Linkage disequilibrium (LD), the association in populations between genes at linked loci, has achieved a high degree of prominence in recent years, primarily because of its use in identifying and cloning genes of medical importance. The field has recently been reviewed by Slatkin (2008). The present article is largely devoted to a review of the theory of LD in populations, including historical aspects.

In traditional East Asian medicine, cold–heat patterns have been widely used in the diagnosis and treatment of patients suffering from various diseases. The present study aimed to estimate the heritability of cold–heat patterns. Trained interviewers administered a cold–heat pattern questionnaire to 1,753 twins (mean age = 19.1 ± 3.1 years) recruited throughout South Korea. Correlations for the cold pattern (CP) were 0.42 (95% CI [0.28, 0.54]) for monozygotic (MZ) males, 0.16 (95% CI [-0.08, 0.39]) for dizygotic (DZ) males, 0.40 (95% CI [0.30, 0.49]) for MZ females, 0.30 (95% CI [0.12, 0.45]) for DZ females, and 0.07 (95% CI [-0.11, 0.25]) for opposite-sex DZ twins. The corresponding twin correlations for the heat pattern (HP) were 0.38 (95% CI [0.24, 0.51]), -0.22 (95% CI [-0.43, 0.02]), 0.34 (95% CI [0.24, 0.43]), 0.21 (95% CI [0.03, 0.37]), and 0.08 (95% CI [-0.10, 0.26]), respectively. These patterns of twin correlations suggested significant genetic effects on the HP and the CP. Model-fitting analysis revealed that heritability estimates in both sexes were 40% (95% CI [38, 42]) for the CP and 33% (95% CI [25, 42]) for the HP, with the remaining variances attributable to unique environmental variances. These estimates did not vary significantly with age during adolescence and young adulthood.

A literature review was carried out to identify pre and perinatal characteristics associated with variation in Apgar scores in population-based studies. The parameters identified in the literature search were included in the classical twin design study to estimate effects of pre and perinatal factors shared and nonshared by twins and to test for a contribution of genetic factors in 1- and 5-min Apgar scores in a large sample of Dutch monozygotic (MZ) and dizygotic (DZ) twins. The sample included MZ and DZ twins (N = 5181 pairs) recruited by the Netherlands Twin Register shortly after birth, with data on prenatal characteristics and Apgar scores at first and/or fifth minutes. The ordinal regression and structural equation modeling were used to analyze the effects of characteristics identified in the literature review and to estimate genetic and nongenetic variance components. The literature review identified 63 papers. Consistent with the review, we observed statistically significant effects of birth order, zygosity and gestational age (GA) for 1- and 5-min Apgar scores of both twins. Apgar scores are higher in first-born versus second-born twins and DZ first-born versus MZ first-born twins. Birth weight had an effect on the 5-min Apgar of the first born. Fetal presentation and mode of delivery had different effects on Apgar scores of first- and second-born twins. Parental characteristics and chorionicity did not have significant main effects on Apgar scores. The MZ twins’ Apgar correlations equaled the DZ Apgar correlations. Our analyses suggest that individual differences in 1- and 5-min Apgar scores are attributable to shared and nonshared pre and perinatal factors, but not to genotypic factors of the newborns. The main predictors of Apgar scores are birth order, zygosity, GA, birth weight, mode of delivery and fetal presentation.

Recent studies comparing cognitive abilities between contemporary twins and singletons in developed countries have suggested that twin deficits in cognitive abilities no longer exist. We examined cognitive abilities in a sample of twins and singletons born recently in Nigeria to determine whether recent findings can be replicated in developing countries. Our sample consisted of 413 pairs of twins and 280 singletons collected from over 45 public schools in Abuja and its neighboring states in Nigeria. The ages of twins and singletons ranged from 9 to 20 years with a mean (SD) of 14.6 years (2.2 years) for twins and 16.1 years (1.8 years) for singletons. Zygosity of the same-sex twins was determined by analysis of 16 deoxyribonucleic acid markers. We asked participants to complete a questionnaire booklet that included Standard Progressive Matrices-Plus Version (SPM+), Mill-Hill Vocabulary Scale (MHV), Family Assets Questionnaire, and demographic questions. The data were corrected for sex and age and then analyzed using maximum likelihood model-fitting analysis. Although twins and singletons were comparable in family social class indicators, singletons did better than twins across all the tests (d = 0.10 to 0.35). The average of d for SPM+ total [0.32; equivalent to 4.8 Intelligence Quotient (IQ) points] and d for MHV (0.24; equivalent to 3.6 IQ points) was 0.28 (equivalent to 4.2 IQ points), similar to the twin–singleton gap found in old cohorts in developed countries. We speculate that malnutrition, poor health, and educational systems in Nigeria may explain the persistence of twin deficits in cognitive abilities found in our sample.

