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PURPOSE: Autosomal recessive bestrophinopathy (ARB) is a disease that results from the mutations in the BEST1 gene. It is characterized by multifocal yellowish lipofuscin deposits, cystoid macular edema, and subretinal fluid. Among approximately 270 BEST1 mutations, only 40 that include both heterozygous and homozygous mutations are associated with ARB. However, very few ARB-related mutations have been reported in the Japanese population. Therefore, in this study, we aimed to identify BEST1 mutations and describe the genotype–phenotype relationship in Japanese dizygotic twins presenting with ARB. MATERIALS AND METHODS: We performed clinical examinations in Japanese dizygotic twin patients (male: 29 years) with ARB as well as whole-exome sequencing in seven family members of these twins. RESULTS: In this study, we have reported on a novel BEST1 mutation, the p. Phe151Cys mutation, associated with ARB in Japanese dizygotic twins who had bi-allelic p. Ala160Pro mutations in BEST1. The clinical features observed were binocular abnormalities of the fundus, such as multifocal yellowish subretinal deposits, cystoid macular edema, and subretinal fluid. The full-field electroretinography results were subnormal. CONCLUSION: It was indicated that the novel BEST1 mutations identified may be strongly correlated with binocular ARB. This study provides significant information of the genotype–phenotype association in Japanese ARB patients. Further, the genetic analysis that we performed was very useful for the differential diagnosis and might have implications in the development of future treatment modalities.

Background Although alterations in posture, flexibility, and motion control of the lumbar spine are associated with low back pain, the underlying interplay between genetic and environmental influences on these traits remains unclear. The aim of this study is to investigate the extent to which genetics and the environment influence lumbar lordosis, flexibility, and motion control. Design The present cross-sectional and observational study employed the classic twin design with structural equation models. Methods An inertial measurement unit with a wireless movement analysis system, the ViMove (DorsaVi, Melbourne, Australia) was used to measure lumbar lordosis, flexibility, and motion control during range of motion and functional tests. Intraclass correlation was used to determine twin resemblance for the traits. Heritability (genetic influence on trait variation) of lumbar lordosis, flexibility and motion control was estimated from 52 healthy twins, 34 monozygotic and 18 dizygotic using age and sex adjusted univariate genetic models. Results A strong heritability estimate was found in lumbar lordosis (77%, 95% confidence interval [CI]: 38%–91%) in standing, followed by lumbar flexibility (67%, 95% CI: 32%–85%) in the sagittal plane. No significant intraclass correlations were found in monozygotic twin pairs for lumbar motion control or in dizygotic twin pairs during the hurdle step and in-line lunge test. Conclusion Genetic factors appear to have a substantial influence on lumbar lordosis and lumbar sagittal flexibility. Lumbar motion control may be more influenced by environmental factors.

Animal cell chimerism denotes the presence of two or more cell lines of different genetic origin. The most common form of chimerism, which occurs spontaneously in mammals, is the presence of two or more cell populations in animals derived from dizygotic twin or multiple pregnancies. The aim of this review is to present extensive information on XX/XY chimerism in cattle, sheep and goats from the Bovidae family. Additionally, it will discuss a methodology for a quick and accurate diagnosis of cell chimerism and make an analysis of cells obtained from gonads of animals derived from twin pregnancies which underwent an exchange of hematopoietic tissue as a result of anastomoses. The studies reviewed here led the authors to conclude that XX/XY chimerism is generally undesirable in livestock breeding. Females (freemartins) are infertile, whereas in male carriers of chimerism, the impact of this abnormality on sperm parameters is still under discussion, therefore every case of different-sex twin or multiple births should be analyzed individually.

Objectives This study was designed to examine the association between loss-of-function mutations in the filaggrin gene (FLG) and atopic dermatitis (AD) and asthma in adult twins. Methods A previously well-characterized cohort of 575 adult twins were genotyped for the loss-of-function mutations in FLG (R501X, 2282del4 and R2447X) most common among northern Europeans. Subjects were examined for symptoms of atopic diseases as well as for lung function, airway responsiveness, and atopy. Results In the whole population of twins, the risk for AD was significantly increased in individuals with FLG mutations in comparison with wild-type carriers (34.3% vs. 21.8%) after adjustment for possible confounders (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.07–3.41; P = 0.028). A significant association was also observed for persistent AD (OR 2.10, 95% CI 1.02–4.36; P = 0.046). There were no significant differences in risk for asthma by FLG mutation status in individuals with and without AD, respectively (P-value for interaction, 0.595). In 11 dizygotic twin pairs discordant for FLG mutation status, risk for AD was higher in the twin carrying the FLG mutation (five of 11 [45.5%] twins had developed AD) than in the non-carrier co-twin (two of 11 [18.2%] twins had developed AD) (OR 2.50, 95% CI 0.45–13.85; P = 0.293). FLG status did not explain a significant proportion of the variation in AD (P = 0.328) or asthma (P = 0.321). Conclusions Filaggrin gene mutations are risk factors for the presence and persistence of AD and explain the discordance of AD within dizygotic twin pairs.

Whole genome sequencing of a severely affected dizygotic twin with an autism spectrum disorder and intellectual disability revealed a compound heterozygous mutation in the HTR7 gene as the only variation not detected in control databases. Each parent carries one allele of the mutation, which is not present in an unaffected stepsister. The HTR7 gene encodes the 5-HT7 serotonin receptor that is involved in brain development, synaptic transmission, and plasticity. The paternally inherited p.W60C variant is situated at an evolutionary conserved nucleotide and predicted damaging by Polyphen2. A mutation akin to the maternally inherited pV286I mutation has been reported to significantly affect the binding characteristics of the receptor. Therefore, the observed sequence alterations provide a first suggestive link between a genetic abnormality in the HTR7 gene and a neurodevelopmental disorder. © 2016 Wiley Periodicals, Inc.

Background and Aims: An adaptive immunological response to microbial antigens has been observed in Crohn’s disease (CD). Intriguingly, this serological response precedes the diagnosis in some patients and has also been observed in healthy relatives. We aimed to determine whether genetic factors are implicated in this response in a CD twin cohort. Methods: In total, 82 twin pairs (Leuven n = 13, Maastricht n = 8, Orebro n = 61) took part: 81 pairs with CD (concordant monozygotic n = 16, discordant monozygotic n = 22, concordant dizygotic n = 3, discordant dizygotic n = 40) and 1 monozygotic pair with both CD and ulcerative colitis. Serology for Pseudomonas fluorescens -related protein (anti-I2), Escherichia coli outer membrane porin C (anti-OmpC), CBir1flagellin (anti-CBir1) and antibodies to oligomannan (anti- Saccharomyces cerevisiae antibody [ASCA]) was determined by standardized enzyme-linked immunoassay. Results: All markers were more often present in CD twins than in their healthy twin siblings. Using the intraclass correlation coefficient (ICC), agreements in concentrations of anti-OmpC and anti-I2 were observed in discordant monozygotic but not in discordant dizygotic twin pairs with CD (anti-OmpC, ICC 0.80 and −0.02, respectively) and (anti-I2, ICC 0.56 and 0.05, respectively). In contrast, no agreements were found in anti-CBir, immunoglobulin (Ig) G ASCA and ASCA IgA. Conclusions: We show that anti-I2 and anti-CBir1 statuses have specificity for CD and confirm previous reported specificities for anti-OmpC and ASCA. Based on quantitative analyses and observed ICCs, genetics seems to predispose to the anti-OmpC and anti-I2 response but less to ASCA and anti-CBir1 responses.

