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Similarities between twins have been widely demonstrated, underscoring the remarkable influence of genetics across numerous traits. In this study, we explore the genetic underpinnings of the human brain by examining MRI data from the Queensland Twin Imaging study. Specifically, this study seeks to compare brain structure and function between twins and unrelated subjects, with an emphasis on describing the effects of genetic factors. To achieve these goals, we employed the source-based morphometry method to extract intrinsic components and elucidate recognizable patterns. Our results show that twins exhibit a higher degree of similarity in gray and white matter density compared with unrelated individuals. In addition, four distinct states of brain activity were identified using coactivation patterns analysis. Furthermore, twins demonstrated a greater degree of similarity in the temporal and spatial features of each state compared with unrelated subjects. Taken together, these results support the hypothesis that twins show greater similarity in both brain structure and dynamic functional brain activity. Further exploration of these methods may advance our understanding of the complex interplay between genes, environment, and brain networks., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

While reports of twin pairs concordant for insanity began to appear in the 19th century, the first modern psychiatric twin study that fulfilled Galton's 1875 promise of the value of the twin method was published by the German Psychiatrist and Geneticist Hans Luxenburger in 1928. Luxenburger introduced four major methodological advances: the use of representative sampling, proband-wise concordance, rigorous zygosity diagnoses, and age correction. He used a narrow Kraepelinian diagnostic approach diagnosis and ascertained twins hospitalized, on a specific day, in all large Bavarian asylums. We include a brief biography of Luxenburger, summarize the findings of his paper and provide a full English translation in the appendix. Luxenburger presents evidence that the frequency of twinning in those with severe mental illness were as expected and reports proband-wise concordance for probable and definite dementia praecox (MZ-76%, DZ-0%) and manic-depressive insanity (MZ-75%, DZ-0%). He also examined eccentricity and hyperthymic or hypothymic personality in the dementia praecox and manic-depressive pairs, respectively. Luxenburger's substantial contributions to the history of psychiatric genetics should be considered in the context of his intimate but ambivalent relationship with the racial-hygiene policy of the German National Socialists., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Electronic cigarettes are now the most commonly used form of tobacco product among youth in the United States. Current evidence suggests that although e-cigarettes are perceived as less harmful and preferred over combustible cigarettes by adolescents, adolescents who try e-cigarettes are at greater risk of transitioning to combustible cigarettes. The genetic and environmental contributions to liability for e-cigarette use have not yet been examined using a behavioral genetic design., Methods: Behavioral genetic models of lifetime and current e-cigarette use and friends who use e-cigarettes were examined among female monozygotic and dizygotic twins., Results: A total of 41 female twin pairs (65.9% monozygotic twins; age = 19.7, SD = 1.6) with complete data on the study variables were included in the present analyses. The majority of the sample (68.1%) had at least some friends who use e-cigarettes. Additive genetic effects on e-cigarette use were not present, but the shared environment explained 98.7% of the variance in lifetime e-cigarette use, 96.6% in current e-cigarette use, and 94.9% in affiliation with friends who use e-cigarettes., Conclusion: This first study on the behavioral genetics of e-cigarette use among adolescents and young adults suggest that environmental factors shared by twins within a family seem to play a predominant role in the initial stages of e-cigarette use, a finding that is consistent with what has been found for tobacco. The findings emphasize the importance of continuing population-based tobacco control interventions to reduce the burden of e-cigarette use among adolescents., Implications: The shared environment significantly influences the initiation and regular use of electronic cigarettes and affiliation with friends who use electronic cigarettes among adolescent and young adult females. These findings underscore the importance of formulating preventive interventions that mitigate the social effects of familial influences on e-cigarette use through social skills training, education on harms of e-cigarettes for young people, or altering social norms regarding initiation of novel tobacco products., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To understand the origins of interhemispheric differences and commonalities/coupling in human brain wiring, it is crucial to determine how homologous interregional connectivities of the left and right hemispheres are genetically determined and related. To address this, in the present study, we analyzed human twin and pedigree samples with high-quality diffusion magnetic resonance imaging tractography and estimated the heritability and genetic correlation of homologous left and right white matter (WM) connections. The results showed that the heritability of WM connectivity was similar and coupled between the 2 hemispheres and that the degree of overlap in genetic factors underlying homologous WM connectivity (i.e., interhemispheric genetic correlation) varied substantially across the human brain: from complete overlap to complete nonoverlap. Particularly, the heritability was significantly stronger and the chance of interhemispheric complete overlap in genetic factors was higher in subcortical WM connections than in cortical WM connections. In addition, the heritability and interhemispheric genetic correlations were stronger for long-range connections than for short-range connections. These findings highlight the determinants of the genetics underlying WM connectivity and its interhemispheric relationships, and provide insight into genetic basis of WM connectivity asymmetries in both healthy and disease states., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Quantifying the degree to which genetic and environmental factors shape brain network connectivity is critical to furthering our understanding of the developing human brain. Sleep, a state of sensory disengagement, provides a unique opportunity to study brain network activity noninvasively by means of sleep electroencephalography (EEG) coherence. We conducted a high-density sleep EEG study in monozygotic (MZ; n = 38; mean age = 12.46; 20 females) and dizygotic (DZ; n = 24; mean age = 12.50; 12 females) twins to assess the heritability of sleep EEG coherence in early adolescence-a period of significant brain rewiring. Structural equation modeling was used to estimate three latent factors: genes, environmental factors shared between twins and environmental factors unique to each twin. We found a strong contribution of unique environmental factors (66% of the variance) and moderate genetic influence (19% of the variance) on sleep EEG coherence across frequencies and sleep states. An exception to this was sleep spindle activity, an index of the thalamocortical network, which showed on average a genetic contribution of 48% across connections. Furthermore, we observed high intraindividual stability of coherence across two consecutive nights suggesting that despite only a modest genetic contribution, sleep EEG coherence is like a trait. Our findings in adolescent humans are in line with earlier findings in animals that show the primordial cerebral map and its connections are plastic and it is through interaction with the environment that the pattern of brain network connectivity is shaped. Therefore, even in twins living together, small differences in the environment may cascade into meaningful differences in brain connectivity., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Whether aberrant cerebral blood flow (CBF) in schizophrenia is affected by genetic influences, and consequently a potential marker for genetic susceptibility, is unknown. Our aims were to determine the heritability of CBF in thalamic, frontal, and striatal areas, and to ascertain if associations with disease were under genetic influence. Monozygotic (MZ) twin pairs concordant (n = 2) or discordant (n = 20) for schizophrenia spectrum disorders (ICD-10 F2x.x), matched on sex and age with dizygotic (DZ; n = 20) and healthy control pairs (MZ: n = 27; DZ: n = 18; total: n = 181 individuals), were recruited via the National Danish Twin Register. CBF in thalamus, frontal lobes, and putamen was measured with pseudo-continuous arterial spin labeling on a 3 T magnetic resonance scanner. Twin statistics were performed with structural equation modeling. CBF in the frontal lobes was heritable (h2 = 0.44, 95% CI [0.22-0.60]) but not correlated to disease. CBF correlated to schizophrenia spectrum disorders in the left thalamus (r = 0.17, [0.03-0.31]; P = 0.02), as well as in the left putamen (r = 0.19, [0.05-0.32]; P = 0.007) and the right putamen (r = 0.18, [0.03-0.32]; P = 0.02). When restricting the sample to schizophrenia (F20.x) only, shared genetic influences between CBF in the left putamen and schizophrenia liability (phenotypic correlation = 0.44, [0.28-0.58], P < 0.001) were found. Our results provide heritability estimates of CBF in the frontal lobes, and we find CBF in thalamus and putamen to be altered in schizophrenia spectrum disorders. Furthermore, shared genetic factors influence schizophrenia liability and striatal perfusion. Specifically, higher perfusion in the left putamen may constitute a marker of genetic susceptibility for schizophrenia., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Structural brain abnormalities and cognitive deficits have been reported in patients with schizophrenia and to a lesser extent in their first-degree relatives (FDRs). Here we investigated whether brain abnormalities in nonpsychotic relatives differ per type of FDR and how these abnormalities are related to intelligent quotient (IQ). Nine hundred eighty individuals from 5 schizophrenia family cohorts (330 FDRs, 432 controls, 218 patients) were included. Effect sizes were calculated to compare brain measures of FDRs and patients with controls, and between each type of FDR. Analyses were repeated with a correction for IQ, having a nonpsychotic diagnosis, and intracranial volume (ICV). FDRs had significantly smaller ICV, surface area, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, thalamus, putamen, amygdala, and accumbens volumes as compared with controls (ds < -0.19, q < 0.05 corrected). Offspring showed the largest effect sizes relative to the other FDRs; however, none of the effects in the different relative types survived correction for multiple comparisons. After IQ correction, all effects disappeared in the FDRs after correction for multiple comparisons. The findings in FDRs were not explained by having a nonpsychotic disorder and were only partly explained by ICV. FDRs show brain abnormalities that are strongly covarying with IQ. On the basis of consistent evidence of genetic overlap between schizophrenia, IQ, and brain measures, we suggest that the brain abnormalities in FDRs are at least partly explained by genes predisposing to both schizophrenia risk and IQ., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Despite advances in life expectancy, low socioeconomic status is associated with a shorter lifespan. This study was conducted to investigate socioeconomic differences in mortality by comparing preventable with non-preventable causes of death in 39 506 participants from the Swedish Twin Registry born before 1935., Methods: Childhood social class, own education, own social class and social mobility were used as separate indicators of socioeconomic status. These data were linked to the Swedish Cause of Death Register. Cause of death was categorized as preventable or non-preventable mortality according to indicators presented in the Avoidable Mortality in the European Union (AMIEHS) atlas. Using Cox proportional hazard models, we tested the association between the socioeconomic measures and all-cause mortality, preventable mortality and non-preventable mortality. Additional co-twin control analyses indicated whether the associations reflected genetic confounding., Results: The social gradient for mortality was most prominent for the adult socioeconomic measures. There was a social gradient in both preventable mortality and non-preventable mortality, but with an indication of a moderately stronger effect in preventable causes of death. In analyses of social mobility, those who experienced life-time low socioeconomic status (SES) or downward social mobility had an increased mortality risk compared with those with life-time high SES and upward social mobility. Adjustments for genetic confounding did not change the observed associations for education, social class or social mobility and mortality. In the co-twin control analyses of reared-apart twins, the association between childhood social class and mortality weakened, indicating possible genetic influences on this association., Conclusions: Our results indicate that there is an association between low adult socioeconomic status and increased mortality independent of genetic endowment. Thus, we do not find support for indirect social selection as the basis for mortality inequalities in Sweden., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Smoking and use of Swedish smokeless tobacco (snus) are associated with increased risk of type 2 diabetes (T2D). Our aim was to estimate the unique and shared genetic components of these traits and to what extent the association is explained by shared genetic factors., Methods: We used twins of the Swedish Twin Registry who responded to a questionnaire between 1998 and 2006 (n = 40 247) and were followed until 2015 in the National Prescription and Patient Registries. We estimated hazard ratios (HRs) and odds ratios (ORs) for the association between smoking/snus use and T2D (n = 2130) and used structural equation models to estimate genetic and environmental variance components and genetic correlations., Results: Current smokers [HR 1.69, 95% confidence interval (CI), 1.49-1.92] and snus users (HR 1.19, 95% CI 1.01-1.41) had an increased risk of T2D. In within-pair analyses of monozygotic twins, corresponding ORs were 1.36, 95% CI 0.75-2.46 (smoking) and 1.54, 95% CI 0.80-2.99 (snus). Heritability was 43% (95% CI 36-51) for ever smoking, 58% (95% CI 44- 70) for ever snus use and 66% (95% CI 59-72) for T2D. The genetic correlation with T2D was 18% (95% CI 1-35) for smoking and -6% (95% CI -24 to 4) for snus use, indicating that only a small fraction of the genetic influence is shared., Conclusions: We could confirm that consumers of snus and cigarettes are at increased risk of T2D. Both snus use and smoking have strong genetic components, which appears to be attributable primarily to genes that are distinct from those promoting T2D., (© The Author(s) 2019; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objectives: To study, whether there are associations between chewing side preference and other lateralities, whether there is a genetic origin for preferred chewing side (PCS), relations to sex, birth order and orthodontic treatment., Materials and Methods: The study included 113 twin pairs, 57 pairs monozygotic, 47 pairs same sex dizygotic and 9 pairs of opposite sex. The lateralities of preferred chewing side, footedness and eyedness were assessed by functional tests and handedness was checked by asking., Results: Right-handed, -footed and -eyed as separated groups, and true-right sided (combined), were evenly distributed by preferred chewing side. By contrast, left-handed, -footed, -eyed and non-right sided used more left or both sides when chewing. Birth order affected preferred chewing side among monozygotic: the first-born twin was more likely to have the preferred chewing side on the non-right, whereas second-born twins used right side. Gender, zygosity and orthodontic treatment were not statistically significant factors., Limitations: Examination of chewing sidedness could have been done in several different ways to provide a definite result. Sample size of opposite sex twins was very small., Conclusions: Preferred chewing side generally seemed to follow the side where other lateralities occur; however, monozygotic twins seemed to be more receptive to it. True-right sided were more evenly distributed than non-right sided by the preferred chewing side., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Orolabial herpes simplex virus type 1 (HSV-1) infection has a wide spectrum of severity in immunocompetent persons. To study the role of viral genotype and host immunity, we characterized oral HSV-1 shedding rates and host cellular response, and genotyped viral strains, in monozygotic (MZ) and dizygotic (DZ) twins., Methods: A total of 29 MZ and 22 DZ HSV-1-seropositive twin pairs were evaluated for oral HSV-1 shedding for 60 days. HSV-1 strains from twins were genotyped as identical or different. CD4+ T-cell responses to HSV-1 proteins were studied., Results: The median per person oral HSV shedding rate was 9% of days that a swab was obtained (mean, 10.2% of days). A positive correlation between shedding rates was observed within all twin pairs, and in the MZ and DZ twins. In twin subsets with sufficient HSV-1 DNA to genotype, 15 had the same strain and 14 had different strains. Viral shedding rates were correlated for those with the same but not different strains. The median number of HSV-1 open reading frames recognized per person was 16. The agreement in the CD4+ T-cell response to specific HSV-1 open reading frames was greater between MZ twins than between unrelated persons (P = .002)., Conclusion: Viral strain characteristics likely contribute to oral HSV-1 shedding rates., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The genetic architecture of birth size may differ geographically and over time. We examined differences in the genetic and environmental contributions to birthweight, length and ponderal index (PI) across geographical-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 57 613 monozygotic and dizygotic twin pairs were pooled. Genetic and environmental variations of birth size were estimated using genetic structural equation modelling., Results: The variance of birthweight 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 geographical-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 1990-99 onwards compared with the birth cohorts from 1970-79 to 1980-89., Conclusions: 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 geographical-cultural regions. Shared environmental factors are important when explaining differences in the variation of birth size globally and over time.

