Congenital heart disease (CHD) is one of the most common birth defects. More than 200 susceptibility loci have been identified for CHDs, yet a large part of the genetic risk factors remain unexplained. Monozygotic (MZ) twins are thought to be completely genetically identical; however, discordant phenotypes have been found in MZ twins. Recent studies have demonstrated genetic differences between MZ twins. We aimed to test whether copy number variants (CNVs) and/or genetic mutation differences play a role in the etiology of CHDs by using single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing of twin pairs discordant for CHDs. Our goal was to identify mutations present only in the affected twins, which could identify novel candidates for CHD susceptibility loci. We present a comprehensive analysis for the CNVs and genetic mutation results of the selected individuals but detected no consistent differences within the twin pairs. Our study confirms that chromosomal structure or genetic mutation differences do not seem to play a role in the MZ twins discordant for CHD.

CDKN1C and KCNQ1OT1 are imprinted genes that might be potential regulators of placental development. This study investigated placental expressions of CDKN1C and KCNQ1OT1 in monozygotic twins with and without selective intrauterine growth restriction (sIUGR). Seventeen sIUGR and fifteen normal monozygotic(MZ) twin pairs were examined. Placental mRNA expressions of CDKN1C and KCNQ1OT1 were detected by real-time fluorescent quantitative PCR. CDKN1C protein expression was detected by immunohistochemical assay and Western-blotting. In the sIUGR group, smaller fetuses had a smaller share of the placenta, and CDKN1C protein expression was significantly increased while KCNQ1OT1 mRNA expression was significantly decreased. The CDKN1C/KCNQ1OT1 mRNA ratio was lower in the larger fetus than in the smaller fetus (p < .05). In the control group, CDKN1C protein expression showed no difference between larger and smaller fetuses, while KCNQ1OT1 mRNA expression was significantly lower in the larger fetus, and the CDKN1C/KCNQ1OT1 mRNA ratio was higher in the larger fetus than in the smaller fetus (p < .05). Our findings showed that pathogenesis of sIUGR may be related to the co-effect of the up-regulated protein expression of CDKN1C and down-regulated mRNA expression of KCNQ1OT1 in the placenta.

We introduce the optimizer CSOLNP, which is a C++ implementation of the R package RSOLNP (Ghalanos & Theussl, 2012, Rsolnp: General non-linear optimization using augmented Lagrange multiplier method. R package version, 1) alongside some improvements. CSOLNP solves non-linearly constrained optimization problems using a Sequential Quadratic Programming (SQP) algorithm. CSOLNP, NPSOL (a very popular implementation of SQP method in FORTRAN (Gill et al., 1986, User's guide for NPSOL (version 4.0): A Fortran package for nonlinear programming (No. SOL-86-2). Stanford, CA: Stanford University Systems Optimization Laboratory), and SLSQP (another SQP implementation available as part of the NLOPT collection (Johnson, 2014, The NLopt nonlinear-optimization package. Retrieved from http://ab-initio.mit.edu/nlopt)) are three optimizers available in OpenMx package. These optimizers are compared in terms of runtimes, final objective values, and memory consumption. A Monte Carlo analysis of the performance of the optimizers was performed on ordinal and continuous models with five variables and one or two factors. While the relative difference between the objective values is less than 0.5%, CSOLNP is in general faster than NPSOL and SLSQP for ordinal analysis. As for continuous data, none of the optimizers performs consistently faster than the others. In terms of memory usage, we used Valgrind's heap profiler tool, called Massif, on one-factor threshold models. CSOLNP and NPSOL consume the same amount of memory, while SLSQP uses 71 MB more memory than the other two optimizers.

