Comorbidity — the clustered occurrence of two traits or disorders — may be studied in genetically informative designs such as the classical twin study, to test whether genetic and/or environmental factors underlying the two disorders are correlated. When a genetic correlation is found, this can be explained by several mechanisms, including pleiotropy (the same genes influencing multiple traits), and causality (one trait causing the other). With a cotwin control design, it can be investigated which scenario is most plausible. In this design, monozygotic twin pairs discordant for the first trait (i.e., one twin is affected, the other is not) are compared in terms of their risk for the second trait: under a causal model, only the twins affected for the first trait will be at increased risk for the second trait. Under genetic pleiotropy, this risk will be increased in both twins because they share the same risk genes. We first discuss the cotwin control design and then illustrate its application with data on migraine and neuroticism that were collected in 5,200 Dutch twins, including 1,648 complete twin pairs (981 monozygotic and 667 dizygotic pairs). There was a significant association between migraine and neuroticism, which could be attributed to genetic and environmental correlations (rG = .27 and rE = .19). In monozygotic and dizygotic twin pairs discordant for neuroticism, the risk of migraine was significantly higher in the twins with a high neuroticism score. This pattern of results is consistent with a causal relationship, suggesting that neuroticism increases the risk of migraine.

The prevalence of the feeling of cold hands and feet (FCHF) is high in the general population but the etiology of FCHF is largely unknown. The aim of the present study was to explore whether the FCHF is heritable. Eight hundred and ninety-four pairs of twins completed a question about FCHF. Tetrachoric correlations for FCHF were .58, .29, .67, .52, and .04 for monozygotic male, dizygotic male, monozygotic female, and dizygotic female twins, respectively. Model-fitting analyses suggested that in the best fitting model, additive genetic and nonshared environmental variance including measurement error were 64% (95% CI: 55%-72%) and 36% (28%-45%), respectively. Sex differences in genetic and environmental influences were not significant.

Age-related hearing impairment (ARHI) is a common condition with complex etiology but a recognized genetic component. Heritability estimates for pure tone audiogram-determined hearing ability lie in the range 26–75%. The speech-in-noise (SIN) auditory test, however, may be better at encapsulating ARHI symptoms, particularly the diminished ability to segregate environmental sounds into comprehendible auditory streams. As heritability of SIN has not previously been reported, we explored the genetic and environmental contributions to ARHI determined by SIN in 2,076 twins (87.8% female) aged 18–87 (mean age 54.4). SIN was found to be significantly heritable (A, unadjusted for age = 40%; 95% confidence intervals, CI = 32%–47%). With age adjustment, heritability fell (A = 25%; 95% CI = 16–33%), and a relatively strong influence of environmental exposure unshared within twin siblings was identified (E = 75%). To explore the environmental aspects further, we assessed the influence of diet (through the Food Frequency Questionnaire, FFQ), smoking (through self-report and cotinine metabolite levels) and alcohol intake (through the FFQ). A negative influence of high cholesterol diet was observed after adjustment (p = .037). A protective effect of raised serum high-density lipoprotein (HDL) cholesterol levels was observed after adjustment (p = .004). This study is the first assessment of the genetic and environmental influence on SIN perception. The findings suggest SIN is less heritable than pure tone audiogram (PTA) ability and highly influenced by the environment unique to each twin. Furthermore, a possible role of dietary fat in the etiology of ARHI is highlighted.