Aims To investigate the association in males between cognitive ability in late adolescence and subsequent substance misuse-related events, and to study the underlying genetic and environmental correlations. Design A population-based longitudinal study with three different family-based designs. Cox proportional hazards models were conducted to investigate the association at the individual level. Bivariate quantitative genetic modelling in (1) full brothers and maternal half-brothers, (2) full brothers reared together and apart and (3) monozygotic and dizygotic twin brothers was used to estimate genetic and environmental correlations. Setting Register-based study in Sweden. Participants The full sample included 1 402 333 Swedish men born 1958-91 and conscripted at mean age 18.2 [standard deviation (SD) = 0.5] years. A total of 1 361 066 men who had no substance misuse events before cognitive assessment at mandatory military conscription were included in the Cox regression models, with a follow-up time of up to 35.6 years. Measures Cognitive ability was assessed at conscription with the Swedish Enlistment Battery. Substance misuse events included alcohol- and drug-related court convictions, medical treatments and deaths, available from governmental registries. Findings Lower cognitive ability in late adolescence predicted an increased risk for substance misuse events [hazard ratio (HR) for a 1-stanine unit decrease in cognitive ability: 1.29, 95% confidence interval (CI) = 1.29-1.30]. The association was somewhat attenuated within clusters of full brothers (HR = 1.21, 95% CI = 1.20-1.23). Quantitative genetic analyses indicated that the association was due primarily to genetic influences; the genetic correlations ranged between -0.39 (95% CI = -0.45, -0.34) and -0.52 (95% CI -0.55, -0.48) in the three different designs. Conclusions Shared genetic influences appear to underlie the association between low cognitive ability and subsequent risk for substance misuse events among Swedish men.

Prader-Willi syndrome (PWS) is a neurobehavioral imprinting disorder, which arises due to an absence of paternally expressed genes within the 15q11.2-q13 region. This occurs via one of the three main genetic mechanisms, as follows: Deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. Recent studies have reported an association between imprinting disorders and assisted reproductive technologies (ART). The current study presents a 6-year-old female patient who is a dizygotic twin, in which one was born with de novo microdeletion at 15q11.2-q13.1 following in vitro fertilization. The patient had characteristic facial features including narrow bifrontal diameter, strabismus, downturned mouth, feeding problems and generalized hypotonia during infancy, developmental delay, mental retardation and rapid weight gain. Based upon phenotypic resemblance and the medical records, methylation-specific multiplex ligation-dependent probe amplification and array-based comparative genome hybridization analyses demonstrate type 2 microdeletion between breaking point 2 (BP2) and BP3, which occur from MKRN3 through HERC2 at 15q11.2-q13.1. To the best of our knowledge, the present study is the first to report a PWS case born following ART reported in South Korea. In addition to previous studies, the present study contributes to the consensus regarding genotype-phenotype comparisons in this respect.

Hippocampal volume deficits have been linked to life stress. However, the degree to which genes and environment influence the association between hippocampal volume and life events is largely unknown. In total, 123 healthy twins from monozygotic and dizygotic twin pairs underwent magnetic resonance imaging (MRI), and 57 healthy twins were interviewed with the Life Events and Difficulties Schedule (LEDS), with an overlap of 54 twins undergoing both MRI and the life events interview. Hippocampal volumes were segmented with Freesurfer software. Data were analyzed with OpenMx software. Smaller hippocampal volume was associated with higher severe life event load (rph = -0.39), where shared environmental factors influencing both measures fully explained the association. Hippocampal volume was not associated with total or mild life event load. Hippocampal volume showed high heritability (range, h(2) : 57%-81%) whereas life event measures were influenced by shared (c(2) ) and unique (e(2) ) environmental factors only (range, c(2) :40%-64%, e(2) : 36%-60%). The results suggested that shared environmental factors influenced the relationship between smaller hippocampal volume and severe (but not mild) stress. This indicated that particularly severe life events that were shared between twins were associated with smaller hippocampal volume. Furthermore, it is suggested to distinguish between mild and severe life events in life event research. © 2016 Wiley Periodicals, Inc.

Background Monochorionic twins are generally considered as a monozygotic twin pregnancy. However, several cases of monochorial dizygotic twin pregnancies have been reported. Case Report: We report on a rare case of monochorionic dizygotic twin pregnancy conceived after induced ovulation in a 32-year-old woman. The diagnosis was made on morphological ultrasound examination at 18+4 weeks of gestation, showing two fetuses with discordant sex. The amniocentesis was declined by the patient. Results The monochorionic status was confirmed after a histopathalogical study of the placenta. At delivery, both a phenotypically normal boy and a phenotypically normal girl without sexual abnormality were observed. This analysis also revealed the presence of vascular anastomoses between both fetal circulations. Postnatal cytogenetic analyses indicated the presence of a chimerism in peripheral blood lymphocytes. This chimerism was not observed in cells obtained from a buccal swab. Molecular determination of zygosity confirmed the existence of the confined peripheral blood chimerism with the presence of four parental alleles. Conclusion We report on a case of monochorionic dizygotic twin pregnancy. This observation underlies the need to carefully assess twin pregnancies, especially when obtained after assisted reproductive technology. Birth Defects Research (Part A) 106:298–303, 2016. © 2016 Wiley Periodicals, Inc.

Two 21-year old dizygotic twin men of Iraqi descent were homozygous for HBB codon 8, deletion of two nucleotides (-AA) frame-shift β(0) -thalassaemia mutation (FSC8; HBB:c25_26delAA). Both were clinically well, had splenomegaly, and were never transfused. They had mild microcytic anaemia (Hb 120-130 g/l) and 98% of their haemoglobin was fetal haemoglobin (HbF). Both were carriers of Hph α-thalassaemia mutation. On the three major HbF quantitative trait loci (QTL), the twins were homozygous for G>A HBG2 Xmn1 site at single nucleotide polymorphism (SNP) rs7482144, homozygous for 3-bp deletion HBS1L-MYB intergenic polymorphism (HMIP) at rs66650371, and heterozygous for the A>C BCL11A intron 2 polymorphism at rs766432. These findings were compared with those found in 22 other FSC8 homozygote patients: four presented with thalassaemia intermedia phenotype, and 18 were transfusion dependent. The inheritance of homozygosity for HMIP 3-bp deletion at rs66650371 and heterozygosity for Hph α-thalassaemia mutation was found in the twins and not found in any of the other 22 patients. Further studies are needed to uncover likely additional genetic variants that could contribute to the exceptionally high HbF levels and mild phenotype in these twins.

Objective We examined the association between the genetic and environmental factors contributing to the liability to having ever engaged in self-induced vomiting (SIV initiation) and the genetic and environmental factors contributing to regular SIV behaviors (weekly or daily) for weight control. Method SIV was assessed in 3,942 women from monozygotic twin pairs and 2,790 women from same-sex dizygotic twin pairs, aged 20–47, from the Swedish Twin study of Adults: Genes and Environment. A causal-contingent-common pathway model assessed the extent to which genetic and environmental factors that influence initiation of SIV also influence regular SIV behaviors. Results In the best-fit model, genetic and individual-specific environmental factors influenced liability to SIV initiation. The genetic factors influencing regular SIV behaviors were the same as the genetic factors influencing SIV initiation. Additional individual-specific environmental factors that were unrelated to SIV initiation influenced regular SIV behaviors. Discussion Our findings provide evidence that the underlying liabilities for SIV initiation and regular SIV lie on the same continuum given the degree of overlap in risk between SIV initiation and regular SIV behaviors. Further, the lack of specific genetic factors and the importance of individual-specific environmental factors for regular SIV behaviors highlight the significance of environmental factors in the etiology of eating disorder symptomatology and the non-deterministic nature of genetic factors. Finally, our results suggest that when it comes to preventing individuals from developing regular SIV behavior, intervening at an environmental level is warranted. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:421–427)

A congenital coronary artery fistula (CAF) is a rare form of heart disease in which a coronary artery and a cardiac chamber or another vascular structure communicate. CAF could worsen ventricular perfusion and function, favoring ventricular ischemia and arrhythmias. To our knowledge, this is the first report of CAF, draining in the pulmonary artery, in two asymptomatic dizygotic twin brothers, diagnosed by echocardiography. Dizygotic twins are siblings with different genes exposed to the same environmental experience during the pregnancy. The occurrence of CAF (with similar instrumental findings) in both twin brothers could depend on a poorly identified environmental factor during pregnancy.