In singletons, asthma may be associated with shorter height and delayed growth during adolescence. Yet, these studies do not account for heritability of asthma, puberty/menarche, and height. We aimed to study the association between asthma and puberty in boys and menarche in girls, and height, in a cohort of twins and subsequently in same-sex twin pairs discordant for asthma. From a Swedish twin cohort, parent- and self-reported data on asthma, puberty/menarche, and height were collected. Pubertal staging was established via the Petersen index. Logistic and linear regression was used to estimate associations between asthma and puberty/menarche and height, respectively. For within-pair analyses in twins discordant for asthma, conditional logistic and linear regression were used. Data on 2,658 (49.1% boys) twins were included. Among boys, asthma prevalence was 8.2% at 8–9 years and 10.2% at 13–14 years. Corresponding numbers for girls were 4.2% and 4.9%, respectively. In the entire cohort, no statistically significant associations were found between current asthma and puberty/menarche. Boys with asthma were shorter than boys without asthma at 8–9 years (on average, 1.86 [0.17–3.56] cm, p = .03) and at 13–14 years (on average, 2.94 [0.98–4.91] cm, p = .003) but not at 19–20 years. No such associations were found for girls. Within same-sex twin pairs discordant for asthma, no statistically significant associations were found for either sex. Twin boys, but not girls, with asthma were shorter than those without asthma. Non-statistically significant estimates from within-pair analyses suggest the association is partly confounded by genetic or familial environmental factors.

In order to further understand why depressive symptoms are associated with negative goal appraisals, the present study examined the genetic and environmental correlations and interactions between depressive symptoms and career-related goal appraisals. A total of 1,240 Finnish twins aged 21–26 years completed a questionnaire containing items on the appraisal of their career goals along five dimensions: importance, progress, effort, strain, and self-efficacy. In the same questionnaire, the 10-item General Behavior Inventory assessed depressive symptoms. Structural equation modeling was used to evaluate the genetic and environmental correlations and gene–environment interactions between the career-goal appraisals and depressive symptoms. Associations were identified, and were attributed to environmental factors. Of the career-related goal appraisals, the shared environmental component was of a higher magnitude for the dimension of strain among the depressed compared with non-depressed subjects. The results indicate that the interplay between depressive symptoms and negative career-related goal appraisals is significantly affected by environmental factors, and thus possibly susceptible to targeted interventions.

The aim of this study was to present the outcome of bichorionic twin pregnancies complicated by early second trimester rupture of membranes in one sac. Data regarding all cases of ruptured membranes at 13–20 weeks in bichorionic twin pregnancies were collected retrospectively from three fetal medicine units. Patients who have chosen to terminate the pregnancy were excluded from the study. Between January 2003 and July 2009, nine patients met inclusion criteria. Three out of nine couples decided on expectant management, and six preferred selective feticide. With expectant management one fetus died in utero and take home baby rate was 83% (5 of 6 fetuses), delivered at 27–32 weeks. When selective termination was performed, all non-reduced fetuses were born alive at 33–40 weeks. Two survivors of rupture of membranes had limb contractures, none had lung hypoplasia. One patient had clinical signs of amnionitis, which was ruled out later on pathological examination. Her post partum course was uncomplicated. Our data suggest that rupture of membranes in one sac of bichorionic twins at 13–20 weeks has favorable prognosis whether an intervention is preformed or not. Nonetheless, selective termination may have an advantage over expectant management, since gestational age at delivery was higher when selective termination was performed.