Objective: A recent Children-of-Female-Twin design suggests that the association between maternal alcohol use disorder and offspring ADHD is due to a combination of genetic and environmental factors, such as prenatal nicotine exposure. We present here a complementary analysis using a Children-of-Male-Twin design examining the association between paternal alcoholism and offspring attention deficit hyperactivity problems (ADHP). Methods: Children-of-twins design: offspring were classified into 4 groups of varying genetic and environmental risk based on father and co-twin's alcohol dependence status. Results: Univariate results are suggestive of a genetic association between paternal alcohol dependence and broadly defined offspring ADHP. Specifically, offspring of male twins with a history of DSM-III-R alcohol dependence, as well as offspring of non-alcohol dependent monozygotic twins whose co-twin was alcohol dependent, were significantly more likely to exhibit ADHP than control offspring. However, multivariate models show maternal variables independently predicting increased risk for offspring ADHP and significantly decreased support for a genetic mechanism of parent-to-child transmission. Conclusions: In support of earlier work, maternal variables (i.e., maternal ADHD and prenatal exposure) were strongly associated with child ADHP; however, the role of paternal alcohol dependence influences was not definitive. While genetic transmission may be important, the association between paternal alcohol dependence and child ADHP is more likely to be indirect and a result of several pathways.

Telegenetics is a new development in the service delivery of Genetic Services in Australia. This project was designed to establish if it was an acceptable alternative to a face-to-face consultation in the genetic assessment of intellectual disability, including morphological assessment, of the patient. Ten children from two outreach clinics in rural NSW who were referred by their pediatrician were assessed by a single geneticist via telehealth and then seen again face-to-face as a ‘gold standard'. Satisfaction surveys were then sent to both the parents and the referring pediatricians. After the face-to-face appointment, the clinical geneticist reviewed the recordings of both the transmitted footage and the high definition footage that was sent separately. There were very few morphological findings missed by the telegenetic assessments. The discrepancies that were noted could decrease in frequency as staff become more familiar with the methods. The parents of the patients reported no problem with the cameras and telehealth. They would have preferred face-to-face appointment but would be happy to have the telehealth appointment if it meant being seen earlier. This pilot study suggests that clinical genetic diagnostic assessment could be performed by telemedicine.

Obstetric complications increase the risk of schizophrenia. However, it is not known whether there is a causal relation or whether the association is mediated by genetic and/or shared environmental effects. The aim of this study was to investigate the associations between birthweight, other birth characteristics, and schizophrenia. Twin pairs discordant for schizophrenia will also control for unmeasured genetic and shared environmental effects. Prospectively filed obstetric records were used for a cohort analysis of 11,360 same-sexed twins, and within–twin pair analyses were conducted on 90 twin pairs discordant for schizophrenia. The results from the cohort study showed that low birthweight (less than or equal to 1999 grams; odds ratio [OR] 1.67, 95% confidence interval [CI] 0.88–3.14 and 2000–2299 grams; OR 1.79, 95% CI 1.07–3.01) and small head circumference (less than or equal to 31.5 cm; OR 1.61, 95% CI 1.03–2.51) were associated with later development of schizophrenia. The associations remained in the within-pair analyses. The association between low birthweight and schizophrenia is partly a function of reduced fetal growth. Fetal growth restriction seems to be associated with risk of schizophrenia independently of familial factors.

The purpose of the present study was to examine the 10 value types from the Portrait Values Questionnaire (PVQ; Schwartz et al., 2001) both at the phenotypic (observed) level as well as the genetic and environmental level. Australian twins (N = 695) completed the PVQ as part of a larger questionnaire battery. Nine of the value types were found to have a genetic component with heritability estimates ranging from 10.8% for power to 38% for conformity. The achievement scale was best explained by environmental factors. The interscale correlations were found to range from –.02 to .70 at the phenotypic level. Of these 45 correlations, 16 were found to be explained by overlapping genetic factors and almost all (41) were found to have significant unique environment correlations.

Cervical cancer is the third most common cancer in women worldwide. Persistent infection with an oncogenic human papillomavirus (HPV) is necessary, but not sufficient, for its development. Over many years, only a small proportion of women with chronic HPV infection progress to develop disease. The role of host genes and environmental factors in the pathogenesis of, or predisposition to, cervical cancer is still unclear. We conducted a systematic review of published literature in MEDLINE–PubMed to identify studies of cervical cancer susceptibility that used a twin study design. We used standard MeSH terms (controlled vocabulary) as well as specific free-text terms and combinations of terms related to cervical cancer, with no restriction on publication date. We performed a full text review to ensure the identified articles met our inclusion criteria and, if so, extracted information on demographics, sample size, study definitions, and key statistical findings. Of the 285 articles identified, three utilized a classical twin design and reported results specific to cervical cancer. The studies were based on cancer registry data from Scandinavia, with sample sizes ranging from 312 to 710 twin pairs. The findings from one study were consistent with a genetic mechanism for the causation of carcinoma in situ. Future research studies using the strength of the classic twin design, together with incorporation of HPV DNA status, are indicated to determine whether there is a potential role for genetic factors in the development of cervical cancer or high-grade cervical dysplasia from chronic oncogenic HPV infection.