In this review, we discuss how samples comprising monozygotic and dizygotic twin pairs can be used for the purpose of strengthening causal inference by controlling for shared influences on exposure and outcome. We begin by briefly introducing how twin data can be used to inform the biometric decomposition of population variance into genetic, shared environmental, and nonshared environmental influences. We then discuss how extensions to this model can be used to explore whether associations between exposure and outcome survive correction for shared etiology (common causes). We review several analytical approaches that can be applied to twin data for this purpose. These include multivariate structural equation models, cotwin control methods, direction of causation models (cross-sectional and longitudinal), and extended family designs used to assess intergenerational associations. We conclude by highlighting some of the limitations and considerations that researchers should be aware of when using twin data for the purposes of interrogating causal hypotheses.

Twin studies provide strong evidence that genetic factors have a major role in the etiology of autism spectrum disorder (ASD) but in most patients the underlying genetic cause of the disease is unknown. Here we used whole-exome sequencing to study genome-wide differences in twins with autism in order to reveal the genetic changes responsible for the etiology of autism. DNA was isolated from peripheral blood samples from six monozygotic twins and one dizygotic twin and analyzed by OneSeq protocol, on an Illumina NextSeq platform. Bioinformatics analyses have revealed 110 disease-related genes, and after further filtering, we have identified 44 single nucleotide polymorphisms (SNPs). Functional network analysis has identified significant associations for 6 different genes, including known ASD candidate genes: FMN2, KCNQ2, NOTCH3, TMRC6A, SHANK3, and SLC6A4. Our results provide an independent evidence for known ASD genes and highlight other genes, which will further improve the understanding of the genetic basis of ASD.

Twin-family designs estimate genetic and environmental influences underlying individual differences in observed traits. The children-of-twins design recognizes human monozygotic (MZ) twins share 100% of their segregating genes, making co-twins the “genetic parents” of their nieces/nephews, as well as their aunts/uncles. Human dizygotic (DZ) twins, who share 50% of their segregating genes on average, retain conventional aunt/uncle-niece/nephew relationships. Twin-family methods can assess hypotheses informed by evolutionary reasoning. Hypothesis 1, derived from inclusive fitness theory, was that MZ twin aunts/uncles should express greater social closeness toward nieces/nephews (co-twin's children) than DZ twin aunts/uncles. This hypothesis was confirmed in prior multivariate analyses from a twin-family project. The present analysis, using a larger sample (n = 482twins), and multivariate analyses and structural equation modeling, extended this finding. Multivariate analyses supported hypothesis 2, derived from the concept of paternity uncertainty, that twins with twin sisters should indicate greater social closeness toward nieces/nephews than twins with twin brothers. Structural equation modeling showed that the relationship between zygosity and closeness (a second-order factor containing perceived closeness and current closeness) is mediated by perceived similarity; factors of perceived closeness, current closeness and perceived similarity were generated by factor analysis. Examining evolutionary-psychological hypotheses via behavioral-genetic methodology is encouraged.

Background The direction of the association between inflammation and depressive symptoms remains inconsistent. The objective of this study was to evaluate the temporal relationship between inflammation and depressive symptoms, and to assess the role of genetic factors on this association. Methods In this longitudinal cross-lagged twin difference study, we examined 166 (83 pairs) middle-aged male twins recruited from the Vietnam Era Twin Registry, who were assessed at baseline and after 7 years of follow-up. We assayed plasma levels of two inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (CRP) and measured depressive symptoms using the Beck Depression Inventory-II (BDI). To evaluate the direction of the association, we constructed multivariable mixed-effects regression models and calculated standardized beta-coefficients to compare the strength of the within-pair association for both pathways. We then conducted a stratified analysis by zygosity and assessed the associations in monozygotic and dizygotic twin pairs separately. Results The 166 twins were 95% white and had a mean (SD) age of 54 (3) years at baseline. The cross-lagged analysis showed significant and positive associations from visit 1 IL-6 to visit 2 BDI across all models (beta-coefficients ranging from 0.18 to 0.22). However, the opposite pathway (visit 1 BDI to visit 2 IL-6) was not significant after adjusting for confounding factors. In contrast, visit 1 BDI was significantly associated with visit 2 CRP in all models (beta-coefficients ranging from 0.23 to 0.33), while the opposite pathway (visit 1 CRP to visit 2 BDI) showed no significant association. When stratifying by zygosity, significant associations from IL-6 to depression were only seen in monozygotic twins, but associations from depression to CRP were more robust in dizygotic twins, which implies that genetic factors may play a role in this association. Conclusions The association between inflammation and depression may be bidirectional. Elevated IL-6 levels are more likely to be a risk factor of depression rather than a consequence, while the opposite may be true for elevated CRP. The biological underpinnings of these bidirectional pathways need further evaluation.

The incidence of type 1 diabetes (T1D) and some other complex diseases is increasing. The cause has been attributed to an undefined changing environment. We examine the role of the environment (or any changing non-genetic mechanism) in causing the rising incidence, and find much evidence against it: 1) Dizygotic twin T1D concordance is the same as siblings of patients in general; 2) If the environment is responsible for both the discordance among identical twins of patients with T1D and its rising incidence, the twin concordance rate should be rising, but it is not; 3) Migrants from high- to low-incidence countries continue to have high-incidence children; 4) TID incidence among the offspring of two T1D parents is identical to the monozygotic twin rate. On the other hand, genetic association studies of T1D have revealed strong susceptibility in the major histocompatibility complex and many optional additive genes of small effect throughout the human genome increasing T1D risk. We have, from an analysis of previously published family studies, developed a stochastic epigenetic Mendelian oligogenic (SEMO) model consistent with published observations. The model posits a few required recessive causal genes with incomplete penetrance explaining virtually all of the puzzling features of T1D, including its rising incidence and the specific low T1D incidence rates among first-degree relatives of patients. Since historic selection against any causal gene could prevent T1D, we postulate that the rising incidence is because of increasing population mixing of parents from some previously isolated populations that had selected against different causal genes.

Background: The genetic architecture of birth size may differ geographically and over time. We examined differences in the genetic and environmental contributions to birth weight, length, and ponderal index (PI) across geographic-cultural regions (Europe, North-America and Australia, and East-Asia) and across birth cohorts and how gestational age modifies these effects.Methods: Data from 26 twin cohorts in 16 countries including 57613 monozygotic and dizygotic twin pairs were pooled. Genetic and environmental variations of birth size were estimated using genetic structural equation modeling.Results: The variance of birth weight and length was predominantly explained by shared environmental factors, whereas the variance of PI was explained both by shared and unique environmental factors. Genetic variance contributing to birth size was small. Adjusting for gestational age decreased the proportions of shared environmental variance and increased the propositions of unique environmental variance. Genetic variance was similar in the geographic-cultural regions, but shared environmental variance was smaller in East-Asia than in Europe and North-America and Australia. The total variance and shared environmental variance of birth length and PI were greater from the birth cohort 1990-1999 onwards compared with the birth cohorts from 1970-1979 to 1980-1989.Conclusion: The contribution of genetic factors to birth size is smaller than that of shared environmental factors, which is partly explained by gestational age. Shared environmental variances of birth length and PI were greater in the latest birth cohorts and differed also across geographic-cultural regions. Shared environmental factors are important when explaining differences in the variation of birth size globally and over time.

Personality is a central high-level psychological concept that defines individual human beings and has been associated with a variety of real-world outcomes (e.g., mental health and academic performance). Using 2 h, high resolution, functional magnetic resonance imaging (fMRI) resting state data of 984 (primary dataset N = 801, hold-out dataset N = 183) participants from the Human Connectome Project (HCP), we investigated the relationship between personality (five-factor model, FFM) and intrinsic whole-brain functional connectome. We found a pattern of functional brain connectivity (“global personality network”) related to personality traits. Consistent with the heritability of personality traits, the connectivity strength of this global personality network is also heritable (more similar between monozygotic twin pairs compared to the dizygotic twin pairs). Validated by both the repeated family-based 10-fold cross-validation and hold-out dataset, our intersubject network similarity analysis allowed us to identify participants' pairs with similar personality profiles. Across all the identified pairs of participants, we found a positive correlation between the network similarity and personality similarity, supporting our “similar brain, similar personality” hypothesis. Furthermore, the global personality network can be used to predict the individual subject's responses in the personality questionnaire on an item level. In sum, based on individual brain connectivity pattern, we could predict different facets of personality, and this prediction is not based on localized regions, but rather relies on the individual connectivity pattern in large-scale brain networks.