Background: Hall (Embryologic development and monozygotic twinning. Acta Geneticae Medicae et Gemellologiae, Vol. 45, 1996, pp. 53–57) hypothesized that chromosomal aberrations can lead to monozygotic (MZ) twinning. However, twinning and chromosomal aberrations increase prenatal mortality and could reduce the prevalence of chromosomal aberrations in live-born twins. We compared prevalence proportion ratios (PPR) of chromosomal aberrations and trisomy 21 (T21) in live-born twins versus singletons born in Denmark during 1968–2009. Methods: We linked the Danish Twin Registry and a 5% random sample of all singletons to the Danish Cytogenetic Central Register and calculated PPR adjusted for maternal age for MZ, dizygotic (DZ), and all twins versus singletons. Zygosity was based on questionnaires or genetic markers. Results: No overall difference in risk of chromosomal aberrations or T21 in twins versus singletons was found. PPR in MZ and DZ twins was 0.87 (95% CI [0.60, 1.27]) and 1.05 (95% CI [0.88, 1.27]), respectively. For T21 there was a tendency to a lower prevalence in MZ twins compared to singletons (PPR: 0.29, 95% CI [0.07, 1.14]), whereas PPR was significantly increased in DZ twins (1.62, 95% CI [1.20, 2.19]). The observed proportion of MZ twin pairs among twin pairs with aberrations (0.22, 95% CI [0.16, 0.28]) was significantly lower than the proportion expected from the Weinberg method (0.32, 95% CI [CI, 0.26, 0.39]). Conclusion: Based on databases providing complete national coverage on twins with chromosomal aberrations, we found no overall difference in risk of chromosomal aberrations or T21 in twins versus singletons. Around conception twins may have an increased risk of chromosomal aberrations, but loss of especially MZ embryos could lead to similar risk among live-born twins and singletons.

Research shows that perceived family cohesion is positively related to prosocial behavior in adolescents. In this study, we investigated heritability of prosocial behavior (PB) and perceived family cohesion (FC) among Nigerian twins attending public schools in Lagos State, Nigeria (mean age = 14.7 years, SD = 1.7 years), and explored the issue of whether children's perception of cohesive family environment moderated genetic and environmental influences on (PB). The PB scale of the Strengths and Difficulties Questionnaire and the FC scale of the Family Adaptability and Cohesion Evaluation Scale III were completed by 2,376 twins (241 monozygotic (MZ) male, 354 MZ female, 440 dizygotic (DZ) male, 553 DZ female, and 788 opposite-sex DZ twins). A general sex-limitation and the bivariate genotype by environment interaction (G×E) models were applied to the data. The general sex-limitation model showed no significant sex differences, indicating that additive genetic and non-shared environmental influences were, 38% (95% CI = 31, 46) and 62% (95% CI = 54, 69) for PB and 33% (95% CI = 24, 40) and 67% (95% CI = 60, 76) for FC in both sexes. These estimates were similar to those found in Western and Asian twin studies to date. The correlation between PB and FC was 0.36. The best-fitting bivariate G×E model indicated that FC significantly moderated non-shared environmental influence unique to PB (E×E interaction). Specifically, non-shared environmental contributions to PB were highest when FC was lowest, and decreased as the levels of FC increased. However, genetic variances in PB were stable across all levels of FC. These findings suggest that FC reduces individual differences in PB by changing non-shared environmental experiences rather than genetic factors in PB.

Background: Shared experiences within families play an important role in the initiation of cigarette use among adolescents. Behavioral genetic studies using various samples have implicated that the shared environment that twins experience is an important source of influence on whether adolescents initiate cigarette use. Whether the special twin environment, in addition to the shared environment, contributes significantly to making twin siblings more similar in cigarette initiation, and whether the influence of the special twin environment persists into adulthood, is less clear. Methods: Data for this study came from the National Longitudinal Survey of Adolescent Health. Twin, full-, and half-sibling pairs between the ages of 12 and 33 were separated into three age groups, with about 3,000 individuals in each age group. The proportion of variance in cigarette use initiation explained by genetic, shared, special twin, and unique environmental factors were examined. Results: The results of separate age-moderated univariate variance decomposition models indicate that the special twin environment does not significantly contribute to the variance in cigarette use initiation in adolescence or young adulthood. Conclusion: Factors shared by individuals in a family, but that are not specific to being a twin, are important in determining whether adolescents will initiate the use of cigarettes.

