic changes specific to IBD presence, but also location, medication, or surgery.

T170. GENE AND ENVIRONMENT INTERPLAY AMONG DIAGNOSTIC CATEGORIES IN THE EUGEI STUDY

BackgroundThe importance of inherited factors in the development of affective psychosis, which includes bipolar disorder and major depression disorder, is widely accepted, but the fact that monozygotic twin concordance is substantially less than 100% suggests that environmental factors (ERF) are likely to play an important role as well. While the link between a variety of ERF and schizophrenia-spectrum disorder is well established, less is known about how these ERF impact in affective psychosis. In the current study we aim to analyse the role of environmental risk factors in the expression of affective disorder compared with schizophrenia-spectrum disorder, and its interaction with the genetic risk by using polygenic risk score (PRS).MethodsDNA was obtained from most participants (73.6% of 1130 cases and 78.5% of 1499 controls) among 16 European cities as part of the EUGEI case-control study. PRS for SZ, BD and MDD were built using the latest available data from the Psychiatric Genomic Consortium (PGC). Multinomial logistic regression models were used to test whether the association of genetic load (by PRSs) with different diagnostic categories based on DSMIV from OPCRIT items were greater if there was also evidence of ERF (urbanicity, migration, cannabis use and childhood trauma) through the inclusion of interaction terms between the different PRSs and the ERF. Analyses were conducted for each environmental factor separately and for a combined poly-environmental risk score based on Maudsley Environmental Score (MPES) will be calculated.ResultsBeing 1st generation migrant was not associated with any of the diagnostic categories, nor independently nor in interaction with PRSs. Living in urban environment increases the risk of SSD (RRR=1.68, 95% CI 1.06 – 2.67), but without interacting with any genetic measure. Regarding cannabis use, having ever used cannabis is independently significantly associated with SSD (RRR=2.26, 95% CI 1.69 – 3.02) and BD (RRR=5.3, 95% CI 2.69 – 10.46), showing as well in the latter group an interaction with PRS MDD (RRR=2.3, 95% CI 1.18 – 4.49). Although daily use of cannabis strongly predicted risk of SSD and BD, having use more than once a week only increased risk for SSD. Neither having used cannabis more than once a week or daily interacted with any of the PRSs. Having been exposed to any childhood trauma was independently significantly associated with all three diagnostic groups, but did not show any significant interaction with PRSs. Lastly, despite MPES increased risk for SSD and BD, it didn’t interact significantly with any PRSs.DiscussionThese results suggest that despite evidence of both PRSs on one hand and urbanicity, cannabis and childhood trauma overall increase risk of belonging to any psychotic diagnostic category separately, we only found some suggestion of potential interaction between genetic vulnerability to MDD and cannabis use associated with BD. Nonetheless, due to most of the interactions showing the expected trend, analyses examining interactions between PRSs and ERF with the different diagnostic groups with bigger samples are warranted.

Genetic Inheritance and Its Contribution to Tinnitus.

Tinnitus is the abnormal perception of sound that affects more than 15% of adult population around the globe. Severe tinnitus is considered a complex disorder that arises as result of the interaction of genetic and environmental factors, and it is associated with several comorbidities such as hearing loss, anxiety, and insomnia. We begin this review with an introduction to human molecular genetics and the role of genetic variation on the inheritance. There are some genetic reports on tinnitus heritability including concordance studies in twins and adoptees or aggregation in families providing some evidence for familial aggregation in patients with severe tinnitus and high concordance in monozygotic twins with bilateral tinnitus. So, sex differences in familial aggregation and heritability of bilateral tinnitus suggest a potential sexual dimorphism in tinnitus inheritance.Molecular genetic studies have been demonstrated to be a useful tool to understand the role of genetic variation in rare diseases and complex disorders. The reported associations in common variants in neurotrophic factors such as GDNF, BDNF, or potassium channels genes were underpowered, and the lack of replication questions these findings. Although candidate gene approaches have failed in replicating these genetic associations, the development of high throughput sequencing technology and the selection of extreme phenotypes are strategies that will allow the clinicians and researchers to combine genetic information with clinical data to implement a personalized diagnosis and therapy in patients with tinnitus.

