The Avera Twin Register (ATR) aims to study environmental and genetic influences on health and disease using a longitudinal repository of biological specimens, survey data, and health information provided by multiples and their family members. The ATR is located in Sioux Falls, South Dakota, which is a rural and frontier area in the Midwestern United States with a density of four people per square kilometer. The target area of the ATR is South Dakota and the four surrounding states: Minnesota, Iowa, North Dakota, and Nebraska. Enrollment of twins and higher-order multiples of all ages and their family members started on May 18, 2016. A description of the first 13 months of enrollment in this longitudinal register will be provided. The ATR will collect longitudinal data on lifestyle, including diet and activity levels, aging, complex traits, and diseases. Upon registration, all participants are genotyped on the Illumina Global Screening Array (GSA) and twins and higher order multiples receive information on their zygosity. The ATR aims to contribute to large international GWAS consortia and collaborates closely with the Netherlands Twin Register, allowing for the comparison of collected data and analyses of results. In addition, the ATR will address twin-specific questions.

Neuroticism, a ‘Big Five’ personality trait, has been associated with sub-clinical traits of both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The objective of the current study was to examine whether causal overlap between ASD and ADHD traits can be accounted for by genetic and environmental risk factors that are shared with neuroticism. We performed twin-based structural equation modeling using self-report data from 12 items of the Neo Five-Factor Inventory Neuroticism domain, 11 Social Responsiveness Scale items, and 12 Adult ADHD Self-Report Scale items obtained from 3,170 young adult Australian individual twins (1,081 complete pairs). Univariate analysis for neuroticism, ASD, and ADHD traits suggested that the most parsimonious models were those with additive genetic and unique environmental components, without sex limitation effects. Heritability of neuroticism, ASD, and ADHD traits, as measured by these methods, was moderate (between 40% and 45% for each respective trait). In a trivariate model, we observed moderate phenotypic (between 0.45 and 0.62), genetic (between 0.56 and 0.71), and unique environmental correlations (between 0.37and 0.55) among neuroticism, ASD, and ADHD traits, with the highest value for the shared genetic influence between neuroticism and self-reported ASD traits (r g = 0.71). Together, our results suggest that in young adults, genetic, and unique environmental risk factors indexed by neuroticism overlap with those that are shared by ASD and ADHD.

Although the correlation between cognition and physical function has been well studied in the general population, the genetic and environmental nature of the correlation has been rarely investigated. We conducted a classical twin analysis on cognitive and physical function, including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), handgrip strength, five-times-sit-to-stand test (FTSST), near visual acuity, and number of teeth lost in 379 complete twin pairs. Bivariate twin models were fitted to estimate the genetic and environmental correlation between physical and cognitive function. Bivariate analysis showed mildly positively genetic correlations between cognition and FEV1, rG = 0.23 [95% CI: 0.03, 0.62], as well as FVC, rG = 0.35 [95% CI: 0.06, 1.00]. We found that FTSST and cognition presented very high common environmental correlation, rC = -1.00 [95% CI: -1.00, -0.57], and low but significant unique environmental correlation, rE = -0.11 [95% CI: -0.22, -0.01], all in the negative direction. Meanwhile, near visual acuity and cognition also showed unique environmental correlation, rE = 0.16 [95% CI: 0.03, 0.27]. We found no significantly genetic correlation for cognition with handgrip strength, FTSST, near visual acuity, and number of teeth lost. Cognitive function was genetically related to pulmonary function. The FTSST and cognition shared almost the same common environmental factors but only part of the unique environmental factors, both with negative correlation. In contrast, near visual acuity and cognition may positively share part of the unique environmental factors.

Traditionally, it is understood that dizygotic (DZ) twins always have a dichorionic placenta. However, with 8% blood chimerism in DZ twins, placental sharing is probably more common than previously has been recognized. In this article, we will review all available cases of monochorionic dizygotic (MCDZ) twins. A total of 31 twins have been described in literature. A monochorionic diamniotic placenta is reported in all cases. Assisted reproductive technology is responsible for the origin of the pregnancy in 82.1% of the cases. In 15.4% of the sex-discordant twins, a genital anomaly was reported in one of the twins. Chimerism is demonstrable in 90.3% of the twins, leading to various diagnostic difficulties. As this review shows that most MCDZ twins are discovered by accident, it can be argued that it is far more common than has been assumed until now. However, the prevalence is still unclear. Awareness of MCDZ twinning is important, with subsequently correct medical strategies. Similarly, the resulting (blood) chimerism is essential to consider in diagnostic procedures, pre- and postnatally. More research on the effect of placental transfusion between sex-discordant twins is required.