Objective: IGF-I may be a marker of later metabolic and cardiovascular disease. The interactions between IGF-I and glucose metabolism are multifactorial, and there is potential confounding from several secondary effects. In this study, we examined the interaction between IGF-I and glucose metabolism in a large cohort of clinically well-characterized elderly twins., Design: A total of 303 twin pairs of the same gender (606 twins) were included in the study; 125 monozygotic and 178 dizygotic twin pairs., Methods: A clinical examination including a standard oral glucose tolerance test (OGTT) and anthropometric measurements was performed., Results: The heritability estimates were high for IGF-I and IGFBP-3 (h 2 : 0.65 (95% CI: 0.55-0.74) and 0.71 (0.48-0.94), respectively) and for insulin secretion (h 2  = 0.56, P  < 0.0001), whereas the heritability estimates for insulin sensitivity were low (h 2  = 0.14, P  = 0.11). In a multiple regression analysis (adjusting for age, gender and twin status), there was a negative association between IGF-I and insulin sensitivity (B: -0.13, SE 0.03, P  < 0.0001) and IGF-I and disposition index (B: -0.05, SE 0.02, P  < 0.001) in the entire cohort of 606 twins. The associations between IGF-I and both DI and HOMA-S did not differ between the DZ and MZ twins. Forty-five twin pairs were discordant for T2D, but the discordant twins had similar concentrations of IGF-I or IGFBP-3., Conclusions: There was a high heritability for IGF-I and IGFBP-3, but a low heritability for insulin secretion and insulin sensitivity in a group of elderly twins. In addition, we found a strong negative relationship between IGF-I and insulin sensitivity, which did not seem to be strongly genetically determined., (© 2018 European Society of Endocrinology.)

The default mode network (DMN) is thought to reflect endogenous neural activity, which is considered as one of the most intriguing phenomena in cognitive neuroscience. Previous studies have found that key regions within the DMN are highly interconnected. Here, we characterized the genetic influences on causal or directed information flow within the DMN during the resting state. In this study, we recruited 46 pairs of twins and collected fMRI imaging data using a 3.0 T scanner. Dynamic causal modeling was conducted for each participant, and a structural equation model was used to calculate the heritability of DMN in terms of its effective connectivity. Model comparison favored a full-connected model. Structural equal modeling was used to estimate the additive genetics (A), common environment (C) and unique environment (E) contributions to variance for the DMN effective connectivity. The ACE model was preferred in the comparison of structural equation models. Heritability of DMN effective connectivity was 0.54, suggesting that the genetic made a greater contribution to the effective connectivity within DMN. Establishing the heritability of default-mode effective connectivity endorses the use of resting-state networks as endophenotypes or intermediate phenotypes in the search for the genetic basis of psychiatric or neurological illnesses., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: There is evidence that birthweight is positively associated with body mass index (BMI) in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. We analysed the association between birthweight and BMI from infancy to adulthood within twin pairs, which provides insights into the role of genetic and environmental individual-specific factors., Methods: This study is based on the data from 27 twin cohorts in 17 countries. The pooled data included 78 642 twin individuals (20 635 monozygotic and 18 686 same-sex dizygotic twin pairs) with information on birthweight and a total of 214 930 BMI measurements at ages ranging from 1 to 49 years. The association between birthweight and BMI was analysed at both the individual and within-pair levels using linear regression analyses., Results: At the individual level, a 1-kg increase in birthweight was linearly associated with up to 0.9 kg/m2 higher BMI (P < 0.001). Within twin pairs, regression coefficients were generally greater (up to 1.2 kg/m2 per kg birthweight, P < 0.001) than those from the individual-level analyses. Intra-pair associations between birthweight and later BMI were similar in both zygosity groups and sexes and were lower in adulthood., Conclusions: These findings indicate that environmental factors unique to each individual have an important role in the positive association between birthweight and later BMI, at least until young adulthood., (© The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association)