On the Nature of Monozygotic Twin Concordance and Discordance for Autistic Trait Severity: A Quantitative Analysis

The characterizing features of autism spectrum disorder (ASD) are continuously distributed in nature; however, prior twin studies have not systematically incorporated this knowledge into estimations of concordance and discordance. We conducted a quantitative analysis of twin–twin similarity for autistic trait severity in three existing data sets involving 366 pairs of uniformly-phenotyped monozygotic (MZ) twins with and without ASD. Probandwise concordance for ASD was 96%; however, MZ trait correlations differed markedly for pairs with ASD trait burden below versus above the threshold for clinical diagnosis, with R2s on the order of 0.6 versus 0.1, respectively. Categorical MZ twin discordance for ASD diagnosis is rare and more appropriately operationalized by standardized quantification of twin–twin differences. Here we provide new evidence that although ASD itself is highly heritable, variation-in-severity of symptomatology above the diagnostic threshold is substantially influenced, in contrast, by non-shared environmental factors which may identify novel targets of early ASD amelioration.

RNA sequencing of identical twins discordant for autism reveals blood-based signatures implicating immune and transcriptional dysregulation

BackgroundA gap exists in our mechanistic understanding of how genetic and environmental risk factors converge at the molecular level to result in the emergence of autism symptoms. We compared blood-based gene expression signatures in identical twins concordant and discordant for autism spectrum condition (ASC) to differentiate genetic and environmentally driven transcription differences, and establish convergent evidence for biological mechanisms involved in ASC.MethodsGenome-wide gene expression data were generated using RNA-seq on whole blood samples taken from 16 pairs of monozygotic (MZ) twins and seven twin pair members (39 individuals in total), who had been assessed for ASC and autism traits at age 12. Differential expression (DE) analyses were performed between (a) affected and unaffected subjects (N = 36) and (b) within discordant ASC MZ twin pairs (total N = 11) to identify environmental-driven DE. Gene set enrichment and pathway testing was performed on DE gene lists. Finally, an integrative analysis using DNA methylation data aimed to identify genes with consistent evidence for altered regulation in cis.ResultsIn the discordant twin analysis, three genes showed evidence for DE at FDR < 10%: IGHG4, EVI2A and SNORD15B. In the case-control analysis, four DE genes were identified at FDR < 10% including IGHG4, PRR13P5, DEPDC1B, and ZNF501. We find enrichment for DE of genes curated in the SFARI human gene database. Pathways showing evidence of enrichment included those related to immune cell signalling and immune response, transcriptional control and cell cycle/proliferation. Integrative methylomic and transcriptomic analysis identified a number of genes showing suggestive evidence for cis dysregulation.LimitationsIdentical twins stably discordant for ASC are rare, and as such the sample size was limited and constrained to the use of peripheral blood tissue for transcriptomic and methylomic profiling. Given these primary limitations, we focused on transcript-level analysis.ConclusionsUsing a cohort of ASC discordant and concordant MZ twins, we add to the growing body of transcriptomic-based evidence for an immune-based component in the molecular aetiology of ASC. Whilst the sample size was limited, the study demonstrates the utility of the discordant MZ twin design combined with multi-omics integration for maximising the potential to identify disease-associated molecular signals.