Background: The link between asthma and exhaled nitric oxide (FENO) is not completely understood. The aim of this study was to estimate the association between FENO and asthma, taking genetics, sensitization, and inhaled corticosteroids (ICS) into account. Methods: A total of 681 twins (53% monozygotic [MZ] and 47% dizygotic [DZ]) from the population-based STOPPA study (mean age 12.6 years) were recruited and information on FENO (parts per billion), parental report of current asthma, sensitization to airborne allergens (Phadiatop; IgE ≥0.35 kUA/l), and ICS-treatment was collected. We estimated the association between FENO and asthma, sensitization, and ICS in all twins and within pairs (DZ and MZ) to address shared genetic and environmental factors. Linear regression of log-transformed FENO was used and results presented as exponentiated regression coefficients (exp[β]), with 95% confidence interval (CI). Results: We found an association between asthma and FENO in all twins, exp(β) 1.31 [1.11, 1.54]. In within-pairs analysis, the association was stronger within DZ pairs discordant for FENO, exp(β) 1.50 [1.19, 1.89], compared to MZ pairs, exp(β) 1.07 [0.84, 1.37], p = .049. There was no difference in FENO in non-sensitized children with asthma, compared to children with neither asthma nor sensitization, exp(β) 0.89 [0.77, 1.03]. However, increased FENO was associated with sensitization, exp(β) 1.48 [1.30, 1.69], and with sensitization together with asthma, exp(β) 1.98 [1.57, 2.51], in all twins and within DZ pairs discordant for FENO, but not in MZ pairs. The FENO asthma association remained in DZ pairs without regular ICS-treatment. Conclusions: The association between FENO and asthma is explained by genetics and sensitization.

In the 19th century, a series of international statistical congresses introduced common rules for the national demographic registers. This activity contributed to the genesis of statistical research. During the history of twin research, Hellin's law has played a central role because it is an approximately correct association between the rates of multiple maternities. However, it has been mathematically proven that Hellin's law cannot hold exactly. The majority of all studies of Hellin's law are based on empirical rates of multiple maternities. Such studies can never confirm the law, but only identify errors too large to be characterized as random. It is of particular interest to examine why the rates of higher multiple maternities are sometimes too high or too low when Hellin's law is used as a benchmark. However, divergences from the law are often difficult to explain and/or eliminate. Different improvements to the law have been proposed. In this article, we study the seasonality of multiple maternities. We apply Hellin's law to compare the seasonality of twin and triplet rates.

Objective: To assess the efficacy of doubling the daily dose of iron supplement in iron-deficient women with twin pregnancies. Study design: Using a prospective randomized controlled trial, iron-deficient women with twin gestations were randomized to receive a single or a double dose of daily iron from 16 weeks of gestation until 6 weeks postpartum. The primary outcome was hemoglobin at 32 weeks. Secondary outcomes included ferritin at 32 weeks, hemoglobin during pregnancy and postpartum, birth weights, preterm birth rate, gastrointestinal side effects, intravenous iron administration, and compliance with treatment. Results: Eighty-five and 87 women were randomized to receive one capsule (group A) or two capsules (group B) of 34 mg of ferrous sulfate, respectively. Mean hemoglobin (9.6 g/dL and 9.7 g/dL) and ferritin (8.6 ng/ml and 8.5 ng/ml) were similar in both groups A and B, respectively, at allocation. Hemoglobin in group B was significantly higher from 32 weeks onward, until 6 weeks postpartum. There were no significant differences in any of the secondary outcomes examined. Conclusions: In twin pregnancies complicated by iron deficiency anemia, doubling the dose of iron increases hemoglobin and ferritin without worsening gastrointestinal side effects.

The seasonality of population data has been of great interest in demographic studies. When seasonality is analyzed, the population at risk plays a central role. In a study of the monthly number of births and deaths, the population at risk is the product of the size of the population and the length of the month. Usually, the population can be assumed to be constant, and consequently, the population at risk is proportional to the length of the month. Hence, the number of cases per day has to be analyzed. If one studies the seasonal variation in twin or multiple maternities, the population at risk is the total number of monthly confinements, and the study should be based on the rates of the multiple maternities. Consequently, if one considers monthly twinning rates, the monthly number of birth data is eliminated and one obtains an unaffected seasonality measure of the twin maternities. The strength of the seasonality is measured by a chi-squared test or by the standard deviation. When seasonal models are applied, one must pay special attention to how well the model fits the data. If the goodness of fit is poor, it can erroneously result in a statement that the seasonality is slight, although the observed seasonal fluctuations are marked.