Using information from Swedish population registries, we attempt to decompose the shared environment (C) into four subcomponents: close family, family, household, and community. Among pairs differing in their genetic and geographical/household relationships, we examine three externalizing syndromes: drug abuse (DA), criminal behavior (CB), and alcohol use disorders (AUD). The best-fitting common pathway model suggested that total estimates for C were higher for DA (21% for males and 18% for females) than for AUD (16% and 14%) and CB (17% and 10%). Concerning syndrome-specific influences in males, close family effects were stronger for CB and AUD, while community effects were stronger for DA. The two C components in between community experiences and close family experiences (family and household) were estimated to almost entirely derive from the common latent factor. In females, among the four components of C, the community experiences were just slightly above zero, while the C components referred to as the household effect were almost zero. The total close family experiences were similar and most important across syndromes were also divided into common and specific components. For all syndromes, for both males and females, the effects of additive genetic factors were 2–4 times the size of the total effect of the shared environment. Applying standard methods to novel relationships, we expand our understanding of how the shared environment contributes to individual differences in three externalizing syndromes.

Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.

Family study can provide estimates of overall genetic influences on a particular trait because family relationships provide accurate measures of average genetic sharing. However, evidence of genetic contributions to skin phenotypes is limited, which may preclude genetic studies to identify genetic variants or to understand underlying molecular biology of skin traits. This study aimed to estimate genetic and environmental contributions to selected dermatologic phenotypes, that is, to melanin index, sebum secretion, and skin humidity level in a Korean twin-family cohort. We investigated more than 2,000 individuals from 486 families, including 388 monozygotic twin pairs and 82 dizygotic twin pairs. Variance component method was used to estimate genetic influences in terms of heritability. Heritability of skin melanin index, sebum secretion, and skin humidity (arm and cheek) were estimated to be 0.44 [95% CI 0.38–0.49], 0.21 [95% CI 0.16–0.26], 0.13 [95% CI 0.07–0.18], and 0.11 [95% CI 0.06–0.16] respectively, after adjusting for confounding factors. Our findings suggest that genetics play a major role on skin melanin index, but only mild roles on sebum secretion and humidity. Sebum secretion and skin humidity are controlled predominantly by environmental factors notably on shared environments among family members. We expect that our findings add insight to determinants of common dermatologic traits, and serve as a reference for biologic studies.

We aimed to assess shared genetic correlations of depressive and anxiety symptoms with concurrent and future estimated cardiovascular risk (CVR) score in Korean twins and family members. For the relationship with Adult Treatment Panel III CVR estimate in subjects aged 30–74 years (n = 1,059, baseline and follow-up after 3.2 ± 1.2 years), Center for Epidemiological Studies Depression Scale (CES-D) and state and trait anxiety inventory (SAI and TAI) were measured at baseline. A mixed linear model for CVR scores at baseline and follow-up was applied to include depressive and anxiety symptoms, twin and family effects, income, education, alcohol use, exercise, body mass index, and baseline CVR score for follow-up analysis. Higher CES-D scores were associated with higher CVR score at baseline in men, while higher TAI score was associated with higher CVR score at follow-up in women. Heritabilities were 0.245~0.326 for CVR score, 0.320 for CES-D score, 0.367 for TAI score, and 0.482 for SAI score. There were significant common genetic correlations in the relationships of CES-D, TAI, and SAI scores with CVR scores at baseline and follow-up (after adjusting for baseline CV risk score). Shared common environmental correlations were observed in the relationships of CES-D and SAI scores with CVR score at baseline; and SAI score with CVR score at follow-up. In the within-monozygotic twin analysis, there were no associations between CES-D, TAI, and SAI scores, and CVR score. In conclusion, shared genetic and environmental influences were observed in the relationship between depressive and anxiety symptoms with concurrent and future CVR estimates.