Previous studies have shown that males and females differ in personality and gender differences have also been reported in brain structure. However, effects of gender on this "personality-brain" relationship are yet unknown. We therefore investigated if the neural correlates of personality differ between males and females. Whole brain voxel-based morphometry was used to investigate the influence of gender on associations between NEO FFI personality traits and gray matter volume (GMV) in a matched sample of 182 males and 182 females. In order to assess associations independent of and dependent on gender, personality-GMV relationships were tested across the entire sample and separately for males and females. There were no significant correlations between any personality scale and GMV in the analyses across the entire sample. In contrast, significant associations with GMV were detected for neuroticism, extraversion, and conscientiousness only in males. Interestingly, GMV in left precuneus/parieto-occipital sulcus correlated with all 3 traits. Thus, our results indicate that brain structure-personality relationships are highly dependent on gender, which might be attributable to hormonal interplays or differences in brain organization between males and females. Our results thus provide possible neural substrates of personality-behavior relationships and underline the important role of gender in these associations., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Context: The joint effects of cardiorespiratory fitness (CRF) and body composition on metabolic health are not well known., Objective: To examine the associations of CRF, fat-free mass index (FFMI), and fat mass index (FMI) with metabolic health in individual twins and controlling for genetic and shared environmental effects by studying monozygotic intrapair differences., Design, Setting, and Participants: Two cross-sectional samples of healthy adult monozygotic and dizygotic twins were drawn from population-based Danish and Finnish national twin registries (n = 996 and n = 309)., Main Measures: CRF was defined as VO2max divided by fat-free mass. Insulin sensitivity and acute insulin response indices were derived from an oral glucose tolerance test. A continuous metabolic syndrome score was calculated. Visceral and liver fat were measured in the Finnish sample. Associations were analyzed separately in both cohorts with multivariate linear regression and aggregated with meta-analytic methods., Results: Insulin sensitivity, acute insulin response, metabolic syndrome score, visceral, and liver fat amount had strong and statistically significant associations with FMI (|β| 0.53 to 0.79), whereas their associations with CRF and FFMI were at most weak (|β| 0.02 to 0.15). The results of the monozygotic intrapair differences analysis showed the same pattern., Conclusions: Although FMI is strongly associated with worsening of metabolic health traits, even after controlling for genetic and shared environmental factors, there was little evidence for the effects of CRF or FFMI on metabolic health. This suggests that changing FMI rather than CRF or FFMI may affect metabolic health irrespective of genetic or early environmental determinants., (Copyright © 2017 by the Endocrine Society)

Context: The associations of body mass index (BMI) and liver fat (LF) with circulating prandial metabolomic markers are incompletely understood., Objective: We aimed to characterize circulating metabolite excursions during an oral glucose tolerance test (OGTT) and evaluate whether the metabolomic signatures of BMI discordance coassociate with LF content., Design, Setting, and Participants: We measured 80 metabolite parameters by nuclear magnetic resonance, together with glucose and insulin, during a 2-hour OGTT in 64 monozygotic (MZ) and 73 dizygotic (DZ) twin pairs (aged 22.8 to 36.2 years). Metabolite excursions during the OGTT were compared within BMI-discordant (intrapair difference, BMI ≥ 3 kg/m2) cotwins separately within MZ and DZ pairs. Insulin-based indices were calculated from the OGTT. LF was measured by magnetic resonance spectroscopy in 25 BMI-discordant MZ pairs. Metabolite profiles were compared with respect to LF discordance (ΔLF% ≥ 2%)., Results: We replicated many previously reported OGTT-induced metabolite excursions in all 274 individuals and report novel lipoprotein excursions. The associations between some metabolite excursions and BMI differed in MZ and DZ twins. In BMI-discordant MZ pairs (mean ΔBMI = 4.9 kg/m2) who were concordant for LF (Δ0.2%), few metabolites differed between the cotwins: very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B were elevated, and high-density lipoprotein size and concentration were decreased in the cotwins with higher BMI. In contrast, in BMI-discordant MZ pairs (ΔBMI = 6.1 kg/m2) who were discordant for LF (Δ6.8%), cotwins with higher BMI exhibited lower insulin sensitivity and widespread metabolomic differences: elevations in small VLDL and low-density lipoprotein particles, fatty acids (FAs), and isoleucine. Within all 64 MZ twin pairs, lower insulin sensitivity associated with higher levels of VLDLs, triglycerides, FAs, and isoleucine., Conclusions: BMI-discordant MZ twin pairs who also are discordant for LF have more pronounced within-pair differences in metabolomics profiles during an OGTT than BMI-discordant pairs without LF discordance., (Copyright © 2017 by the Endocrine Society)

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, Örebro 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., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Heritability of naevi counts is widely acknowledged as a potential surveillance parameter for prevention purposes. The contribution of heritability to the changes seen in naevus number and morphology over time and their corresponding dermoscopic characteristics is unknown, but is important to understand in order to account for adequate prevention measures., Objectives: To identify naevus characteristics that are strongly influenced by heritability., Methods: This cross-sectional study included 220 individuals [76 monozygotic (MZ), 144 dizygotic (DZ)], recruited from the Brisbane Twin Naevus Study. Participants received full body imaging and dermoscopy of naevi ≥ 5 mm in diameter. Dermoscopic type, total naevus count (TNC), change in TNC with age, and naevus distribution, size, colour and profile were compared between MZ and DZ twins. Heritability of these traits was assessed via Falconer's estimate., Results: Significant differences were found in comparing MZ and DZ twins for TNC, numbers of naevi 5·0-7·9 mm in diameter, counts of light-brown naevi, naevi on the back and sun-protected sites, and naevi with the 'nonspecific' dermoscopic pattern., Conclusions: This study strongly supports a heritable component to TNC, as well as changes in TNC, and the number of medium-sized naevi, light-brown naevi, specific sites and certain dermoscopic features in adults. These characteristics should be taken into account by naevus surveillance programmes and further studied to identify candidate gene associations for clinical and dermoscopic patterns in conjunction with melanoma risk stratification., (© 2015 British Association of Dermatologists.)