This study was performed to determine the rates of breastfeeding among singletons, twins and triplets in Japan, and identify factors associated with the decision to breastfeed or bottle-feed. We analyzed a database of medical check-up of infants aged 3 to 6 months between April 2001 and July 2004 in Nishinomiya City in Japan. This medical check-up is given to almost 100% of infants in Japan and the data of 15,262 infants were analyzed. Among these, 14,963 (98.0%) were singletons, 290 (1.9%) were twins and 9 (0.1%) were triplets. Exclusive breast-feeding was chosen by 6680 (43.8%) mothers, mixed-feeding by 4645 (30.4%) mothers, and bottle-feeding with formula milk only by 3900 (25.6%) mothers. The rate of exclusive breastfeeding among twins or triplets was significantly lower than among singleton babies: 4.1% among twins or triplets, and 44.7% among singletons. Moreover, twins and triplets were independently associated with a higher rate of bottle-feeding: the odds ratio indicated that mothers who had twins or triplets were 2.44 times more likely to choose bottle-feeding with formula milk only than those who had singletons. Sucking ability at birth was associated with a higher rate of bottle-feeding: the odds ratio indicated that mothers who had infants with poor sucking ability at birth were 1.56 times more likely to choose bottle-feeding as those who had infants with normal sucking ability.

Background: Previous genome-wide association studies (GWAS) have identified a large number of genetic variants for obesity and its related traits, representing a group of potential key genes in the etiology of obesity. Emerging evidence suggests that epigenetics may play an important role in obesity. It has not been explored whether the GWAS-identified loci contribute to obesity through epigenetics (e.g., DNA (deoxyribonucleic acid) methylation) in addition to genetics. Method: A multi-stage cross-sectional study was designed. We did a literature search and identified 117 genes discovered by GWAS for obesity and its related traits. Then we analyzed whether the methylation levels of these genes were also associated with obesity in two genome-wide methylation panels. We examined an initial panel of seven adolescent obese cases and seven age-matched lean controls, followed by a second panel of 48 adolescent obese cases and 48 age- and gender-matched lean controls. The validated CpG sites were further replicated in two independent replication panels of youth (46 vs. 46 and 230 cases vs. 413 controls, respectively) and a general population of youth, including 703 healthy subjects. Results: One CpG site in the lymphocyte antigen 86 (LY86) gene, which showed higher methylation in the obese in both the initial (p = .009) and second genome-wide DNA methylation panel (p = .008), was further validated in both replication panels (meta p = .00016). Moreover, in the general population of youth, the methylation levels of this region were significantly correlated with adiposity indices (p ≤ .02), insulin resistance (p = .001), and inflammatory markers (p < .001). Conclusion: By focusing on recent GWAS findings in genome-wide methylation profiles, we identified a solid association between LY86 gene DNA methylation and obesity.

In previous studies we obtained evidence that variation in loneliness has a genetic component. Based on adult twin data, the heritability estimate for loneliness, which was assessed as an ordinal trait, was 48%. These analyses were done on loneliness scores averaged over items (‘I feel lonely’ and ‘Nobody loves me’) and over time points. In this article we present a longitudinal analysis of loneliness data assessed in 5 surveys (1991 through 2002) in Dutch twins (N = 8389) for the two separate items of the loneliness scale. From the longitudinal growth modeling it was found sufficient to have non-zero variance for the intercept only, while the other effects (linear, quadratic and cubic slope) had zero variance. For the item ‘I feel lonely’ we observed an increasing age trend up to age 30, followed by a decline to age 50. Heritability for individual differences in the intercept was estimated at 77%. For the item ‘Nobody loves me’ no significant trend over age was seen; the heritability of the intercept was estimated at 70%.