Previous genome-wide association studies on anthropometric measurements have identified more than 100 related loci, but only a small portion of heritability in obesity was explained. Here we present a bivariate twin study to look for the genetic variants associated with body mass index and waist-hip ratio, and to explore the obesity-related pathways in Northern Han Chinese. Cholesky decomposition model for 242 monozygotic and 140 dizygotic twin pairs indicated a moderate genetic correlation (r = 0.53, 95%CI: 0.42–0.64) between body mass index and waist-hip ratio. Bivariate genome-wide association analysis in 139 dizygotic twin pairs identified 26 associated SNPs with p < 10−5. Further gene-based analysis found 291 nominally associated genes (P < 0.05), including F12, HCRTR1, PHOSPHO1, DOCK2, DOCK6, DGKB, GLP1R, TRHR, MMP1, GPR55, CCK, and OR2AK2, as well as 6 enriched gene-sets with FDR < 0.05. Expression quantitative trait loci analysis identified rs2242044 as a significant cis-eQTL in both the normal adipose-subcutaneous (P = 1.7 × 10−9) and adipose-visceral (P = 4.4 × 10−15) tissue. These findings may provide an important entry point to unravel genetic pleiotropy in obesity traits.

It is well established that boys are born heavier and longer than girls, but it remains unclear whether birth size in twins is affected by the sex of their co-twin. We conducted an individual-based pooled analysis of 21 twin cohorts in 15 countries derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), including 67,850 dizygotic twin individuals. Linear regression analyses showed that boys having a co-twin sister were, on average, 31 g (95%Cl 18 to 45) heavier and 0.16 cm (95%CI 0.045 to 0.274) longer than those with a co-twin brother. In girls, birth size was not associated (5 g birth weight; 95%Cl -8 to -18 and -0.089 cm birth length; 95% CI -0.202 to 0.025) with the sex of the co-twin. Gestational age was slightly shorter in boy-boy pairs than in boy-girl and girl-girl pairs. When birth size was standardized by gestational age, the magnitude of the associations was attenuated in boys, particularly for birth weight. In conclusion, boys with a co-twin sister are heavier and longer at birth than those with a co-twin brother. However, these differences are modest and partly explained by a longer gestation in the presence of a co-twin sister. This study was conducted within the CODATwins project (Academy of Finland #266592). The Australian Twin Registry is supported by a Centre of Research Excellence (grant ID 1079102) from the National Health and Medical Research Council administered by the University of Melbourne. The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K.E. Whitfield. The CATSS-Study is supported by the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Swedish Heart-Lung Foundation and the Swedish Asthma and Allergy Association's Research Foundation. Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R J Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J Kaprio). Gemini was supported by a grant from Cancer Research UK (C1418/A7974). Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Longitudinal Israeli Study of Twins was funded by the Starting Grant no. 240994 from the European Research Council (ERC) to Ariel Knafo. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and 11-SPG-2518 from the MSU Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD, or the National Institutes of Health. PETS was supported by grants from the Australian National Health and Medical Research Council (grant numbers 437015 and 607358 to JC, and RS), the Bonnie Babes Foundation (grant number BBF20704 to JMC), the Financial Markets Foundation for Children (grant no. 032-2007 to JMC), and by the Victorian Government's Operational Infrastructure Support Program. The Quebec Newborn Twin Study acknowledges financial support from the Fonds Quebecois de la Recherche sur la Societe et la Culture, the Fonds de la Recherche en Sante du Quebec, the Social Science and Humanities Research Council of Canada, the National Health Research Development Program, the Canadian Institutes for Health Research, Sainte-Justine Hospital's Research Center, and the Canada Research Chair Program (Michel Boivin). The Twins Early Development Study (TEDS) is supported by a program grant (G0901245) from the UK Medical Research Council and the work on obesity in TEDS is supported in part by a grant from the UK Biotechnology and Biological Sciences Research Council (31/D19086). Currently TEDS is supported by MRC grant 'MR/M021475/1'. The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant number 15H05105) from the Japan Society for the Promotion of Science. Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; VU University's Institute for Health and Care Research (EMGO+); the European Research Council (ERC - 230374), the Avera Institute, Sioux Falls, South Dakota (USA).

Early detection of karyotype abnormalities, including aneuploidy, could aid producers in identifying animals which, for example, would\ud not be suitable candidate parents. Genome-wide genetic marker data in the form of single nucleotide polymorphisms (SNPs) are now\ud being routinely generated on animals. The objective of the present study was to describe the statistics that could be generated from the\ud allele intensity values from such SNP data to diagnose karyotype abnormalities; of particular interest was whether detection of\ud aneuploidy was possible with both commonly used genotyping platforms in agricultural species, namely the Applied BiosystemsTM\ud AxiomTM and the Illumina platform. The hypothesis was tested using a case study of a set of dizygotic X-chromosome monosomy 53,X\ud sheep twins. Genome-wide SNP data were available from the Illumina platform (11 082 autosomal and 191 X-chromosome SNPs) on\ud 1848 male and 8954 female sheep and available from the AxiomTM platform (11 128 autosomal and 68 X-chromosome SNPs) on\ud 383 female sheep. Genotype allele intensity values, either as their original raw values or transformed to logarithm intensity ratio (LRR),\ud were used to accurately diagnose two dizygotic (i.e. fraternal) twin 53,X sheep, both of which received their single X chromosome from\ud their sire. This is the first reported case of 53,X dizygotic twins in any species. Relative to the X-chromosome SNP genotype mean allele\ud intensity values of normal females, the mean allele intensity value of SNP genotypes on the X chromosome of the two females\ud monosomic for the X chromosome was 7.45 to 12.4 standard deviations less, and were easily detectable using either the AxiomTM or\ud Illumina genotype platform; the next lowest mean allele intensity value of a female was 4.71 or 3.3 standard deviations less than the\ud population mean depending on the platform used. Both 53,X females could also be detected based on the genotype LRR although this\ud was more easily detectable when comparing the mean LRR of the X chromosome of each female to the mean LRR of their respective\ud autosomes. On autopsy, the ovaries of the two sheep were small for their age and evidence of prior ovulation was not appreciated. In\ud both sheep, the density of primordial follicles in the ovarian cortex was lower than normally found in ovine ovaries and primary follicle\ud development was not observed. Mammary gland development was very limited. Results substantiate previous studies in other species\ud that aneuploidy can be readily detected using SNP genotype allele intensity values generally already available, and the approach\ud proposed in the present study was agnostic to genotype platform.

Background Smoking has been reported to be associated with peripheral blood DNA methylation, but the causal aspects of the association have rarely been investigated. We aimed to investigate the association and underlying causation between smoking and blood methylation. Methods The methylation profile of DNA from the peripheral blood, collected as dried blood spots stored on Guthrie cards, was measured for 479 Australian women including 66 monozygotic twin pairs, 66 dizygotic twin pairs, and 215 sisters of twins from 130 twin families using the Infinium HumanMethylation450K BeadChip array. Linear regression was used to estimate associations between methylation at ~ 410,000 cytosine-guanine dinucleotides (CpGs) and smoking status. A regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess putative causation. Results At a 5% false discovery rate, 39 CpGs located at 27 loci, including previously reported AHRR, F2RL3, 2q37.1 and 6p21.33, were found to be differentially methylated across never, former and current smokers. For all 39 CpG sites, current smokers had the lowest methylation level. Our study provides the first replication for two previously reported CpG sites, cg06226150 (SLC2A4RG) and cg21733098 (12q24.32). From the ICE FALCON analysis with smoking status as the predictor and methylation score as the outcome, a woman’s methylation score was associated with her co-twin’s smoking status, and the association attenuated towards the null conditioning on her own smoking status, consistent with smoking status causing changes in methylation. To the contrary, using methylation score as the predictor and smoking status as the outcome, a woman’s smoking status was not associated with her co-twin’s methylation score, consistent with changes in methylation not causing smoking status. Conclusions For middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with smoking. Our study suggests that smoking has a causal effect on peripheral blood DNA methylation, but not vice versa. Electronic supplementary material The online version of this article (10.1186/s13148-018-0452-9) contains supplementary material, which is available to authorized users.