P5540Familial clustering of spontaneous coronary artery dissection

Abstract Background There is increasing evidence that patients with spontaneous coronary artery dissection (SCAD) have an underlying genetic susceptibility (Goel et al JAMA Intern Med175:821–826, 2015). Moreover, in a collaborative study involving 1,055 SCAD cases and 7,190 controls, we recently reported the first risk allele for SCAD, a variant (rs9349379-A) in the PHACTR1/EDN1 genetic locus (Adlam et al J Amer Coll Cardiol73:58–66, 2019). Purpose We sought to determine the clinical characteristics and initial genetic data for 11 families, in which more than one member has had an episode of SCAD. Methods Participants were recruited largely via a social media platform. Informed consent was obtained in all cases for analysis of genetic information using whole genome sequencing, as well as collection of clinical information. SCAD was confirmed by review of coronary angiogram images and clinical data collected by phone interview, as well as review of specialist letters and hospital records. Results Of 235 participants recruited to date, 23 cases showed familial clustering involving sister-sister pairs in six families, three first-degree cousins in one family (picture), two first-degree cousins in two families, a mother-son pair, and a family with concordant monozygotic twins, that is both twins having had SCAD. In an additional family, SCAD is discordant in monozygotic twins. A comparison of symptoms, age at SCAD, clinical syndrome, cardiovascular risk factors, SCAD risk factors, environmental triggers, SCAD location, acute management, left ventricular function and recurrent SCAD events in these families versus isolated cases, will be presented. Three sister-sister pairs have undergone whole genome sequencing and these data sets are undergoing segregation analysis to identify rare variants that are present exclusively in affected family members. Family E Pedigree. Shaded circles represent first cousins affected with SCAD. The top number represents age (in years) of the SCAD event and the bottom number represents current age (in years). Conclusions To our knowledge, this is the largest assembly of SCAD cases with familial clustering reported to date. It provides strong evidence supporting an underlying genetic basis for SCAD, which most likely is a multi-genic disorder that also involves important gene-environment interactions.

Genetic and Early-Life Environmental Influences on Dental Caries Risk: A Twin Study.

To explore the relative contributions of genetic and environmental influences on dental caries risk and to investigate fetal and developmental risk factors for dental caries. We recruited children from 250 twin pregnancies midgestation and collected demographic, health, and phenotypic data at recruitment, 24 and 36 weeks' gestational age, birth and 18 months, and 6 years of age. 25-hydroxyvitamin D was quantified in mothers at 28 weeks' gestation and in infants at birth. Dental caries and enamel defects were measured at six years of age. We compared concordance for the presence of any caries and advanced caries in monozygotic and dizygotic twin pairs. To investigate environmental risk factors for caries, we fitted multiple logistic regression models using generalized estimating equations to adjust for twin correlation. A total of 345 twins underwent dental assessment, with 111 (32.2%) showing signs of any caries and 83 (24.1%) having advanced caries. There was no evidence of higher concordance in monozygotic twins compared with dizygotic twins, with a difference of 0.05 (95% confidence interval -0.14 to 0.25; P = .30) and 0.00 (95% confidence interval -0.26 to 0.26; P = .50) for any caries and advanced caries, respectively, suggesting that environmental factors, rather than genetics, are the predominant determinant of caries risk. After adjusting for potential confounders, lack of community water fluoridation, hypomineralized second primary molars, dichorionic placenta, and maternal obesity were associated with caries. Environmental rather than genetic factors drive dental caries risk and arise as early as prenatal life.

Etiology of Hypomineralized Second Primary Molars: A Prospective Twin Study

The etiology of hypomineralized second primary molars (HSPM) is unclear, but genetic and environmental factors have been proposed. The aim of this study was to investigate the relative contribution of genes and environment to the etiology of HSPM and to identify potential environmental risk factors in a longitudinal twin cohort. Children from twin pregnancies (N = 250) were recruited antenatally, and detailed demographic, health, and phenotypic data were collected at recruitment, 24- and 36-wk gestation, birth, and 18 mo of age. 25-Hydroxyvitamin D was quantified for mothers at 28-wk gestation and infants at birth. Dental examinations were conducted on the twins at 6 y of age to determine the presence, severity, and extent of HSPM per standardized criteria. To investigate associations of environmental risk factors with HSPM, multiple logistic regression models were fitted with generalized estimating equations to adjust for twin correlation. Within- and between-pair analyses were performed for unshared continuous variables: birthweight and birth 25-hydroxyvitamin D. Twin-twin concordance for monozygotic (MZ) and dizygotic (DZ) pairs was calculated and compared after adjusting for identified risk factors. A total of 344 twins underwent the 6-y-old dental assessment; HSPM occurred in 68 (19.8%). After adjusting for potential confounders, vitamin D levels at birth, infantile eczema, dizygosity, in vitro fertilization, socioeconomic position, and maternal smoking beyond the first trimester of pregnancy demonstrated the strongest associations with HSPM. Overall concordance for HSPM was 0.47 (95% CI, 0.32 to 0.62) with weak evidence (P = 0.078) of higher concordance in MZ twins (0.63; 95% CI, 0.38 to 0.89) as compared with DZ twins (0.41; 95% CI, 0.24 to 0.58). After adjusting for known risk factors, there was no evidence (P = 0.172) for an additive genetic influence. These findings suggest that shared and unshared environmental factors, such as maternal smoking later in pregnancy and infantile eczema, are important in the etiology of HSPM.