Causes of individual differences in happiness, as assessed with the Subjective Happiness Scale, are investigated in a large of sample twins and siblings from the Netherlands Twin Register. Over 12,000 twins and siblings, average age 24.7 years (range 12 to 88), took part in the study. A genetic model with an age by sex design was fitted to the data with structural equation modeling in Mx. The heritability of happiness was estimated at 22% for males and 41% in females. No effect of age was observed. To identify the genomic regions contributing to this heritability, a genome-wide linkage study for happiness was conducted in sibling pairs. A subsample of 1157 offspring from 441 families was genotyped with an average of 371 micro-satellite markers per individual. Phenotype and genotype data were analyzed in MERLIN with multipoint variance component linkage analysis and age and sex as covariates. A linkage signal (logarithm of odds score 2.73, empirical p value 0.095) was obtained at the end of the long arm of chromosome 19 for marker D19S254 at 110 cM. A second suggestive linkage peak was found at the short arm of chromosome 1 (LOD of 2.37) at 153 cM, marker D1S534 (empirical p value of .209). These two regions of interest are not overlapping with the regions found for contrasting phenotypes (such as depression, which is negatively associated with happiness). Further linkage and future association studies are warranted.

Longitudinal height and weight data from 4649 Dutch twin pairs between birth and 2.5 years of age were analyzed. The data were first summarized into parameters of a polynomial of degree 4 by a mixed-effects procedure. Next, the variation and covariation in the parameters of the growth curve (size at one year of age, growth velocity, deceleration of growth, rate of change in deceleration [i.e., jerk] and rate of change in jerk [i.e., snap]) were decomposed into genetic and nongenetic sources. Additionally, the variation in the estimated size at birth and at 2 years of age interpolated from the polynomial was decomposed into genetic and nongenetic components. Variation in growth was best characterized by a genetic model which included additive genetic, common environmental and specific environmental influences, plus effects of gestational age. The effect of gestational age was largest for size at birth, explaining 39% of the variance. The differences between monozygotic and dizygotic twin correlations were largest for size at 1 and 2 years of age and growth velocity of weight, which suggests that these parameters are more influenced by heritability than size at birth, deceleration and jerk. The percentage of variance explained by additive genetic influences for height at 2 years of age was 52% for females and 58% for males. For weight at 2 years of age, heritability was approximately 58% for both sexes. Variation in snap height for males was also mainly influenced by additive genetic factors, while snap for females was influenced by both additive genetic and common environmental factors. The correlations for the additive genetic and common environmental factors for deceleration and snap are large, indicating that these parameters are almost entirely under control of the same additive genetic and common environmental factors. Female jerk and snap, and also female height at birth and height at 2 years of age, are mostly under control of the same additive genetic factor.

microRNAs are small, non-coding RNAs that influence gene expression on a post-transcriptional level. They participate in diverse biological pathways and may act as either tumor suppressor genes or oncogenes. As they may have an effect on thousands of target mRNAs, single-nucleotide polymorphisms in microRNA genes might have major functional consequences, because the microRNA's properties and/or maturation may change. miR-196a has been reported to be aberrantly expressed in breast cancer tissue. Additionally, the SNP rs11614913 in hsa-mir-196a-2 has been found to be associated with breast cancer risk in some studies although not in others. This study evaluated the association between rs11614913 and breast cancer risk in a Caucasian case-control cohort in Queensland, Australia. Results do not support an association of the tested hsa-mir-196a-2 polymorphism with breast cancer susceptibility in this cohort. As there is a discrepancy between our results and previous findings, it is important to assess the role of rs11614913 in breast cancer by further larger studies investigating different ethnic groups.