Growth and differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-secreted factors with a leading role in the control of ovarian function in female reproduction, modulating both the cell fate of the somatic granulosa cells and the quality and developmental competence of the egg. This short review aims to consolidate the molecular aspects of GDF9 and BMP15 and their integral actions in female fertility to understand particularly their effects on oocyte quality and fetal growth. The significant consequences of mutations in the GDF9 and BMP15 genes in women with dizygotic twins as well as the clinical relevance of these oocyte factors in the pathogenesis of primary ovarian insufficiency and polycystic ovary syndrome are also addressed.

Here we aimed to identify cortical endophenotypes for anxiety-depression. Our data-driven approach used vertex-wise genetic correlations (estimated from a twin sample: 157 monozygotic and 194 dizygotic twin pairs) to parcellate cortical thickness (CT) and surface area (SA) into genetically homogeneous regions (Chen et al., 2013). In an overlapping twin and sibling sample (n= 834; aged 15–29, 66% female), in those with anxiety-depression Somatic and Psychological Health Report (SPHERE) scores (Hickie et al., 2001) above median, we found a reduction of SA in an occipito-temporal cluster, which comprised part of the right lingual, fusiform and parahippocampal gyrii. A similar reduction was observed in the Human Connectome Project (HCP) sample (n= 890, age 22–37, 56.5% female) in those with Adult Self Report (ASR) DSM-oriented scores (Achenbach et al., 2005) in the 25–95% quantiles. Apost hocvertex-wise analysis identified the right lingual and, to a lesser extent the fusiform gyrus. Overall, the surface reduction explained by the anxiety-depression scores was modest (r= −0.10, 3rd order spline, andr= −0.040, 1st order spline in the HCP). The discordant results in the top 5% of the anxiety-depression scores may be explained by differences in recruitment between the studies. However, we could not conclude whether this cortical region was an endophenotype for anxiety-depression as the genetic correlations did not reach significance, which we attribute to the modest effect size (post hocstatistical power

Background: There is evidence that birth size is positively associated with height in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. Aim: To analyze the associations of birth weight, length and ponderal index with height from infancy through adulthood within mono- and dizygotic twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. Methods: This study is based on the data from 28 twin cohorts in 17 countries. The pooled data included 41,852 complete twin pairs (55% monozygotic and 45% same-sex dizygotic) with information on birth weight and a total of 112,409 paired height measurements at ages ranging from 1 to 69 years. Birth length was available for 19,881 complete twin pairs, with a total of 72,692 paired height measurements. The association between birth size and later height was analyzed at both the individual and within-pair level by linear regression analyses. Results: Within twin pairs, regression coefficients showed that a 1-kg increase in birth weight and a 1-cm increase in birth length were associated with 1.14-4.25 cm and 0.18-0.90 cm taller height, respectively. The magnitude of the associations was generally greater within dizygotic than within monozygotic twin pairs, and this difference between zygosities was more pronounced for birth length. Conclusion: Both genetic and individual-specific environmental factors play a role in the association between birth size and later height from infancy to adulthood, with a larger role for genetics in the association with birth length than with birth weight. This work was supported by the Academy of Finland (grant number #266592). The Australian Twin Registry is supported by a Centre of Research Excellence (grant ID 1079102) from the National Health and Medical Research Council administered by the University of Melbourne. The Boston University Twin Project is funded by grants (#R01 HD068435 #R01 MH062375) from the National Institutes of Health to K. Saudino. The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. The CATSS-Study is supported by the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Swedish Heart-Lung Foundation and the Swedish Asthma and Allergy Association's Research Foundation. Colorado Twin Registry is funded by NIDA funded center grant DA011015, & Longitudinal Twin Study HD10333; Author Huibregtse is supported by 5T32DA017637 and 5T32AG052371. Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R J Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), Centre of Excellence in Research on Mitochondria, Metabolism and Disease (FinMIT, grant 272376), the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J Kaprio and grant 266286 and 314383 to K Pietilainen), the Finnish Diabetes Research Foundation, Novo Nordisk Foundation, Helsinki University Central Hospital and University of Helsinki. K Silventoinen is supported by Osaka University's International Joint Research Promotion Program. Gemini was supported by a grant from Cancer Research UK (C1418/A7974). Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220-E00006). Longitudinal Israeli Study of Twins was funded by the Starting Grant no. 240994 from the European Research Council (ERC) to Ariel Knafo. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and 11-SPG-2518 from the MSU Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD, or the National Institutes of Health. PETS was supported by grants from the Australian National Health and Medical Research Council (grant numbers 437015 and 607358 to JC, and RS), the Bonnie Babes Foundation (grant number BBF20704 to JMC), the Financial Markets Foundation for Children (grant no. r 032-2007 to JMC), and by the Victorian Governments Operational Infrastructure Support Program. The Quebec Newborn Twin Study acknowledges financial support from the Fonds Quebecois de la Recherche sur la Societe et la Culture, the Fonds de la Recherche en Sante du Quebec, the Social Science and Humanities Research Council of Canada, the National Health Research Development Program, the Canadian Institutes for Health Research, Sainte-Justine Hospital's Research Center, and the Canada Research Chair Program (Michel Boivin). The Twins Early Development Study (TEDS) is supported by a program grant (MR/M021475/1) from the UK Medical Research Council and the work on obesity in TEDS is supported in part by a grant from the UK Biotechnology and Biological Sciences Research Council (31/D19086). The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant number 15H05105) from the Japan Society for the Promotion of Science. Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; VU University's Institute for Health and Care Research (EMGO +); the European Research Council (ERC - 230374), the Avera Institute, Sioux Falls, South Dakota (USA).

Summary Background & aims While environmental factors are presumed to be primary drivers of food timing, preliminary evidence suggests that genetics may be an additional determinant. The aim was to explore the relative contribution of genetics and environmental factors to variation in the timing of food intake in a Spanish twin population. Because chronotype, bedtime and wake time are related to food timing, covariance with food timing was further assessed. Methods In this observational study, 53 pairs of adult (mean (SD) = 52 (6.03) years) female twins (28 monozygotic; 25 dizygotic) were recruited from the Murcia Twin Register. Zygosity was determined by DNA-testing. Timing of the three main meals of the day was assessed via 7-day dietary records, and the midpoint of food intake was computed by calculating the midpoint between breakfast and dinner times. Chronotype, bedtime and wake time were self-reported. Heritability of food timing and related traits were estimated by comparing monozygotic and dizygotic twin correlations and fitting genetic structural equation models to measured variables. Results We observed genetic influences for food timing, with highest heritability for the midpoint of food intake (64%) in an overweight/obese population (BMI = 26.01 ± 3.77). Genetic factors contributed to a higher degree to the timing of breakfast (56%) than the timing of lunch (38%) or dinner (n.s.). Similarly, heritability estimates were larger in related behavioral traits earlier on in the day (i.e. wake time, (55%)), than those later on in the day (i.e. bedtime, (38%)). Bivariate analyses revealed a significant genetic overlap between food timing and bedtime and chronotype (rG between 0.78 and 0.91). Conclusions Genetic influences appear to account for a significant proportion of the variability in food timing, particularly breakfast. Thus, interventions related to food timing may be more effective when targeting afternoon/evening traits, such as lunch or dinner times. Furthermore, our data suggest shared genetic architecture underlying food timing and phenotypically related traits. Clinical trial NCT03059576 . https://clinicaltrials.gov/ct2/show/NCT03059576 .