Two areas of the occipitotemporal cortex show a remarkable hemispheric lateralization: written words activate the visual word form area (VWFA) in the left fusiform gyrus and faces activate a symmetrical site in the right hemisphere, the fusiform face area (FFA). While the lateralization of the VWFA fits with the leftward asymmetry of the speech processing network, origin of the rightward asymmetry for faces is still unclear. Using fMRI data from 64 subjects (including 16 monozygotic (MZ) and 13 dizygotic (DZ) twin pairs), we investigated how activations evoked by written words, faces, and spoken language are co-lateralized in the temporal lobe, and whether this organization reflects genetic factors or individual reading expertise. We found that the lateralization of the left superior temporal activation for spoken language correlates with the lateralization of occipitotemporal activations for both written words and faces. Behavioral reading scores also modulate the responses to words and faces. Estimation of genetic and environmental contributions shows that activations of the VWFA, the occipital face area, and the temporal speech areas are partially under genetic control whereas activation of the FFA is primarily influenced by individual experience. Our results stress the importance of both genetic factors and acquired expertise in the occipitotemporal organization., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Study Question: What are the pregnancy outcomes for women with a twin pregnancy that is reduced to a singleton pregnancy?, Summary Answer: Fetal reduction of a twin pregnancy significantly improves gestational age at birth and neonatal birthweight, however at an increased risk of pregnancy loss and preterm delivery., What Is Known Already: Women with a multiple pregnancy are at increased risk for preterm delivery. Fetal reduction can be considered in these women., Study Design, Size, and Duration: Retrospective cohort study of 118 women with a twin pregnancy reduced to a singleton pregnancy between 2000 and 2010., Participants/materials, Setting, and Methods: We compared the outcome of pregnancy in consecutive women with a dichorionic twin pregnancy that was reduced to a singleton pregnancy to that of women with a dichorionic twin pregnancy that was managed expectantly and women with a primary singleton pregnancy. Reductions were performed between 10-23(6/7) weeks' gestation by intracardiac or intrathoracic injection of potassium chloride, mostly for congenital anomalies. We compared median gestational age, pregnancy loss <24 weeks, preterm delivery <32 weeks, neonatal birthweight and perinatal deaths., Main Results and the Role of Chance: We studied 118 women with a twin pregnancy that was reduced to a singleton, 818 women with an ongoing dichorionic twin pregnancy and 611 women with a primary singleton pregnancy. Loss of the entire pregnancy <24 weeks and preterm delivery occurred significantly more in the reduction group compared with the ongoing twin group (11.9 versus 3.1% <24 weeks, P< 0.001 and 18.6 versus 11.5% <32 weeks, respectively, P < 0.001). In the reduction group, the percentage of women without any surviving child was significantly higher compared with the ongoing twin and primary singleton group (14.4, 3.4 and 0.7%, respectively, P < 0.001). Median gestational age was 38.9 weeks (interquartile range (IQR) 34.7-40.3) for reduced pregnancies, 37.1 weeks (IQR 35.3-38.1) for ongoing twin pregnancies and 40.1 (IQR 39.1-40.9) for primary singletons (P < 0.001 for all comparisons)., Limitations, Reasons for Caution: The main limitations of the study were its retrospective character, and the fact that indications for reduction were heterogeneous., Wider Implications of the Findings: In women with a dichorionic twin pregnancy fetal reduction increases median gestational age only at considerable risk of complete early pregnancy loss., Study Funding/competing Interests: The study was not funded. None of the authors has conflicts of interest., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Total gray matter volume is associated with general cognitive ability (GCA), an association mediated by genetic factors. It is expectable that total neocortical volume should be similarly associated with GCA. Neocortical volume is the product of thickness and surface area, but global thickness and surface area are unrelated phenotypically and genetically in humans. The nature of the genetic association between GCA and either of these 2 cortical dimensions has not been examined. Humans possess greater cognitive capacity than other species, and surface area increases appear to be the primary driver of the increased size of the human cortex. Thus, we expected neocortical surface area to be more strongly associated with cognition than thickness. Using multivariate genetic analysis in 515 middle-aged twins, we demonstrated that both the phenotypic and genetic associations between neocortical volume and GCA are driven primarily by surface area rather than thickness. Results were generally similar for each of 4 specific cognitive abilities that comprised the GCA measure. Our results suggest that emphasis on neocortical surface area, rather than thickness, could be more fruitful for elucidating neocortical-GCA associations and identifying specific genes underlying those associations., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Homosexuality is a stable population-level trait in humans that lowers direct fitness and yet is substantially heritable, resulting in a so-called Darwinian "paradox." Evolutionary models have proposed that polymorphic genes influencing homosexuality confer a reproductive benefit to heterosexual carriers, thus offsetting the fitness costs associated with persistent homosexuality. This benefit may consist of a "sex typicality" intermediate phenotype. However, there are few empirical tests of this hypothesis using genetically informative data in humans., Aim: This study aimed to test the hypothesis that common genetic factors can explain the association between measures of sex typicality, mating success, and homosexuality in a Western (British) sample of female twins., Methods: Here, we used data from 996 female twins (498 twin pairs) comprising 242 full dizygotic pairs and 256 full monozygotic pairs (mean age 56.8) and 1,555 individuals whose co-twin did not participate. Measures of sexual orientation, sex typicality (recalled childhood gender nonconformity), and mating success (number of lifetime sexual partners) were completed., Main Outcome Measure: Variables were subject to multivariate variance component analysis., Results: We found that masculine women are more likely to be nonheterosexual, report more sexual partners, and, when heterosexual, also report more sexual partners. Multivariate twin modeling showed that common genetic factors explained the relationship between sexual orientation, sex typicality, and mating success through a shared latent factor., Conclusions: Our findings suggest that genetic factors responsible for nonheterosexuality are shared with genetic factors responsible for the number of lifetime sexual partners via a latent sex typicality phenotype in human females. These results may have implications for evolutionary models of homosexuality but are limited by potential mediating variables (such as personality traits) and measurement issues., (© 2015 International Society for Sexual Medicine.)