Deciphering the relative importance of genetic and environmental factors, which play a major role in the prevalence of early childhood caries (ECC), can help clinicians with planning a long-term preventive treatment. The objective of the study was to determine the prevalence and heritability of ECC among monozygotic (MZ) and dizygotic (DZ) twins in Chennai, India, in the year 2013. A cross-sectional study was designed to estimate the prevalence of ECC among twins. Zygosity classification for the survey framework was adapted from a highly accurate parental report questionnaire pertaining to the physical similarity between twins. The associated heritability index was estimated. The Decayed, Missing, Filled Surface (DMFS) Index was used as the diagnostic criterion for dental caries. The prevalence of ECC was estimated at 18.7%. The correlation coefficient between the twin pair showed significant correlation. The heritability index for ECC was estimated at 15% higher prevalence of ECC found among children in the age group 25–36 months. The heritability estimate indicated a relatively low genetic influence for early childhood caries among twins. There was no significant difference detected in the concordance rate for the MZ and DZ twins. Further research could be directed toward the prevalence of ECC among higher age group children to explore the role of genetic and environmental factors.

The purpose of the present study was to do a psychometric evaluation of the somatic and psychological health report (SPHERE) among Chinese adolescents. Our participants were 116 twins (50 females). Psychometric evaluation indicated that the reliability and validity of this scale were good. The internal consistencies and split-half reliabilities of all subscales were above 0.80. Furthermore, the item-total correlations were acceptable for all the subscales (all the values were higher than 0.20). The present findings suggest that the SPHERE can be well used to measure Chinese adolescents’ somatic and psychological health.

Acne vulgaris is a skin disease with a multifactorial and complex pathology. While several twin studies have estimated that acne has a heritability of up to 80%, the genomic elements responsible for the origin and pathology of acne are still undiscovered. Here we performed a twin-based structural equation model, using available data on acne severity for an Australian sample of 4,491 twins and their siblings aged from 10 to 24. This study extends by a factor of 3 an earlier analysis of the genetic factors of acne. Acne severity was rated by nurses on a 4-point scale (1 = absent to 4 = severe) on up to three body sites (face, back, chest) and on up to three occasions (age 12, 14, and 16). The phenotype that we analyzed was the most severe rating at any site or age. The polychoric correlation for monozygotic twins was higher (rMZ = 0.86, 95% CI [0.81, 0.90]) than for dizygotic twins (rDZ = 0.42, 95% CI [0.35, 0.47]). A model that includes additive genetic effects and unique environmental effects was the most parsimonious model to explain the genetic variance of acne severity, and the estimated heritability was 0.85 (95% CI [0.82, 0.87]). We then conducted a genome-wide analysis including an additional 271 siblings — for a total of 4,762 individuals. A genome-wide association study (GWAS) scan did not detect loci associated with the severity of acne at the threshold of 5E-08 but suggestive association was found for three SNPs: rs10515088 locus 5q13.1 (p = 3.9E-07), rs12738078 locus 1p35.5 (p = 6.7E-07), and rs117943429 locus 18q21.2 (p = 9.1E-07). The 5q13.1 locus is close to PIK3R1, a gene that has a potential regulatory effect on sebocyte differentiation.

The association between birth weight and later life outcomes is of considerable interest in life-course epidemiology. Research often relies on self-reported measures of birth weight, and its validity is consequently of importance. We assessed agreement between self-reported birth weight and official birth records for Norwegian twins born 1967–1974. The intraclass correlation between self-reported birth weight and register-based birth weight was 0.91 in our final sample of 363 twins. It could be expected that 95% of self-reported birth-weight values will deviate from official records within a maximum of +446 grams and a minimum of −478 grams — around a mean deviation of 16 grams. Self-reported birth weight had a sensitivity of 0.78–0.89 and a positive predictive value of 0.59–0.85, and an overall weighted kappa of 0.71. We further assessed agreement by conducting two linear regression models where we respectively regressed self-reported birth weight and register-based birth weight on adult body mass index, a known association. The two models were not significantly different; however, there were different levels of significance in parameter estimates that warrant some caution in using self-reported birth weight. Reliability of self-reported birth weight was also assessed, based on self-reports in another sample of twins born 1935–1960 who had reported their birth weight in two questionnaires 34 years apart. The intraclass correlation was 0.86, which indicates a high degree of reliability. In conclusion, self-reported birth weight, depending on context and age when birth weight was reported, can be cautiously used.