Twin DNA Methylation Profiling Reveals Flare-Dependent Interferon Signature and B Cell Promoter Hypermethylation in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) has limited monozygotic twin concordance, implying a role for pathogenic factors other than genetic variation, such as epigenetic changes. Using the disease-discordant twin model, we investigated genome-wide DNA methylation changes in sorted CD4+ T cells, monocytes, granulocytes, and B cells in twin pairs with at least 1 SLE-affected twin. Peripheral blood obtained from 15 SLE-affected twin pairs (6 monozygotic and 9 dizygotic) was processed using density-gradient centrifugation for the granulocyte fraction. CD4+ T cells, monocytes, and B cells were further isolated using magnetic beads. Genome-wide DNA methylation was analyzed using Infinium HumanMethylation450K BeadChips. When comparing probes from SLE-affected twins and co-twins, differential DNA methylation was considered statistically significant when the P value was less than 0.01 and biologically relevant when the median DNA methylation difference was >7%. Findings were validated by pyrosequencing and replicated in an independent case-control sample. In paired analyses of twins discordant for SLE restricted to the gene promoter and start region, we identified 55, 327, 247, and 1,628 genes with differentially methylated CpGs in CD4+ T cells, monocytes, granulocytes, and B cells, respectively. All cell types displayed marked hypomethylation in interferon-regulated genes, such as IFI44L, PARP9, and IFITM1, which was more pronounced in twins who experienced a disease flare within the past 2 years. In contrast to what was observed in the other cell types, differentially methylated CpGs in B cells were predominantly hypermethylated, and the most important upstream regulators included TNF and EP300. Hypomethylation of interferon-regulated genes occurs in all major cellular compartments in SLE-affected twins. The observed B cell promoter hypermethylation is a novel finding with potential significance in SLE pathogenesis.

Preventing Common Hereditary Disorders through Time-Separated Twinning

Biomedical advances have led to a relaxation of natural selection in the human population of developed countries. In the absence of strong purifying selection, spontaneous and frequently deleterious mutations tend to accumulate in the human genome and gradually increase the genetic load; that is, the frequency of potentially lethal genes in the gene pool. Gradual increase in incidence of many complex disorders suggests deleterious impact of the genetic load on human well-being. Recent advances in in vitro fertilization (IVF) combined with artificial twinning and transgenerational embryo cryoconservation offer the possibility of preventing significant accumulation of genetic load and reducing the incidence of hereditary disorders. Many complex diseases such as type 1 and 2 diabetes, autism, bipolar disorder, allergies, Alzheimer’s disease, and some cancers show significantly higher concordance in monozygotic (MZ) twins than in fraternal twins (dizygotic, DZ) or parent-child pairs, suggesting their etiology is strongly influenced by genetics. Preventing these diseases based on genetic data alone is frequently impossible due to the complex interplay between genetic and environmental factors. We hypothesize that the incidence of complex diseases could be significantly reduced in the future through a strategy based on time-separated twinning. This strategy involves the collection and fertilization of human oocytes followed by several rounds of artificial twinning. If preimplantation genetic screening (PGS) reports no aneuploidy or known Mendelian disorders, one of the MZ siblings would be implanted and the remaining embryos cryoconserved. Once the good health of the adult MZ sibling(s) is established, subsequent parenthood with the cryoconserved co-twins could substantially lower the incidence of hereditary disorders with complex etiology and virtually eradicate simple Mendelian disorders. The proposed method of artificial twinning has the potential to alleviate suffering and reduce the negative social impact induced by dysgenic effects associated with known and unknown genetic factors. Time-separated twinning has the capacity to prevent further accumulation of the genetic load and to provide source of isogenic embryonic stem cells for future regenerative therapies.