One salient characteristic of twin studies and the related behavioral genetics paradigm is the requirement of a large sample size. Countries or regions that are large in size and highly populated are at an advantage when implementing twin studies. However, given the fascinating and promising results obtained from twin studies, many researchers based in smaller countries or regions may still want to conduct twin studies in order to address local and theoretical issues. In this article, we have outlined the development of twin studies in Hong Kong, one of the Special Administrative Regions of China. The historical development and design of the two major twin studies of language and reading development implemented within Hong Kong are discussed, providing insights to researchers who also aspire to conduct twin studies in small regions.

VEGAS (versatile gene-based association study) is a popular methodological framework to perform gene-based tests based on summary statistics from single-variant analyses. The approach incorporates linkage disequilibrium information from reference panels to account for the correlation of test statistics. The gene-based test can utilize three different types of tests. In 2015, the improved framework VEGAS2, using more detailed reference panels, was published. Both versions provide user-friendly web- and offline-based tools for the analysis. However, the implementation of the popular top-percentage test is erroneous in both versions. The p values provided by VEGAS2 are deflated/anti-conservative. Based on real data examples, we demonstrate that this can increase substantially the rate of false-positive findings and can lead to inconsistencies between different test options. We also provide code that allows the user of VEGAS to compute correct p values.

In different pathophysiological conditions plasminogen activator inhibitor-1 (PAI-1) plasma concentrations are elevated. As dietary patterns are considered to influence PAI-1 concentration, we aimed to determine active PAI-1 plasma concentrations and mRNA expression in adipose tissue before and after consumption of a high-fat diet (HFD) and the impact of additive genetic effects herein in humans. For 6 weeks, 46 healthy, non-obese pairs of twins (aged 18–70) received a normal nutritionally balanced diet (ND) followed by an isocaloric HFD for 6 weeks. Active PAI-1 plasma levels and PAI-1 mRNA expression in subcutaneous adipose tissue were assessed after the ND and after 1 and 6 weeks of HFD. Active PAI-1 plasma concentrations and PAI-1 mRNA expression in adipose tissue were significantly increased after both 1 and 6 weeks of HFD when compared to concentrations determined after ND (p < .05), with increases of active PAI-1 being independent of gender, age, or changes of BMI and intrahepatic fat content, respectively. However, analysis of covariance suggests that serum insulin concentration significantly affected the increase of active PAI-1 plasma concentrations. Furthermore, the increase of active PAI-1 plasma concentrations after 6 weeks of HFD was highly heritable (47%). In contrast, changes in PAI-1 mRNA expression in fatty tissue in response to HFD showed no heritability and were independent of all tested covariates. In summary, our data suggest that even an isocaloric exchange of macronutrients — for example, a switch to a fat-rich diet — affects PAI-1 concentrations in humans and that this is highly heritable.

Fetal growth discordance is a relatively common complication of monochorionic diamniotic (MCDA) twin pregnancies and is caused by a combination of maternal and placental factors. The aim of the study was to survey placental gene expression patterns and identify genes associated with growth discordance. Clinical samples comprised eight growth-discordant MCDA twin placentas (31+3–34+4 weeks gestational age) and six growth-concordant twin placentas (31+2–37 weeks gestational age). Gene expression libraries were constructed from placental biopsy samples and analyzed by RNA-sequencing. The distribution and relative abundance of mRNA transcripts expressed in the smaller and larger placentas from growth-discordant and concordant MCDA twins was remarkably similar. However, leptin (LEP) and age-related maculopathy susceptibility 2 (ARMS2) mRNA levels were exclusively up-regulated in all of the eight smaller growth-discordant twin placentas. Quantitative real-time PCR of independent biopsy samples confirmed the levels of differential mRNA expression for both genes. Immunohistochemical analysis of tissue sections from matching twin placentas showed increased leptin expression in 5–10% of blood vessel cells of the smaller placenta and marginally higher levels of ARMS2 expression in the microvillous membrane of the smaller placenta. Based on these findings, we speculate that up-regulation of leptin and ARMS2 forms part of an important survival mechanism to compensate for placental growth discordance. Since, leptin and ARMS2 are both expressed as soluble proteins, they may have clinical potential as measurable biomarkers for predicting the onset of growth discordance in MCDA twin pregnancies.