Posttraumatic stress disorder (PTSD) is associated with an increased risk of ischemic heart disease, though the pathophysiologic mechanisms remain unclear. Carotid artery intima-media thickness (CIMT) is a measure of subclinical atherosclerosis. We examined whether PTSD and combat exposure were associated with CIMT in Vietnam War-era twins after controlling for shared genetic and childhood factors. Between 2002 and 2010, we studied 465 middle-aged twins from the Vietnam Era Twin Registry who were free from cardiovascular disease. PTSD was diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and CIMT was measured by ultrasound. Mixed-effects regression models were used to examine individual, between-pair, and within-pair associations. Approximately 13% of participants met the criteria for PTSD, and 45% served in the Vietnam Theater. PTSD was associated with 32.7 μm higher CIMT (95% confidence interval (CI): 0.9, 64.5) after adjustment for confounders. The average CIMT for the pair increased by 59.7 μm for each additional twin with PTSD (95% CI: 15.9, 104.2). We found no significant within-pair differences in CIMT when comparing PTSD-discordant co-twins. Results for combat exposure were similar, but its association with CIMT weakened after adjustment for PTSD (95% CI: 7.0, 45.3). Among Vietnam War-era veterans, combat exposure and PTSD are associated with CIMT, though the associations are largely mediated by shared childhood factors., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Question: Are all twin births following single embryo transfer (SET) monozygotic?, Summary Answer: Between 1 in 10 and in 1 in 5 twins born after SET are the result of a concurrent natural conception., What Is Known Already: The twinning rate after SET is higher than following natural conception. Most studies of twins following SET have incorrectly assumed monozygosity or have not been able to assess the zygosity., Study Design, Size, Duration: This study is a retrospective cohort study assessing the gender discordance of all live born twins following fresh or frozen SET., Participants/materials, Setting, Methods: A total of 4701 patients in a large private IVF unit who gave birth following SET with a fresh or frozen embryo with complete follow-up. Of 137 viable twins at the 7-week ultrasound, 109 were delivered as twins. Gender discordance and Weinberg's differential rule were used to estimate dizygosity. Twin rates were compared for fresh and frozen transfers by insemination method and transfer day., Main Results and the Role of Chance: The overall live twin birth rate was 2.3% (109/4701). Based on the 7-week scan, 2 of the twins were monochorionic monoamniotic, 62 were monochorionic diamniotic and 45 were dichorionic diamniotic. There were a total of 12 gender discordant twins (11%), 7 from the Day 2/3 transfers and 5 from Day 5 transfers. Nine of the 12 discordant twins were from natural cycle frozen embryo transfers, the remaining 3 were from fresh cycles. LIMITATIONS, REASONS FOR CAUTION; To assess gender discordance only live born twins were studied. DNA fingerprinting of twins is a more accurate way to assess zygosity than measuring gender discordance. Same sex twins in this study are not necessarily monozygotic and the dizygotic rate in this study may therefore be higher. This rate was estimated using Weinberg's differential rule., Wider Implications of the Findings: As many as 1 in 5 twins born after SET may be the result of a concurrent natural conception. Couples therefore need to be counselled regarding the relative benefits and risks of intercourse in assisted reproduction technology cycles where spontaneous conception is possible., Study Funding/competing Interest(s): None., Trial Registration Number: Not applicable.

Background: Identifying mild cognitive impairment (MCI) in midlife could improve early identification of Alzheimer's disease (AD). Also, AD is highly heritable, but the heritability of MCI has not been established. We estimated prevalence rates, association with premorbid general cognitive ability (GCA) and heritability for different definitions of neuropsychologically defined MCI in adults in their 50s., Method: We examined 1126 twins aged 51-59 years when recruited into the Vietnam Era Twin Study of Aging (VETSA). Six neurocognitive domains were assessed using tests designed to avoid ceiling effects. To differentiate MCI from low overall ability, criteria included adjustment for GCA measured at approximately age 20 years., Results: As in older adults, prevalence rates varied widely. Among the lower prevalence rates were some definitions of multiple-domain MCI and single-domain amnestic MCI, which may be less likely than other MCI categories to revert to normal on follow-up. Low prevalence rates in middle-aged adults are also more likely to be valid. MCI was also associated with lower premorbid GCA. Heritability estimates for any MCI and amnestic MCI averaged .40-.48., Conclusions: By testing multiple cognitive domains and avoiding ceiling effects, MCI can be identified before age 60 years. Premorbid GCA is a risk/protective factor, but deficits after adjusting for early adult GCA suggest additional processes leading to declining trajectories. Heritabilities were comparable to AD, suggesting MCI as an appropriate phenotype for genetic association studies. Full validation will require follow-up assessments (currently under way). Community-based studies are important for this early identification because adults of this age are unlikely to present in clinics.

Introduction: Among smokers, former smokers, and never-smokers, this study aimed to (a) determine the predictive value of smoking expectancy on future smoking status, and (b) test the relative contribution of genes and environment to a person's ability to accurately predict future smoking status. For smokers, smoking expectancy reflects the intention to continue smoking; for former smokers, it reflects the intention to take up smoking again; and for never-smokers, it reflects the intention to initiate smoking., Methods: A longitudinal design was employed in which participants of the Netherlands Twin Register completed 2 consecutive surveys 2 years apart between 1993 and 2011 (3,591 adolescents aged 14-18 years), or between 1993 and 2004 (11,568 adults, aged 18+ years). Smoking expectancy was measured by asking, "Do you think you'll smoke in a year's time?", with answer categories ranging from "certainly not" to "absolutely yes" on a 5-point scale. To determine the predictive value of smoking expectancy, analyses were performed in smokers, former smokers, and never-smokers separately. Data of 2,987 adolescents and 4,911 adult twins were analyzed to estimate heritability. A dichotomous variable reflected the ability to predict future smoking status (correct/incorrect)., Results: Smoking expectancy significantly predicted future smoking status among former smokers and never-smokers. The ability to accurately predict future smoking status was explained by additive genetic factors for 59% of adolescents and 27% of adults, with the remainder being explained by unique environmental factors., Conclusions: A single question on smoking expectancy helps predict future smoking status. Variation in how well subjects predict their future smoking behavior is influenced by genetic factors, especially during adolescence.