Substantial effort has been put into the exploration of the biological background of eating disorders, through family, twin and molecular genetic studies. Family studies have shown that anorexia (AN) and bulimia nervosa (BN) are strongly familial, and that familial etiologic factors appear to be shared by both disorders. Twin studies often focus on broader phenotypes or subthreshold eating disorders. These studies consistently yielded moderate to substantial heritabilities. In addition, there has been a proliferation of molecular genetic studies that focused on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) AN and BN. Seven linkage regions have been identified in genome-wide screens. Many genetic association studies have been performed, but no consistent association between a candidate gene and AN or BN has been reported. Larger genetic association studies and collaborations are needed to examine the involvement of several candidate genes and biological pathways in eating disorders. In addition, twin studies should be designed to assist the molecular work by further exploring genetic determinants of endophenotypes, evaluating the magnitude of contribution to liability of measured genotypes as well as environmental risk factors related to eating disorders. In this manner twin and molecular studies can move the field forward in a mutually informative way.

Sex differences in mental rotation ability have been observed in many countries. A previous study of Finnish participants reported that genetic and environmental influences on mental rotation ability differ between sexes. In this study, we assessed genetic and environmental influences on variance in mental rotation ability in 649 Japanese twins using a mental rotation test. To explain the influence of sex on variance in mental rotation ability, we applied genetic analysis using the sex limitation model. The following two factors explained variance in mental rotation ability: (1) the additive genetic factor, which reflects the accumulated small influence of many genes, and (2) the unique environmental factor, which is a type of environmental factor that differs between co-twins. The shared environmental factor, a type of environmental factor common for co-twins, could not explain the variance in mental rotation ability. Furthermore, the additive genetic factor was the same between sexes (i.e., not qualitative sex differences for the additive genetic factor), indicating that the same genes affect mental rotation ability in both sexes. Despite this observation, the additive genetic influence was greater in males than in females. In contrast, the unique environmental influence was not different between sexes. Considering the current results and those of a previous study, the quantitative sex difference for the additive genetic influences in mental rotation ability may be universal, while the unique environmental differences may depend on the characteristics of specific populations.

Personality disorders (PDs) reduce global functioning, are associated with high levels of work disability, and are thus also likely to influence long-term sick leave (LTSL). Previous research has indicated significant genetic influence on both DSM-IV PDs and LTSL. To what degree genes contributing to PDs also influence LTSL has not been investigated. The aims of the current study were to investigate which PDs were significantly associated with LTSL, to what extent the genetic contributions to these PDs account for the heritability of LTSL, and to explore the hypothesis of a causal association between PDs and LTSL. The sample consisted of 2,771 young, adult Norwegian twins, born 1967–1979. PDs were assessed using the Structured Interview for DSM-IV Personality (SIDP-IV). The age range for the interview was 20–32. The data were subsequently linked to public records of LTSL (sick leave >16 days) up to 11 years later. The odds ratio for being in the highest LTSL category (>15% sick leave) when fulfilling the DSM-IV criteria for any PD diagnosis was 2.6 (1.8–3.8, 95% CI). Dimensional representations of schizotypal, paranoid, and borderline PD were independently and significantly associated with LTSL. The heritability of LTSL was 0.50. Genetic factors shared with the PDs accounted for 20% of this. The association between PDs and LTSL was due to shared genetic and not environmental influences, and was mainly explained by one common genetic factor. The hypothesis of a causal association was not supported, indicating that the association is explained by overlapping genetic liability between PDs and LTSL.

The rate of multiple births is substantially elevated in women who have had assisted reproduction treatment (ART; ˜26%) compared to the general population (˜1%), and these offspring are usually included in twin studies. Several studies have attempted to identify possible consequences of undergoing ART on the subsequent offspring. However, most studies have only included singleton births. We first examined whether twins born by ART differed from other twins on measures of childhood psychopathology, putative risk factors and correlates, and secondly tested for differences in the degree of twin similarity for available outcome measures. From a population-based twin sample, 101 families with dizygotic (DZ) twins conceived via ART were identified and compared with 1073 naturally conceived (NC) control DZ twin pairs. Analyses performed were (1) univariate and multivariate comparisons of between-group mean differences; and (2) comparison of twin 1–twin 2 correlations between the groups. The groups differed significantly on demographic factors (parental age, family size and social class) and pregnancy variables (smoking during pregnancy and birthweight) but did not differ on family conflict scores or in the frequency of obstetric complications. Family cohesion was higher in the ART group but this was accounted for by demographic factors. For child psychopathology there was a difference between the groups only for teacher-rated ADHD (Attention Deficit Hyperactivity Disorder). Differences were also found between groups for twin correlations. The differences found between ART and NC twins on group means and twin correlations suggest that researchers should be aware that including ART twins may influence results from twin studies.