Despite the significant advancements being made in the neurogenetics for mental health, the identification and validation of potential endophenotype markers of risk and resilience remain to be confirmed. The TWIN-E study (The Twin study in Wellbeing using Integrative Neuroscience of Emotion) aims to validate endophenotype markers of mental health across cognitive, brain, and autonomic measures by testing the heritability, clinical plausibility, and reliability of each of these measures in a large adult twin cohort. The specific gene and environmental mechanisms that moderate prospective links between endophenotype-phenotype markers and the final outcome of wellbeing will also be identified. TWIN-E is a national prospective study with three phases: I) baseline testing on a battery of online questionnaires and cognitive tasks, and EEG, MRI, and autonomic testing; II) 12-month follow-up testing on the online assessments; and III) randomized controlled trial of brain training. Minimum target numbers include 1,500 male/female twins (18–65 years) for the online assessments (Phase I and II), 300 twins for the EEG testing component, and 244 twins for the MRI testing component. For Phase III, each twin out of the pair will be randomized to either the treatment or waitlist control group to test the effects of brain training on mental health over a 30-day period, and to confirm the gene–environment and endophenotype contributions to treatment response. Preliminary heritability results are provided for the first 50% of the MRI subgroup (n = 142) for the grey matter volume, thickness, and surface area measures, and white matter diffuse tensor imaging fractional anisotropy.

Most analyses of data collected from a classical twin study of monozygotic (MZ) and dizygotic (DZ) twins assume that zygosity has been diagnosed without error. However, large scale surveys frequently resort to questionnaire-based methods of diagnosis which classify twins as MZ or DZ with less than perfect accuracy. This article describes a mixture distribution approach to the analysis of twin data when zygosity is not perfectly diagnosed. Estimates of diagnostic accuracy are used to weight the likelihood of the data according to the probability that any given pair is either MZ or DZ. The performance of this method is compared to fully accurate diagnosis, and to the analysis of samples that include some misclassified pairs. Conventional analysis of samples containing misclassified pairs yields biased estimates of variance components, such that additive genetic variance (A) is underestimated while common environment (C) and specific environment (E) components are overestimated. The bias is non-trivial; for 10% misclassification, true values of Additive genetic: Common environment: Specific Environment variance components of .6: .2: .2 are estimated as .48: .29: .23, respectively. The mixture distribution yields unbiased estimates, while showing relatively little loss of statistical precision for misclassification rates of 15% or less. The method is shown to perform quite well even when no information on zygosity is available, and may be applied when pair-specific estimates of zygosity probabilities are available.

Context: The detection and replication of genes involved in psychiatric outcome has been notoriously difficult. Phenotypic measurement has been offered as one explanation, although most of this discussion has focused on problems with binary diagnoses. Objective: This article focuses on two additional components of phenotypic measurement that deserve further consideration in evaluating genetic associations: (1) the measure used to reflect the outcome of interest, and (2) the developmental stage of the study population. We focus our discussion of these issues around the construct of impulsivity and externalizing disorders, and the association of these measures with a specific gene, GABRA2. Design, Setting, and Participants: Data were analyzed from the Collaborative Study on the Genetics of Alcoholism Phase IV assessment of adolescents and young adults (ages 12–26; N = 2,128). Main Outcome Measures: Alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder symptoms were measured by psychiatric interview; Achenbach youth/adult self-report externalizing scale; Zuckerman Sensation-Seeking scale; Barratt Impulsivity scale; NEO extraversion and consciousness. Results: GABRA2 was associated with subclinical levels of externalizing behavior as measured by the Achenbach in both the adolescent and young adult samples. Contrary to previous associations in adult samples, it was not associated with clinical-level DSM symptom counts of any externalizing disorders in these younger samples. There was also association with sensation-seeking and extraversion, but only in the adolescent sample. There was no association with the Barratt impulsivity scale or conscientiousness. Conclusions: Our results suggest that the pathway by which GABRA2 initially confers risk for eventual alcohol problems begins with a predisposition to sensation-seeking early in adolescence. The findings support the heterogeneous nature of impulsivity and demonstrate that both the measure used to assess a construct of interest and the age of the participants can have profound implications for the detection of genetic associations.