Study Objectives: Previous studies with limited follow-up times have suggested that sleep-related traits are associated with an increased risk of incident dementia or cognitive decline. We investigated the association between midlife sleep characteristics and late life cognitive function., Design: A follow-up study with a median follow-up time of 22.5 (range 15.8-25.7) years assessing the association between midlife sleep characteristics and later cognitive function., Setting: Questionnaire data from 1981 were used in the assessment of sleep characteristics, use of hypnotics, and covariates at baseline. Between 1999 and 2007, participants were assigned a linear cognitive score with a maximum score of 51 based on a telephone interview (mean score 38.3, SD 6.1). Linear regression analyses were controlled for age, sex, education, ApoE genotype, and follow-up time., Participants: 2,336 members of the Finnish Twin cohort who were at least 65 years of age., Interventions: N/A., Measurements and Results: Baseline short (< 7 h/day) and long (> 8 h/day) sleepers had lower cognitive scores than participants sleeping 7-8 h/ day (β = -0.84, P = 0.014 and β = -1.66, P < 0.001, respectively). As compared to good sleep quality, poor or rather poor sleep quality was associated with a lower cognitive score (β = -1.00, P = 0.011). Also, the use of hypnotics ≥ 60 days per year was associated with poorer cognitive function (β = -1.92, P = 0.002)., Conclusions: This is the first study indicating that midlife sleep length, sleep quality, and use of hypnotics are associated with late life cognitive function. Further confirmation is needed, but sleep-related characteristics may emerge as new risk factors for cognitive impairment.

Background: Previous twin studies have shown greater concordance rates for psoriasis in MZ than in DZ twins, and heritability estimates between 66% and 90%. This supports a genetic influence on psoriasis, but also highlights the fact that genes are not the only explanation for the disease., Objectives: To study the concordance of psoriasis in a population-based twin sample., Methods: Data on psoriasis in 10 725 twin pairs, aged 20-71 years, from the Danish Twin Registry was collected via a questionnaire survey. The concordance and heritability of psoriasis were estimated., Results: In total, 4·1% of the men and 4·2% of the women had a lifetime history of psoriasis. The proband-wise concordance for psoriasis was larger in monozygotic than in dizygotic twins, 0·33 vs. 0·17. Genetic factors explained 68% (60-75%) of the variation in the susceptibility to psoriasis, whereas the rest of the variation was explained by nonshared environmental factors., Conclusion: The results confirm that psoriasis is a complex multifactorial disease controlled by both exogenous and endogenous factors., (© 2013 The Authors BJD © 2013 British Association of Dermatologists.)

Background: The mechanisms behind increased fecal calprotectin (FC) in healthy relatives of patients with inflammatory bowel disease (IBD) are unknown. Our aims were to explore if there is a subclinical inflammation with increased neutrophil activity in healthy twin siblings in discordant twin pairs with IBD and to assess the influence of genetics in this context., Methods: Nuclear factor kappa B (NF-κB) and neutrophil activity, based on myeloperoxidase (MPO) and FC, were analyzed in healthy twin siblings in discordant twin pairs with IBD and compared with healthy controls. NF-κB and MPO were assessed by immunohistochemistry and FC by enzyme-linked immunosorbent assay., Results: In total, 33 of 34 healthy twin siblings were histologically normal. Increased NF-κB was more often observed in healthy twin siblings in discordant twin pairs with Crohn's disease (13/18 [73%]) and with ulcerative colitis (12/16 [75%]) than in healthy controls (8/45 [18%]). MPO was more often increased in healthy twin siblings in discordant pairs with Crohn's disease (12/18 [67%]) than in healthy controls (11/45 [24%]) and FC more often in healthy twin siblings in discordant pairs with ulcerative colitis (14/21 [67%]) than in healthy controls (6/31 [19%]). Interestingly, the observed differences remained when healthy monozygotic and dizygotic twin siblings were analyzed separately., Conclusions: We observed increased NF-κB, MPO, and FC in healthy twins in both monozygotic and dizygotic discordant pairs with IBD. These novel findings speak for an ongoing subclinical inflammation with increased neutrophil activity in healthy first-degree relatives.

Introduction: Sexual interest in children resembles sexual gender orientation in terms of early onset and stability across the life span. Although a genetic component to sexual interest in children seems possible, no research has addressed this question to date. Prior research showing familial transmission of pedophilia remains inconclusive about shared environmental or genetic factors. Studies from the domains of sexual orientation and sexually problematic behavior among children pointed toward genetic components. Adult men's sexual interest in youthfulness-related cues may be genetically influenced., Aim: The aim of the present study was to test whether male sexual interest in children and youth under age 16 involves a heritable component., Main Outcome Measures: The main outcome measure was responses in a confidential survey concerning sexual interest, fantasies, or activity pertaining to children under the age of 16 years during the previous 12 months., Methods: The present study used an extended family design within behavioral genetic modeling to estimate the contributions of genetic and environmental factors in the occurrence of adult men's sexual interest in children and youth under age 16. Participants were male twins and their male siblings from a population-based Finnish cohort sample aged 21-43 years (N = 3,967)., Results: The incidence of sexual interest in children under age was 3%. Twin correlations were higher for monozygotic than for dizygotic twins. Behavioral genetic model fitting indicated that a model including genetic effects as well as nonshared environmental influences (including measurement error), but not common environmental influences, fits the data best. The amount of variance attributable to nonadditive genetic influences (heritability) was estimated at 14.6%., Conclusions: The present study provides the first indication that genetic influences may play a role in shaping sexual interest toward children and adolescents among adult men. Compared with the variance attributable to nonshared environmental effects (plus measurement error), the contribution of any genetic factors seems comparatively weak. Future research should address the possible interplay of genetic with environmental risk factors, such as own sexual victimization in childhood., (© 2013 International Society for Sexual Medicine.)