Objective: The genetic and environmental influences on prefrontal function in childhood are underinvestigated due to the difficulty of measuring prefrontal function in young subjects, for which near‐infrared spectroscopy (NIRS) is a suitable functional neuroimaging technique that facilitates the easy and noninvasive measurement of blood oxygenation in the superficial cerebral cortices., Method: Using a two‐channel NIRS arrangement, we measured changes in bilateral prefrontal blood oxygenation during a category version of the verbal fluency task (VFT) in 27 monozygotic twin pairs and 12 same‐sex dizygotic twin pairs ages 5–17 years. We also assessed the participant's full‐scale intelligence quotient (FIQ) and retrieved parental socioeconomic status (SES). Classical structured equation modeling was used to estimate the heritability., Results: The heritability of VFT‐related brain activation was estimated to be 44% and 37% in the right and left prefrontal regions, respectively. We also identified a significant genetic contribution (74%) to FIQ, but did not to VFT task performance. Parental SES was not correlated with FIQ, task performance, or task‐related prefrontal activation., Conclusions: This finding provides further evidence that variance in prefrontal function has a genetic component since childhood and highlights brain function, as measured by NIRS, as a promising candidate for endophenotyping neurodevelopmental disorders.

Objective To evaluate the incidence and characteristics of unusual twinning by using single nucleotide polymorphism (SNP) array to identify twin zygosity. Methods This study reviewed 386 twin pairs who were seen for prenatal or postnatal diagnosis and underwent SNP array to detect zygosity. Results The incidence of monozygotic (MZ) twins was 11.36% (25/220) in the assisted reproductive technology (ART)-conceived group. Monochorionic dizygotic twins represented 3 of 24 monochorionic ART-conceived twin pairs (3/24, 12.50%) but none in the spontaneous twin pairs. Among 4 single-embryo transfer twin pairs, 3 represented unusual twinning, including 2 MZ twin pairs with discordant karyotypes and 1 dizygotic twin pair of the same gender. Of the pregnancies with 2 or more embryos transferred, 7.77% (15/193) were MZ. Additionally, there was a dichorionic monozygotic twin pair with placental vascular anastomoses from a day-5 blastocyst transfer. Conclusion Single nucleotide polymorphism array can provide zygosity diagnosis in addition to chromosomal copy number variation and uniparental disomy detection. ART twin pregnancies have a risk of unusual twinning, such as monochorionic dizygotic, single-embryo transfer twin pairs with discordant karyotypes or dizygotic, and dichorionic monozygotic with vascular anastomoses from day-5 transfer.

The heritability of coronary atherosclerotic plaque burden, coronary geometry, and phenotypes associated with increased cardiometabolic risk are largely unknown. The primary aim of the Burden of Atherosclerotic Plaques Study in Twins-Genetic Loci and the Burden of Atherosclerotic Lesions (BUDAPEST-GLOBAL) study is to evaluate the influence of genetic and environmental factors on the burden of coronary artery disease. By design this is a prospective, single-center, classical twin study. In total, 202 twins (61 monozygotic pairs, 40 dizygotic same-sex pairs) were enrolled from the Hungarian Twin Registry database. All twins underwent non-contrast-enhanced computed tomography (CT) for the detection and quantification of coronary artery calcium and for the measurement of epicardial fat volumes. In addition, a single non-contrast-enhanced image slice was acquired at the level of L3-L4 to assess abdominal fat distribution. Coronary CT angiography was used for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. For the primary analysis, we will assess the presence and volume of atherosclerotic plaques. Furthermore, the 3-dimensional coronary geometry will be assessed based on the coronary CT angiography datasets. Additional phenotypic analyses will include per-patient epicardial and abdominal fat quantity measurements. Measurements obtained from monozygotic and dizygotic twin pairs will be compared to evaluate the genetic or environmental effects of the given phenotype. The BUDAPEST-GLOBAL study provides a unique framework to shed some light on the genetic and environmental influences of cardiometabolic disorders.

Prior behavioral genetic studies in positive psychology were entirely based on data from Western democracies, leaving the question open whether the magnitude of genetic effects on well-being indicators is similar in substantially different societal contexts. The aim of this study, therefore, was to investigate the structure of the genetic and environmental influences on happiness, life satisfaction, meaning in life, optimism, sense of coherence, and general well-being in a non-Western sample. Altogether, 100 monozygotic and 36 same-sex dizygotic twin pairs from Hungary (73 % female; Mage = 43 years, SD = 16 years) participated in the survey. Univariate classical twin modeling (ACE analysis) was performed using structural equation models. Heritability estimates of the positive psychological variables were largely variable, ranging from 0 % (happiness and meaning in life) to 67 % (life satisfaction). Also, estimates for the influence of common environment fell between 0 % (life satisfaction, sense of coherence, and well-being) and 60 % (meaning in life). Unshared environmental influences however, explained a moderate variance of all investigated variables (33–62 %). Most results were in line with previous findings from Western countries; however, some notable differences—e.g., lower hereditary influence for happiness or more robust role of shared environmental effects for optimism—were also established. These findings suggest that the communist and post-communist legacy did not produce drastic differences in the structure of heritability and environmental influences as compared to countries with longer traditions of democracy and economic prosperity.

To quantify heredity's effects on the burden of illness in the Medicare population, this study linked information between participants in a research twin registry to a comprehensive set of Medicare claims. To calculate disease categories, the authors used the Centers for Medicare & Medicaid Services Hierarchical Conditions Categories (HCC) model that was developed to risk adjust Medicare's capitation payments to private health care plans based on the health expenditure risk of their enrollees. Using the Medicare database, 2 sets of unrelated but demographically matched control pairs (MCPs) were generated, one specific for the monozygotic twin population and the second specific for the dizygotic twin population. The concordance and correlation rates of the 70 HCC categories for the 2 twin populations, in comparison to their corresponding MCP, was then calculated using Medicare claims data from 1991 through 2011. When indicated, HCCs for which there was a statistically significant difference between the twin and corresponding MCP control group were analyzed by calculating concordance and correlation rates of the International Classification of Diseases, Ninth Revision codes that compose the HCC. Findings reveal that monozygotic twins share 6.5% more HCC disease categories than their MCP while dizygotic twins share 3.8% more HCC disease categories than their MCP. Atrial fibrillation is a highly heritable disease category, a finding consistent with prior literature describing the heritability of the cardiac arrhythmias. These findings are consistent with qualitative assessments of heredity's role found in previous models of population health, and provide both novel methods and quantitative evidence to support future model development.

This study examined the genetic and environmental effects on variances in weight, height, and body mass index (BMI) under 18 years in a population-based sample from China. We selected 6,644 monozygotic and 5,969 dizygotic twin pairs from the Chinese National Twin Registry (CNTR) aged under 18 years (n = 12,613). Classic twin analyses with sex limitation were used to estimate the genetic and environmental components of weight, height, and BMI in six age groups. Sex-limitation of genetic and shared environmental effects was observed, especially when puberty begins. Heritability for weight, height, and BMI was low at 0–2 years old (less than 20% for both sexes) but increased over time, accounting for half or more of the variance in the 15–17 year age group for boys. For girls, heritabilities for weight, height and BMI was maintained at approximately 30% after puberty. Common environmental effects on all body measures were high for girls (59–87%) and presented a small peak during puberty. Genetics appear to play an increasingly important role in explaining the variation in weight, height, and BMI from early childhood to late adolescence, particularly in boys. Common environmental factors exert their strongest and most independent influence specifically in the pre-adolescent period and more significantly in girls. These findings emphasize the need to target family and social environmental interventions in early childhood years, especially for females. Further studies about puberty-related genes and social environment are needed to clarify the mechanism of sex differences.

The incidence of twinning in avian species is a phenomenon that has been rarely encoun- tered. A number of domestic species have been shown to produce twins but in very low numbers. In wild populations, only 14 species have been documented producing twin embryos or nestlings. Despite this, it has been postulated that birds are just as likely as any other vertebrate to produce twin offspring. Here we describe the discovery of dizygotic twins in a long-term study of breeding ecology in the White-throated Sparrow (Zonotrichia albicollis). The twin containing egg was 12% heavier than the mean and had a mass greater than 94% of eggs collected. The twin containing egg was wider and longer than the majority of other eggs collected during 2010 but still within the expected range for White-throated Sparrows. Genetic analysis demon- strated that the twin embryos were full siblings but of different morph and sex. This is the first documented case of twinning in our study site out of over 2000 samples over 25 years of study, and likely the first confirmed case of twinning in this species. Received 30 June 2014. Accepted 27 March 2015.