Migraine frequently co-occurs with depression. Using a large sample of Australian twin pairs, we aimed to characterize the extent to which shared genetic factors underlie these two disorders. Migraine was classified using three diagnostic measures, including self-reported migraine, the ID migraine™ screening tool, or migraine without aura (MO) and migraine with aura (MA) based on International Headache Society (IHS) diagnostic criteria. Major depressive disorder (MDD) and minor depressive disorder (MiDD) were classified using the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. Univariate and bivariate twin models, with and without sex-limitation, were constructed to estimate the univariate and bivariate variance components and genetic correlation for migraine and depression. The univariate heritability of broad migraine (self-reported, ID migraine, or IHS MO/MA) and broad depression (MiDD or MDD) was estimated at 56% (95% confidence interval [CI]: 53–60%) and 42% (95% CI: 37–46%), respectively. A significant additive genetic correlation (rG = 0.36, 95% CI: 0.29–0.43) and bivariate heritability (h2 = 5.5%, 95% CI: 3.6–7.8%) was observed between broad migraine and depression using the bivariate Cholesky model. Notably, both the bivariate h2 (13.3%, 95% CI: 7.0–24.5%) and rG (0.51, 95% CI: 0.37–0.69) estimates significantly increased when analyzing the more narrow clinically accepted diagnoses of IHS MO/MA and MDD. Our results indicate that for both broad and narrow definitions, the observed comorbidity between migraine and depression can be explained almost entirely by shared underlying genetically determined disease mechanisms.

The genetic contribution of blood pressure and heart rate (HR) varied widely between studies. Demographic factors such as ethnicity, age and/or sex might explain some of the heterogeneity. We performed a systematic review focusing on four phenotypes: systolic blood pressure (SBP), diastolic blood pressure (DBP), HR and pulse pressure (PP). Meta-regression was conducted to analyze potential factors in relation to SBP and DBP heritability. A total of 10,613 independent twins that came from 17 studies were included in the analysis. The weighted mean value of heritability for SBP and DBP was 0.54 (95% CIs: 0.48–0.60) and 0.49 (95% CIs: 0.42–0.56). Comparatively, three studies of HR and four studies of PP heritability were limited for the heterogeneity test. Meta-regression showed that, on average, SBP heritability with additive genes/unique environment (AE) model tend to have a higher heritability than additive genes/shared environment/unique environment (ACE) model (coefficient = 0.0947, p = .0142). A similar result was found for DBP as well. No other factors such as sex, age, ethnicity, publication year were significantly associated with heritability variance. Our study shows heritability estimates based on twin studies of both SBP and DBP are around 50%, using an AE rather than an ACE model; the variance due to C ended up in A, suggesting that the AE model may overestimate heritability if a small contribution of shared environment exists.

The Nonshared Environment in Adolescent Development (NEAD) project is a longitudinal study of twins/siblings and parents that has been assessed 3 times: middle adolescence, late adolescence and young adulthood (N = 720 families at Time 1). Siblings varied in degree of genetic relatedness including identical twins, fraternal twins, full siblings, half siblings and genetically unrelated (or step) siblings. There were also two family types: nondivorced and step. A multimeasure, multirater approach was taken in NEAD, with data collected from all participants (2 twins or siblings, mother and father) as well as from coded videotaped observations of family interactions. Detailed assessments of family relationships, adolescent adjustment and competence were collected at all 3 times. The original aim of NEAD was to identify systematic sources of nonshared environmental influences that contribute to differences among family members. Although systematic sources of nonshared environmental influences were not found in NEAD, three major sets of findings emerged: (1) genetic influences on family relationships and on associations between family relationships and adolescent adjustment; (2) genetic and environmental influences on adolescent adjustment, comorbidity and stability and change in adolescent adjustment from middle to late adolescence; and (3) genetic influences on relationships outside the family.