Background: Dizygotic twin pregnancies after IVF treatment are the result of multiple embryos transferred into the uterine cavity, followed by successful double implantation. Factors that increase the chance of multiple implantation after IVF are relatively unknown. The present study aimed to investigate whether features of body composition, such as maternal height, weight and body mass index (BMI) are associated with an increased chance of dizygotic twinning after IVF with double embryo transfer (DET)., Methods: This study was conducted using data from a large Dutch nationwide cohort that comprised 19 861 women who had IVF or ICSI treatment between 1983 and 1995 (OMEGA study). First 'fresh' IVF and ICSI cycles with DET resulting in a delivery of a singleton or twin (living as well as stillborn) were selected. A multivariable logistic regression analysis was performed, with the delivery of a singleton or twin as the dependent variable and height, weight, BMI, maternal age, number of retrieved oocytes, use of alcohol, smoking, highest level of education and parity as independent variables., Results: Of the 6598 women who completed their first IVF or ICSI cycle, 2375 had DET, resulting in 496 deliveries of 371 singletons and 125 twins. Multivariable regression analysis revealed that tall women (>1.74 cm) and women with a high number of retrieved oocytes (>8) had an increased chance of dizygotic twinning [OR: 1.8 (95% CI: 1.0-3.4) and OR: 2.2 (95% CI: 1.3-3.8), respectively]., Conclusions: Our data demonstrate that tall stature and increased number of retrieved oocytes independently increase the chance of dizygotic twinning after IVF with DET.

The cross-odds ratio is defined as the ratio of the conditional odds of the occurrence of one cause-specific event for one subject given the occurrence of the same or a different cause-specific event for another subject in the same cluster over the unconditional odds of occurrence of the cause-specific event. It is a measure of the association between the correlated cause-specific failure times within a cluster. The joint cumulative incidence function can be expressed as a function of the marginal cumulative incidence functions and the cross-odds ratio. Assuming that the marginal cumulative incidence functions follow a generalized semiparametric model, this paper studies the parametric regression modeling of the cross-odds ratio. A set of estimating equations are proposed for the unknown parameters and the asymptotic properties of the estimators are explored. Non-parametric estimation of the cross-odds ratio is also discussed. The proposed procedures are applied to the Danish twin data to model the associations between twins in their times to natural menopause and to investigate whether the association differs among monozygotic and dizygotic twins and how these associations have changed over time.

Context: We report on a case of nondiabetic ketoacidosis due to mild starvation in a third term twin pregnancy., Objective: The aim was to present a case report and review of the literature in nondiabetic ketoacidosis in pregnancy, including precipitating factors and underlying pathophysiology., Design: The case report includes collation of earlier data and literature review., Setting: The patient was admitted to the obstetrics ward of a large general hospital and, after cesarean section, was transferred to the intensive care unit., Patient: We present the case of a 26-yr-old obese patient with a 35-wk twin pregnancy., Intervention: We provided appropriate management with fluid infusion after cesarean delivery., Results: The patient and her two daughters survived, and no disabilities were foreseen. Alcohol, methanol, and lactic acid levels were normal. No signs of renal disease or diabetes were present. Pathological examination revealed no abnormalities of the placentae. Toxicological tests revealed a salicylate level of less than 5 mg/liter, an acetaminophen level of less than 1 mg/liter, and an acetone level of 300 mg/liter (reference, 5-20 mg/liter)., Conclusions: We present a case of third term twin pregnancy with high anion gap metabolic acidosis due to (mild) starvation. Starvation, obesity, third term twin pregnancy, and perhaps a gastroenteritis were the ultimate provoking factors. In the light of the erroneous suspicion of sepsis and initial fluid therapy lacking glucose, one wonders whether, under a different fluid regime, cesarean section could have been avoided. Severe ketoacidosis in the pregnant woman is associated with impaired neurodevelopment. It therefore demands early recognition and immediate intervention.

Context: The incidence of type 1 diabetes has been increasing over time., Objective: We estimated the genetic and environmental components of type 1 diabetes susceptibility in a twin cohort of recent-onset cases to explore the sources of changing disease epidemiology., Design: We linked the population-based Italian Twin Registry with 14803 type 1 diabetes records from 36 pediatric diabetes care centers throughout Italy, except Sardinia, and identified 173 diabetic twins. Patients were positive for at least one autoantibody to islet cell, glutamate decarboxylase, tyrosine phosphatase, insulin, or zinc transporter 8 and were insulin dependent since their diagnosis. Zygosity was determined by DNA genotyping or by questionnaire., Outcome Measures: We estimated proband-wise concordance, cotwin recurrence risk with Kaplan-Meier method, and genetic and environmental proportions of susceptibility variance by structural equation models., Results: We recruited 104 diabetic twins (53 males) from 88 pairs (34 monozygotic, 54 dizygotic) and one triplet. The mean age at diagnosis was 8.1 yr (range 1.1-20.5 yr), and the median year of diagnosis was 2002. Proband-wise concordances were 45.5 and 16.4% in monozygotic and dizygotic pairs (P = 0.01). Recurrence risks in monozygotic and dizygotic cotwins were 37 and 12% after 10 yr from the proband's diagnosis (P = 0.005). Genetic contribution to type 1 diabetes susceptibility was 40% (95% confidence interval 8-78), and the shared and individual-specific environmental components were 51% (14-77) and 9% (4-19), respectively., Conclusions: In addition to the moderate genetic effects on type 1 diabetes susceptibility, our results draw attention to the substantial shared environmental effects, suggesting that exposures in fetal or early postnatal life may contribute to the increasing incidence of the disease.

Objective: To examine genetic and environmental contributions to stability and change in sleep problems (SP) in early childhood., Methods: The sample comprised over 300 twin pairs assessed at ages 2 and 3 years. Parents rated SP on the Sleep Problems subscale of the Child Behavior Checklist for ages 1.5-5 years., Results: Longitudinal quantitative genetic analyses indicated that SP were genetically influenced at both ages. The stability of SP from ages 2 to 3 years was largely due to genetic factors common to both ages. Nonshared environmental influences displayed modest continuity across age. New genetic and nonshared environmental factors emerged at age 3 years., Conclusions: Genetic factors contribute to the stability in SP, whereas change is due to both genetic and nonshared environmental influences. Early interventions on SP and individualized treatments based on children's unique environmental experiences may be fruitful.