The determination of potential sibship is a common task in routine kinship analysis, but often the putative parents are not available for analysis anymore. Then, a sibling analysis has to be conducted investigating only the potential siblings, thus reducing the power of the conclusion. In an attempt to determine meaningfulness of biostatistical calculations, 346 dizygotic twin pairs, 30 confirmed half siblings, and 112 unrelated people (to generate 6216 pair comparisons) were studied, all genetically typed using at least the Powerplex® 16 STRs. From every pair, the probabilities for a full sibship (identical parents) and half sibship (different fathers) were calculated using a commercially available computer program. Additionally, we simulated marker data for one million pairs of full sibs, half sibs, and unrelated persons each. Ninety-five percent of full sibling pairs demonstrated a likelihood ratio (LR) 9 (W-value 90 %) and less than 4% of these showed a LR 3 (W-value 75%) for full sibship after analysis of 15 STRs. The results for half siblings are less unambiguous. Here, only 57% achieved a LR 9 and 23% a LR 3. Regarding the unrelated pairs, more than 90% had a LR 1/9 and only 2% reached a LR 9. All in all, our results show that 15 to 20 STRs have sufficient power for analyses in kinship. Moreover, our data provide a statistical basis for the determination of the information content of a LR/W-value in a sibship case. Investigating an identical number of full siblings and unrelated pairs, it could be shown that 92% of pairs with a LR 9 for full sibship probability really are full siblings. So, setting a cutoff level for full sibship at LR 9, less than 10% of pairs will be wrongly assumed as full siblings even though they are unrelated.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder characterized by intractable seizures in neonates and infants. The seizures cannot be controlled with antiepileptic medications but respond both clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). PDE is caused by mutations in the ALDH7A1 gene. Molecular genetic analysis of the ALDH7A1 gene was performed in seven patients, referred with clinical diagnosis of PDE. Mutations were detected in a dizygotic twin pair and a non-related boy with classical form of PDE. Direct sequencing of the ALDH7A1 gene revealed one novel (c.297delG, p.Trp99*) and two already reported (c.328C>T, p.Arg110*; c.584A>G, p.Asn195Ser) mutations. Here, we report the first genetically proven cases of PDE in Bulgaria.

Abstract. Although self-reports are often distorted by response biases, nearly all knowledge about interests rely on self-reports. This multiple-rater twin study investigated the degree to which interest self-reports reflect substance. Specifically, we examined whether genetic variance in interest self-reports reflect substance in terms of genetically based motivational attributes or artifact in terms of genetically influenced self-rater biases. We compared normative and ipsatized self- and peer reports on interests from 844 individuals (incl. 225 monozygotic and 113 dizygotic twin pairs) regarding psychometric qualities and further regarding the estimates of genetic and environmental components in self-other agreement and self-rater specificity. Ipsatized interest scores showed lower internal consistency but higher consensus and self-other agreement. Self-other agreement showed a large genetic component, whereas variance specific to self-reports was not significantly attributable to genetic influences. The results provide strong support that genetic variance in interest self-reports reflect substance rather than artifact.

We tested a hypothesis that there is no genetic correlation between general factors of intelligence and personality, despite both having been selected for in human evolution. This was done using twin samples from Australia, the United States, the Netherlands, Great Britain, and Croatia, comprising altogether 1,748 monozygotic and 1,329 same-sex dizygotic twin pairs. Although parameters in the model-fitting differed among the twin samples, the genetic correlation between the two general factors could be set to zero, with a better fit if the U.S. sample was excepted.

Se presenta el caso de una paciente de 4 años de edad, con hermano gemelo dicigoto asintomático, hija de padres no consanguíneos y sin antecedentes familiares de enfermedad renal. Inicia su cuadro clínico con edemas y proteinuria severa como manifestación de un síndrome nefrótico primario de cambios mínimos; este se diagnosticó por biopsia renal y, en un principio, se manejó con esteroides. Su evolución no fue adecuada debido a múltiples recaídas que la clasificaron como síndrome nefrótico corticorresistente. Por ello, se requirió un cambio en su tratamiento y una segunda biopsia renal, cuyo resultado histológico sorprendió al grupo médico tratante porque los cambios en la membrana basal glomerular confirmaban que se trataba de un Síndrome de Alport. We present the case of a 4 year-old girl patient, with an asymptomatic dizygotic twin brother, child of non-consanguineous parents and with no family history of renal disease. Her clinical picture started with edema and severe proteinuria as manifestations of a minimal change nephrotic syndrome that was diagnosed by renal biopsy and initially treated with steroids. Her clinical course was complicated by multiple relapses that classified her as a patient presenting a steroid-resistant nephrotic syndrome, her treatment was changed and a second renal biopsy was needed. Histology outcome of biopsy surprised the treating medical group because changes in glomerular basal membrane revealed that it was in fact an Alport syndrome.

Preterm birth (PTB), defined as birth prior to a gestational age (GA) of 37 completed weeks, affects more than 10% of births worldwide. PTB is the leading cause of neonatal mortality and is associated with a broad spectrum of lifelong morbidity in survivors. The etiology of spontaneous PTB (SPTB) is complex and has an important genetic component. Previous studies have compared monozygotic and dizygotic twin mothers and their families to estimate the heritability of SPTB, but these approaches cannot separate the relative contributions of the maternal and the fetal genomes to GA or SPTB. Using the Utah Population Database, we assessed the heritability of GA in more than 2 million post-1945 Utah births, the largest familial GA dataset ever assembled. We estimated a narrow-sense heritability of 13.3% for GA and a broad-sense heritability of 24.5%. A maternal effect (which includes the effect of the maternal genome) accounts for 15.2% of the variance of GA, and the remaining 60.3% is contributed by individual environmental effects. Given the relatively low heritability of GA and SPTB in the general population, multiplex SPTB pedigrees are likely to provide more power for gene detection than will samples of unrelated individuals. Furthermore, nongenetic factors provide important targets for therapeutic intervention.

BACKGROUND: Course of alcohol use disorders (AUD) during midlife is understudied, and most research designs are unable to attribute an unambiguous environmental explanation to observed findings. OBJECTIVES & METHODS: Test whether socio-contextual factors are linked to differences in the course of problem drinking during midlife. Participants were 163 monozygotic and dizygotic twin pairs concordant for a history of AUD but discordant on problem drinking in the past 10 years. RESULTS: Frequency of drinking with spouse, and peer and emotional problems were associated with discordance. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Socio-contextual factors are linked to differences in course of problem drinking in midlife and are not confounded by genetic effects. (Am J Addict 2015;XX:XX-XX). Language: en

Context: The interindividual variability in thyroid hormone function parameters is much larger than the intraindividual variability, suggesting an individual set point for these parameters. There is evidence to suggest that environmental factors are more important than genetic factors in the determination of this individual set point. Objective: This study aimed to quantify the effect of genetic factors and (fetal) environment on the early postnatal blood T4 concentration. Methods: This was a classical twin study comparing the resemblance of neonatal screening blood T4 concentrations in 1264 mono- and 2566 dizygotic twin pairs retrieved from the populationbased Netherlands Twin Register. Maximum-likelihood estimates of variance explained by genetic and environmental influences were obtained by structural equation modeling in data from fullterm and preterm twin pairs. Results: In full-term infants, genetic factors explained 40%/31% of the variance in standardized T4 scores in boys/girls, and shared environment, 27%/22%. The remaining variance of 33%/47% was due to environmental factors not shared by twins. For preterm infants, genetic factors explained 34%/0% of the variance in boys/girls, shared environment 31%/57%, and unique environment 35%/43%. In very preterm twins, no significant contribution of genetic factors was observed. Conclusion: Environment explains a large proportion of the resemblance of the postnatal blood T4 concentration in twin pairs. Because we analyzed neonatal screening results, the fetal environment is the most likely candidate for these environmental influences. Genetic influences on the T4 set point diminished with declining gestational age, especially in girls. This may be due to major environmental influences such as immaturity and nonthyroidal illness in very preterm infants.