Genetic and environmental factors contribute to the etiology of anorexia nervosa (AN). The co-twin control design is one of the most powerful methods available to evaluate environmental factors that could contribute to differences between monozygotic (MZ) twins who are discordant for AN. Using available data from a unique and rare sample of 22 Swedish female MZ pairs discordant for AN, we compared personality, life events, comorbidity, and health factors. Twins with AN had significantly higher perfectionism scores than unaffected co-twins and reported younger ages at first diet than unaffected co-twins who had dieted. Consistent with previous literature, more twins with AN reported gastrointestinal problems than unaffected co-twins. Although not significant due to low statistical power, more unaffected co-twins reported experiencing emotional neglect than twins with AN. Early dieting may be a harbinger of the development of AN or an early symptom. Higher perfectionism may represent a risk factor, sequela, or both. Sibling perception of neglect is noteworthy given the impact of an ill child with AN on family function and wellbeing. The health and wellbeing of siblings should be addressed clinically when one child in the family suffers from AN.

An accessory navicular bone (AN) is the most common accessory ossicle in the foot. The presence of an AN bone can trigger various foot problems, such as posterior tibial tendon pathology, flattening of the medial longitudinal arch, and medial foot pain. Despite the clinical influence of presence of an AN in foot disease, the research regarding its inheritance is still insufficient. A total of 135 pairs of monozygotic (MZ) twins, 25 pairs of dizygotic (DZ) twins, and 676 singletons from families were enrolled in order to estimate genetic influences on AN. After confirmation of zygosity and family relationship with a tandem repeat marker kit and questionnaires, the presence and type of the AN was classified through bilateral feet radiographic examination. The heritability of an AN was estimated using quantitative genetic analysis based on a variance decomposition model considering various types of family relationships: father–offspring pair, mother–offspring pair, and pooled DZ twin and sibling pairs. As a result, approximately 40.96% of the participants in this study had an AN in either foot, with type II being the most common type. The heritability for the presence of any type of an AN in any foot was estimated as 0.88 (95% CI [0.82, 0.94]) after adjusting for age and sex. Specifically, type II AN showed the highest heritability of 0.82 (95% CI [0.71–0.93]). The high heritability of an AN found in this large twin and family study suggests that an AN is determined by the substantial influence of genetic factor.

Genetic and environmental influences on predictors of decline in daily functioning, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), handgrip, and five-times-sit-to-stand test (FTSST), have not been addressed in the aging Chinese population. We performed classical twin modeling on FEV1, FVC, handgrip, and FTSST in 379 twin pairs (240 MZ and 139 DZ) with median age of 50 years (40–80 years). Data were analyzed by fitting univariate and bivariate twin models to estimate the genetic and environmental influences on these measures of physical function. Heritability was moderate for FEV1, handgrip, and FTSST (55–60%) but insignificant for FVC. Only FVC showed moderate control, with shared environmental factors accounting for about 50% of the total variance. In contrast, all measures of pulmonary function and muscle strength showed modest influences from the unique environment (40–50%). Bivariate analysis showed highly positive genetic correlations between FEV1 and FVC (rG = 1.00), and moderately negative genetic correlations between FTSST and FEV1 (rG = −0.33) and FVC (rG = −0.42). FEV1 and FVC, as well as FEV1 and handgrip, displayed high common environmental correlations (rC = 1.00), and there were moderate correlations between FVC and handgrip (rC = 0.44). FEV1 and FVC showed high unique environmental correlations (rE = 0.76) and low correlations between handgrip and FEV1 (rE = 0.17), FVC (rE = 0.14), and FTSST (rE = −0.13) with positive or negative direction. We conclude that genetic factors contribute significantly to the individual differences in common indicators of daily functioning (FEV1, handgrip, and FTSST). FEV1 and FVC were genetically and environmentally correlated. Pulmonary function and FTSST may share similar sets of genes but in the negative direction. Pulmonary function and muscle strength may have a shared environmental background.