Craniofacial duplication or diprosopus is a very rare malformation that is present in approximately 0.4% of conjoined twins. Here is presented a case of craniofacial duplication in association with bilateral cleft lip/palate in both heads found in a ceramic representation from the early Chimú culture from Peru. A comparative analysis is made with a current case of a 28-week-old fetus with similar characteristics. After reviewing the medical literature on conjoined twins, very few reports of facial cleft in both twins were found, with no reports at all of bilateral cleft lip/palate. This ceramic crock is considered one of the first representations suggestive of craniofacial duplication, and probably the first reporting it in association with facial cleft.

Diurnal preference (e.g., being an owl or lark) has been associated with several psychiatric disorders including bipolar disorder (BP), major depressive disorder, and substance use disorders. Previous large-scale genome-wide association studies (GWAS) aimed at identifying genetic influences on diurnal preference have exclusively included subjects of European ancestry. This study examined the genetic architecture of diurnal preference in two minority samples: a young adult sample of Mexican Americans (MAs), and a family-based sample of American Indians (AIs). Typed or imputed variants from exome chip data from the MA sample and low pass whole-genome sequencing from the AI cohort were analyzed using a mixed linear model approach for association with being an owl, as defined by a usual bedtime after 23:00 hrs. Genetic risk score (GRS) profiling detected shared genetic risk between evening preference and related disorders. Four variants in KIAA1549 like (KIAA1549L), a gene previously associated with attempted suicide in bipolar patients, were suggestively associated with being an owl at p < 1.82E-05; post hoc analyses showed the top variant trending in both the MA and AI cohorts at p = 2.50E-05 and p = .030, respectively. Variants associated with BP at p < .03 from the Psychiatric Genomics Consortium nominally predicted being an owl in the MA/AI cohort at p = .012. This study provides some additional evidence that genetic risk factors for BP also confer risk for being an owl in MAs/AIs and that evening preference may be a useful endophenotype for future studies of BP.

Recent research has provided strong support for the existence of a familial risk for suicide, and efforts have been made to separate genetic from enviromental risk factors. Twin studies have played a major role in the identification of genetic factors, and the results indicate that the concordance rate for suicide is higher in identical than in fraternal twins (Baldessarini & Hennen, 2004). Moreover, Segal and Roy (1995) reported a significantly higher frequency of nonfatal suicidal attempts by monozygotic (MZ) than by dyzygotic (DZ) twins whose co-twins had committed suicide. However, doubts remain as to whether the increased risk of suicide in MZ twins is a response to the intense grief over the loss of a close relative, or whether a common genotype is associated with suicidal behavior. Sudden loss, which may carry a stigma in the case of a suicide, has been linked to increased persistent emotional stress and physiological changes (Epstein, 1993; Martin & Dean, 1993). A number of researchers have reported greater suicidal ideation among bereaved MZ twins as compared to DZ twins, suggesting that a loss due to suicide may increase the risk of suicidal behavior in the surviving co-twin (Segal & Bouchard, 1993; Segal & Roy, 1995; Segal et al., 1995). The aim of the present article is to address the issue of the intense grief experienced by twins after the co-twin suicide.

Perinatal mortality is higher in twins. Effects of twin order have not previously been studied in the context of single fetal demise. Our objective was to determine whether death of the fetus more proximal to the cervix will result in worse perinatal outcomes. Our population included multiple pregnancies with two viable fetuses confirmed prior to 20 weeks’ gestation with the subsequent death of at least one twin. All the pregnancies were managed at The Royal Women's Hospital, Melbourne between 2006 and 2014. We excluded pregnancies of higher order multiples, the death of both twins simultaneously, and cases with incomplete outcome data. Maternal and neonatal data were reviewed. Of 46 pregnancies included, in 24 (52%), the dead twin was presenting. Gestational age at delivery was significantly earlier in these cases (mean difference: -5.0 weeks, 95% CI [-7.4, -2.6], p < .001), and emergency cesarean rates were higher 67% versus 32% (OR 4.29, 95% CI [1.25, 14.7], p = .02). There were no differences in the frequency of chorioamnionitis, preterm prelabor rupture of membranes, or placental abruption. Survival rates for co-twins were similar in both groups (presenting 83%; not presenting 91%; OR 0.41, 95% CI [0.07, 2.50], p = .29). The increase in neonatal morbidities was related to prematurity rather than to order. Findings were more common in dichorionic twins. Analysis was limited by a small sample size. If the dead twin is presenting, delivery is likely to occur earlier, with associated morbidity for the survivors. This is especially relevant for dichorionic twin pregnancies.