Objective: The purpose of the present study was to explore the heritability of psychoanalyst Karen Horney’s three core neurotic trends (i.e., compliance, aggression, and detachment) in a twin paradigm to evaluate the validity of her theoretically assumed origins of neuroses. Method: Data were collected from 168 adult participants (M age = 21.54 years; range = 18 - 25 years) including 60 monozygotic twin pairs (10 male pairs and 50 female pairs) and 24 dizygotic twin pairs (4 male pairs and 20 female pairs). Participants completed the 57-item Horney-Coolidge Tridimensional Inventory (HCTI). Results: The best fitting model for compliance and detachment included additive genetic and nonshared environmental influences. For aggression, phenotypic variance was completely traced back to shared and nonshared environmental influences. Conclusions: The results are discussed in light of Horney’s hypotheses for the genesis of neurotic trends as well as findings from behavioral genetic research.

The microbiome influences humans in many still underappreciated respects, including but not limited to development and growth, immunity, metabolism and even behavior1,2. Most bacterial communities exist in mutualistic relationships with the healthy human host, and it is clear that our microbiota evolved in concert with our genome, the product of which is a true human-microbial symbiosis. However, it is also clear that microbial dysbiosis can result in disease, and the outgrowth of opportunistic pathogens can threaten the health and life of the human host. Fueled in part by the Human Microbiome Project (HMP) of the National Institutes of Health (NIH), and similar efforts by other groups worldwide3–5, large-scale efforts have been made to define the “normal” microbiome of healthy individuals across multiple body sites. Facilitated by the advent of next-generation sequencing, a major success of the first phase of these efforts has been the wealth of data generated, which collectively has revealed the previously poorly recognized complexity and dynamic nature of the human microbiome and its stunning impacts on human health and well-being. To further explore the functional role of the microbiome in human health and disease, the NIH has launched HMP2, now termed the integrative HMP or iHMP, a second phase of study that mandates a more in depth ‘multi-omic’ approach to explore host-bacterial interactions and community dynamics in the context of human health and disease. The Vaginal Microbiome Consortium (vmc.vcu.edu) at Virginia Commonwealth University (VCU) has a two-stage project funded by the NIH HMP1 and iHMP programs. The first stage, the Vaginal Human Microbiome Project, is a cross-sectional community based study on over 6,000 visitors to multiple women's clinics in Central Virginia, with the goal of investigating the roles of the vaginal microbiome in women's urogenital health. Vaginal and buccal samples were collected from women volunteers over the age of 18, with the exception of women who were incarcerated, independent of their state of health. Embedded within this study is the collection and analysis of samples from approximately 250 monozygotic and dizygotic twin pairs from VCU's Mid Atlantic Twin Registry6. The microbial populations in each sample were defined by high-throughput metagenomic 16S rRNA gene sequencing, whole metagenome shotgun analysis, and by microbiologically culturing, cloning by single colony isolation and sequencing of the genomes of target bacterial species or taxa. In the Multi-Omic Microbiome Study-Pregnancy Initiative, the second stage of this program, samples from over 2,000 pregnant women and their infants are being collected longitudinally at multiple prenatal visits during their pregnancies, at delivery and at early post natal visits. Samples are collected from the vagina, rectum, nares, mouth and skin from each participant over the age of 15 who is not incarcerated and who is not a surrogate. Samples from these participants are subjected to six ‘omics’ technologies: i) targeted 16S rRNA gene surveys to generate species-level microbiome profiles; ii) whole genome sequencing of relevant taxa that we are able to culture and bacteriologically clone; iii) whole metagenomic shotgun sequencing (WMGS) to generate ‘gene-centric’ and ‘taxonomy-centric’ profiles of the metabolic and pathogenic potential, and to generate genome sequences of abundant taxa that we are unable to cultivate; iv) metatranscriptomic analysis to assess expression levels of relevant prokaryotic and host genes; v) metabolomic/lipidomic analyses to provide insight into the signaling and regulatory pathways controlling the environment in the vagina; and vi) immunoproteomic analyses to measure cytokines and immune factors impacting vaginal function during pregnancy. The objective of the latter study is to elucidate the role(s) of the vaginal microbiome in the etiology or prevention of adverse outcomes of pregnancy, with a specific focus on preterm birth and stillbirth.

Here we imaged serotonin 2A receptor (5-HT2AR) binding in a very rare population of monozygotic twins discordant for schizophrenia to provide insight into trait and state components in brain 5-HT2AR patterns. In four twin pairs not medicated with drugs that target 5-HT2AR, frontal 5-HT2AR binding was consistently lower (33%) in schizophrenic- relative to their healthy co-twins. Our results strongly imply low frontal 5-HT2AR availability as a state feature of schizophrenia. If replicated, ideally in a larger sample also including dizygotic twin pairs and drug-naïve patients, this finding critically advance our understanding of the complex pathophysiology of schizophrenia.

Several temporal paradoxes exist in physics. These include General Relativity's grandfather and ontological paradoxes and Special Relativity's Langevin-Einstein twin-paradox. General relativity paradoxes can exist due to a Godel universe that follows Godel's closed timelike curves solution to Einstein's field equations. A novel biological temporal paradox of General Relativity is proposed based on reproductive biology's phenomenon of heteropaternal fecundation. Herein, dizygotic twins from two different fathers are the result of concomitant fertilization during one menstrual cycle. In this case an Oedipus-like individual exposed to a Godel closed timelike curve would sire a child during his maternal fertilization cycle. As a consequence of heteropaternal superfecundation, he would father his own dizygotic twin and would therefore generate a new class of autofraternal superfecundation, and by doing so creating a 'twin-father' temporal paradox.

Purpose: To determine the genetic contribution to the pattern of retinal vascular branching expressed by its fractal dimension.Methods: This was a cross-sectional study of 50-degree, disc-centred fundus photographs from 59 monozygotic and 55 dizygotic, same-sex twin pairs aged 20-46 years. The retinal vascular fractal dimension was measured using the box-counting method and compared within monozygotic and dizygotic twin pairs using Pearson correlation coefficents. Falconer´s formula and quantitative genetic models were used to determine the genetic component of variation.Results: The retinal vascular fractal dimensions were measurable for both twins in 50 monozygotic and 49 dizygotic twin pairs. The mean fractal dimension did not differ statistically significantly between monozygotic and dizygotic twin pairs (1.505 vs. 1.495, p=0.06), supporting that the study population was suitable for quantitative analysis of heritability. The intrapair correlation was markedly higher (0.505, p=0.0002) in monozygotic twins than in dizygotic twins (0.108, p=0.46), corresponding to a heritability h2 for the fractal dimension of 0.79. In quantitative genetic models, 54% of the variation was explained by dominant genetic effects and 46% was individually environmentally determined.Conclusion: In young adult twins, the branching pattern of the retinal vessels demonstrated a higher structural similarity in monozygotic than in dizygotic twin pairs. The retinal vascular fractal dimension was mainly determined by genetic factors, which accounted for 54% of the variation. The genetically predetermination of the

Massive perivillous fibrinoid deposition (MFD) and maternal floor infarction (MFI) are lesions of unknown etiology associated with poor perinatal outcomes, including fetal intrauterine growth restriction and neurodevelopmental injury, high risks of pregnancy loss, and recurrence in subsequent gestations. MFI comprises massive intervillous fibrinoid deposition concentrated at the maternal floor. MFD is a similar lesion but is diffuse within the parenchyma. MFD/MFI lesions represent a spectrum of severity of cloak-like perivillous fibrinoid deposition, and there is mounting evidence that, often, they represent sequelae of immune-mediated phenomena and/or an imbalance in factors that normally maintain the fluidity of blood in the maternal space. There are only a handful of reported instances of discordant MFD/MFI occurrence in twin placentas. We present a fourth such occurrence in a fused, dichorionic diamniotic twin placenta and submit that our dizygotic twin gestation case provides additional supportive evidence that immune-mediated mechanisms are involved in the formation of pathological accumulations of fibrinoid, at least in some cases.