Heritability of Addison\u2019s disease and prevalence of associated autoimmunity in a cohort of 112,100 Swedish twins

PurposeThe pathophysiology behind autoimmune Addison’s disease (AAD) is poorly understood, and the relative influence of genetic and environmental factors remains unclear. In this study, we examined the heritability of AAD and explored disease-associated autoimmune comorbidity among Swedish twins.MethodsA population-based longitudinal cohort of 112,100 Swedish twins was used to calculate the heritability of AAD, and to explore co-occurrence of 10 organ-specific autoimmune disorders in twin pairs with AAD. Diagnoses were collected 1964–2012 through linkage to the Swedish National Patient Register. The Swedish Prescribed Drug Register was used for additional diagnostic precision. When available, biobank serum samples were used to ascertain the AAD diagnosis through identification of 21-hydroxylase autoantibodies.ResultsWe identified 29 twins with AAD. Five out of nine (5/9) monozygotic pairs and zero out of fifteen (0/15) dizygotic pairs were concordant for AAD. The probandwise concordance for monozygotic twins was 0.71 (95% CI 0.40–0.90) and the heritability 0.97 (95% CI 0.88–99). Autoimmune disease patterns of monozygotic twin pairs affected by AAD displayed a higher degree of similarity than those of dizygotic twins, with an incidence rate ratio of 15 (95% CI 1.8–116) on the number of shared autoimmune diagnoses within pairs.ConclusionsThe heritability of AAD appears to be very high, emphasizing the need for further research on the genetic etiology of the disease. Monozygotic twin concordance for multiple autoimmune manifestations suggests strong genetic influence on disease specificity in organ-specific autoimmunity.

The Promise and Practice of Genetics on Diabetes Care: The Fog Rises to Reveal a Field of Genetic Complexity in HNF1B.

Diabetes is a common disease characterized by the disruption of glucose homeostasis that results when insulin, the hormone that converts glucose from the blood into energy used by the body’s cellular machinery, is absent (through autoimmune destruction of the pancreatic β-cells in type 1 diabetes) or inefficient (increased insulin resistance or reduced insulin sensitivity in type 2 diabetes). There are multiple pathways to developing diabetes, yet practically all involve an underlying genetic etiology with an environmental trigger. The extent of knowledge of genetic factors and environmental factors differs across the forms of diabetes. In the case of type 1 diabetes, the concordance in monozygotic twins (genetically identical) is ∼50%, with familial aggregation and modeling suggesting a major impact of genetics on risk (1). The genetic contribution to type 1 diabetes is well described, with HLA genes accounting for one-half of the genetic risk (2) and ∼50 other sites in the genome contributing the majority of the remaining genetic risk (3). The familial (heritable) contribution to type 2 diabetes has also been estimated through twin studies, with monozygotic twin concordance rising from ∼50% in middle age to nearly 80% later in life (4). Complexity in assessment of the contribution of genetic factors to type 2 diabetes arises from the impact of other familial and behavioral factors that are associated with risk, including obesity, reduced physical activity, and dietary habits. Although the overall risk of type 2 diabetes appears “more heritable” than type 1 diabetes, the estimated effects of ∼100 sites across the genome account for ∼10% of the risk (5). Similar investigations have shown other types of diabetes to be heritable, including neonatal diabetes (6), maturity-onset diabetes of the young (MODY) (7), gestational diabetes mellitus (8), and latent autoimmune diabetes in adults (LADA) (9), and numerous studies have shown diabetes complications …

TWIN CORRELATIONS FOR AMYLOID PATHOLOGY MEASURED WITH POSITRON EMISSION TOMOGRAPHY AND IN CEREBROSPINAL FLUID IN COGNITIVELY HEALTHY ELDERLY MONOZYGOTIC TWIN PAIRS