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

Fine mapping of linkage peaks is one of the great challenges facing researchers who try to identify genes and genetic variants responsible for the variation in a certain trait or complex disease. Once the trait is linked to a certain chromosomal region, most studies use a candidate gene approach followed by a selection of polymorphisms within these genes, either based on their possibility to be functional, or based on the linkage disequilibrium between adjacent markers. For both candidate gene selection and SNP selection, several approaches have been described, and different software tools are available. However, mastering all these information sources and choosing between the different approaches can be difficult and time-consuming. Therefore, this article lists several of these in silico procedures, and the authors describe an empirical two-step fine mapping approach, in which candidate genes are prioritized using a bioinformatics approach (ENDEAVOUR), and the top genes are chosen for further SNP selection with a linkage disequilibrium based method (Tagger). The authors present the different actions that were applied within this approach on two previously identified linkage regions for muscle strength. This resulted in the selection of 331 polymorphisms located in 112 different candidate genes out of an initial set of 23,300 SNPs.

Based on results from a survey study in a sample of Australian parents of twins, Raj and Morley (2007) reported that questions concerning the mode of conception of twins may be offensive to parents. We looked at the willingness to reply to questions about mode of conception of twin pregnancies in a large survey study that was completed by 20,150 mothers of twins from the Netherlands Twin Registry. Data collection took place in 2005/2006. The amount of missing data was examined and by using data from earlier survey studies, responders and nonresponders were compared with respect to their answers to questions on assisted reproduction techniques. In addition, we assessed the reliability of the question on mode of conception by comparing the survey data with hospital records in a subsample of 80 mothers of twins. We found no indication that mothers of twins were not prepared to reply to questions on mode of conception. Only a small number of mothers did not fill in the question on mode of conception (0.8%). Also, the use of artificial fertility techniques did not differ between mothers who returned and mothers who did not return the 2005/2006 survey. The comparison of the survey data with the hospital records showed that mothers can accurately report on the mode of conception of their twins.

Irving Gottesman is known primarily for his work in psychopathology, but he also had a long-standing interest in understanding psychological development generally (typical and atypical). Through his mentorship, he also influenced work in gender development. Characteristics related to sex and gender are ideally suited to study the interplay of genes and environment across development. We discuss how gender development is influenced by gonadal hormones present during early life, but not in a simple way. We describe some of the challenges and opportunities to extend our understanding of the complexity of gender development. Throughout, we consider the kinds of questions Gottesman would likely have asked and emphasize his influence on our work.

There is a well-established relationship between cannabis use and psychosis, although the exact nature of this relationship is not fully understood. Recent studies have observed significant genetic overlap between a diagnosis of schizophrenia and lifetime cannabis use. Expanding on this work, the current study aimed to examine whether genetic overlap also occurs for subclinical psychosis (schizotypy) and cannabis use, as well as examining the phenotypic association between the traits. Phenotypic correlations were calculated for a variety of schizotypy and cannabis phenotypes in the UK Biobank (UKB), and single nucleotide polymorphism (SNP)-based heritability estimates and genetic correlations were calculated for these UKB phenotypes as well as for several other variables taken from recent genomewide association studies. Positive phenotypic correlations were observed between 11 out of 12 pairs of the cannabis use and schizotypy phenotypes (correlation range .05–.18), indicating a robust association between increased symptoms of schizotypy and cannabis use. SNP-based heritability estimates for two schizotypy phenotypes remained significant after multiple testing correction: social anhedonia (h2SNP = .08, SE = .02, N = 4025) and ever seen an unreal vision (h2SNP = .35, SE = .10, N = 150,717). Finally, one significant genetic correlation was observed between schizotypy and cannabis use, a negative correlation between social anhedonia and number of times used cannabis (rg = −.30, p = .012). The current study suggests the relationship between cannabis use and psychosis is also seen in subclinical symptoms of psychosis, but further research with larger samples is needed to determine the biological mechanisms underlying this association.