The aim of this study was to determine the effects of intrauterine environment on the magnitude of intrapair differences in six somatic traits of monozygotic (MZ) and dizygotic (DZ) twins (1,263 pairs; 424 MZ twins and 839 DZ twins). Differences in intrauterine environments of MZ twins enforced division of the research material into four groups: (1) MZ-MC-TTTS — MZ twins from monochorionic (MC) pregnancies with twin-to-twin transfusion syndrome (TTTS), (2) MZ-MC (without TTTS)—MZ twins from MC pregnancies without TTTS, (3) MZ-DC—MZ twins from dichorionic (DC) pregnancies, and (4) DZ—DZ twins. The intrapair differences in all analyzed somatic traits, especially body weight and circumference of the chest, were the largest in the case of MZ twins from MC pregnancies with TTTS. DZ twins were the group presenting with the second largest intrapair differences in the analyzed traits. At the end of pregnancy, that is, in lunar months 9 and 10, the magnitude of intrapair differences in all traits of twins from this group was significantly greater than in MZ twins from both MC and DC pregnancies. Irrespective of the analyzed period, the least evident, statistically insignificant intrapair differences in the studied traits were documented in the case of MZ twins from MC pregnancies without TTTS and twins from DC pregnancies. These findings imply that the differentiating effect of intrauterine environment is associated with the occurrence of TTTS, rather than with chorionicity, as postulated previously.

Cryptorchidism represents one of the most common human congenital anomalies. In most cases, its etiology remains unclear and seems to be multifactorial. In the present study, a pair of monozygotic twins discordant for cryptorchidism was identified. Twin zygosity was confirmed by microsatellite genotyping. Whole exome sequencing and methylated DNA immunoprecipitation sequencing (MeDIP-Seq) of DNA extract from leucocytes were performed to, respectively, evaluate their exomes and epigenomes. No differences in exome sequencing data were found between the twins after validation. MeDIP-Seq analysis detected 5,410 differentially hypermethylated genes and 2,383 differentially hypomethylated genes. Bioinformatic analysis showed that these genes belonged to several biological processes and signaling pathways, including regulation of actin cytoskeleton, which has been previously implicated in the etiology of cryptorchidism. The findings of the present study suggest that non-genetic factors might contribute to the pathogenesis of cryptorchidism.

Findings from twin studies of musical interests and talent are reviewed as a backdrop to the lives and careers of twin jazz musicians, Peter and Will Anderson. The Anderson twins exemplify many aspects of twin research, namely their matched musical abilities, shared musical interests, and common career. This overview is followed by reviews of studies and case reports of bereavement in families who have lost a preterm multiple birth infant, the conception of conjoined twins following in vitro fertilization (IVF), depression in fathers of twins, and twin-to-twin transfusion incidence in monochorionic-diamniotic IVF twin pairs. Twins highlighted in the media include high-achieving identical female twins with nearly identical academic standing, tennis star Roger Federer's two sets of identical twin children, surgical separation of craniopagus conjoined twins, and the rare delivery of twins to a 23-year-old giant panda.

Dizygotic (DZ) co-twins born to mothers and fathers from different racial or ethnic backgrounds often resemble one parent much more than the other. As such, these pairs comprise a unique subset of twins for investigating how others’ responses to their different looks may affect their personalities and self-esteem. This article describes some of these twin pairs and some challenges of raising them, and suggests ways they may be used in research. Next, recent twin research on cystic teratomas, relations between sleep quality and body mass index, and previable membrane rupture is described. The final section concerns twins, twin studies, and related events in the media, namely: twins born to a sister surrogate, the NASA twin investigation, inspiring African-Cosmopolitan twins in fashion, and triplet Hockey Stars.

A January 2017 reunion of 10-year-old reared-apart Chinese twin girls was captured live on ABC's morning talk show Good Morning America, and rebroadcast on their evening news program Nightline. The twins’ similarities and differences, and their participation in ongoing research will be described. This story is followed by reviews of twin research concerning genetic and environmental influences on media use, twin relations across the lifespan and the breast-feeding of opposite-sex twins. Popular interest items include twins in fashion, the second twin pair born to an internationally renowned tennis star, twin primes and twin pandas.