Amyloid (Aß) pathology precedes Alzheimer's Disease dementia (AD) by decades. It is unclear to what extent genetic and environmental influences play a role in Aß pathology. Twin studies showed monozygotic (MZ) twin concordance for AD-dementia of around 0.8 but estimates for Aß pathology are lacking. Aß can be measured on positron emission tomography (PET) scans and in cerebrospinal fluid (CSF). This study aims to compare the genetic contribution to Aβ on PET and in CSF and to test the association between these modalities in cognitively healthy elderly MZ twins. MZ twins were selected from the EMIF-AD PreclinAD study. Inclusion criteria were age ≥60 years and delayed recall score above -1.5 SD of normative data. Dynamic [18F]flutemetamol (FMM) scans were performed on a Philips PETMRI system with specific binding (BPND) as outcome. In CSF we measured Aβ1–42, which decreases in AD as result of Aβ aggregation, and Aβ1–40, which only slightly changes in AD, using ADx Neurosciences/Euroimmun. Within twin pair correlations of Aβ pathology were calculated using Pearson's correlation, the association between Aβ on PET and in CSF was calculated using generalized estimating equations. We included 94 twin pairs and 5 individual twins (total 193 subjects), with a mean age of 70.4±7.5 years, of which 116 had CSF available (mean global PET Aβ=0.16±0.13, CSF Aβ1–42=868±298 and Aβ1–40=9476±2853 pg/mL). Twin correlations were 0.47 for global PET Aβ and 0.60 for CSF Aβ1–42, 0.82 for Aβ1–40, and 0.68 for ratio Aβ1–42/Aβ1–40, figure 1–2. We found a negative association between global Aβ on PET and Aβ1–42 in CSF (r=-0.373; p<0.001, figure 3).

Situs Inversus Totalis in Twins: A Brief Review and a Life History / Twin Research: Twin Studies of Trisomy 21; Monozygotic Twin Concordance for Bilateral Coronoid Hyperplasia; Prenatal Hormonal Effects in Mixed-Sex Non-Human Primate Litters; Insurance Mandates and Twinning After In Vitro Fertilization / News Reports: First Report of Identical Twin Puppies; Twins Sisters Turn 100; Remembering an Identical Twin

The presence of situs inversus totalis (full reversal of internal organs) in twins is briefly reviewed. Information gathered from 35-year-old monozygotic (MZ) female twin pair discordant for this condition is presented. This is followed by summaries of research on the frequency of trisomy 21 (Down syndrome) in twins, the first case of MZ twin concordance for bilateral coronoid hyperplasia, prenatal hormonal effects in mixed-sex non-human primate litters, and links between insurance mandates and twinning following in vitro fertilization. The final section of this article describes twin-related events reported in the news, namely, the first recorded birth of identical twin puppies; the 100th birthday celebration of a pair of fraternal female twins, the passing of an award-winning identical twin production designer, and the first running of the New York City Marathon by a set of quadruplets.

Environmental factors and primary biliary cirrhosis

The complex interplay between immune factors and genetic susceptibility plays an essential role in autoimmune diseases. This is especially true for primary biliary cirrhosis (PBC). PBC is an autoimmune cholestatic liver disease characterized by the destruction of the small intrahepatic bile ducts and the presence of high-titer antimitochondrial antibodies (AMA). Among the currently known risk factors, genetic predisposition remains to be the dominant one. However, it is insufficient to explain the different geographic distributions of PBC and the incomplete concordance in identical twins. This suggests an association between specific environmental factors and the development of PBC. Nevertheless, a clear and rational association of environmental factors with primary biliary cirrhosis has not yet been fully elucidated. Our current understanding of the environmental triggers of PBC is limited to numerous suspected factors involved in its development, such as xenobiotics, electrophilic drugs, infection, and other physical, chemical, and even biological factors. Although the factors leading to the breakdown of immune tolerance in PBC are still largely unknown, related geoepidemiological studies may help us better understand the impact of the environment. In addition, a better understanding of the interplay between environmental factors and PBC is the critical step toward improving our management and control of PBC and autoimmunity in general.