Twin research has offered evidence that monozygotic (MZ) twins are more socially close than dizygotic (DZ) twins, but has not paid much attention to the way twins compare themselves with their co-twin. The few studies in this area suggest that ‘horizontal comparisons’ (social comparison motivated by solidarity or communion with others) matter more for MZ twins than for DZ twins, at least when the co-twin is the social comparison standard. Consistent with this view, we predicted higher interest in MZ twins relative to DZ twins to select their co-twin rather than other people in general as the social comparison standard. The Social Comparison Orientation (SCO) scale, which measures the inclination to compare with others in a horizontal rather than vertical mode (comparing either upward or downward), was administered in 90 MZ pairs and 57 same-sex DZ pairs (63% female; average age 18.06 years) from the Netherlands Twin Register. MZ twin pairs showed significantly higher SCO scores than DZ twin pairs (with a large effect size) on the co-twin SCO, whereas the two groups did not differ from each other on the general SCO excluding the co-twin as social comparison standard. In MZ twin pairs, anxiety was associated with social comparison with others in general, not with their co-twin. For both scales, twin resemblance was explained by additive genetic variance. The present findings provide direct evidence that horizontal comparisons with the co-twin are of particular importance for MZ twins.

Massively parallel sequencing (MPS) technology has become increasingly available and has been widely used to screen for trisomies 21, 18, and 13 in singleton pregnancies. This study assessed the performance of MPS testing of cell-free fetal DNA (cffDNA) from maternal plasma for trisomies 21, 18, and 13 in twin pregnancies. Ninety-two women with twin pregnancies were recruited. The results were identified through karyotypes of amniocentesis or clinical examination and follow-up of the neonates. Fluorescent in-situ hybridization was used to examine the placentas postnatally in cases of false-positive results. The fetuses with autosomal trisomy 21 (n = 2) and trisomy 15 (n = 1) were successfully detected via MPS testing of cffDNA. There was one false-positive for trisomy 13 (n = 1), and fluorescence in-situ hybridization (FISH) identified confined placental mosaicism in this case. For twin pregnancies undergoing second-trimester screening for trisomy, MPS testing of cffDNA is feasible and can enhance the diagnostic spectrum of non-invasive prenatal testing, which could effectively reduce invasive prenatal diagnostic methods. In addition to screening for trisomy 21, 18, and 13 by cffDNA, MPS can detect fetal additional autosomal trisomy. False-positive results cannot completely exclude confined placental mosaicism.

We investigated the association between maternal expressed emotion and twin relationship quality, after controlling for a maternal questionnaire measure of the mother–child relationship. This was explored within a community sample of 156 mothers and their two young twin children (Mchild age = 3.69 years; SDchild age = 0.37). Mothers reported on the twin–twin relationship and the mother–child relationship via questionnaire. They were also interviewed about each child using the innovative Preschool Five Minute Speech Sample (Daley et al., 2003), which yields information about relative positive:negative maternal expressed emotion. Mothers who expressed more family-wide positive emotion and less family-wide negative emotion also reported more positivity, but not negativity, within the twin relationship — even when controlling for questionnaire reports of the mother–child relationship. Counter to expectations, discrepancies in mothers’ expressed emotion between their twins also predicted more positive sibling relationships. Our findings corroborate the well established spill-over effect, whereby families are viewed as emotional units of interdependent individuals, none of whom can be understood in isolation from one another. Most importantly, the Preschool Five Minute Speech Sample provides information about mothering that questionnaire reports may not, and thus it is a useful tool in better understanding the twin family system.