Lummaa et al. (2007) presented historical data collected from twins born in Finland between 1734 and 1888 which suggested that females (N = 31) born as part of an opposite sex (OS) twin pair were 25% less likely to reproduce than female twins (N = 35) born as part of a same sex (SS) pair. They hypothesized that this reduction in fitness was due to masculinization of the female fetus via prenatal effects of the hormones of a male fetus. Because such masculinization would presumably take place in modern populations as well, it would seem important to establish to what degree it does so, and if so, whether reproduction is affected. We therefore address the question of reproduction differences in individual female twins from same-sex (N = 1979) and opposite-sex (N = 913) dizygotic pairs in studies carried out in Australia, the Netherlands, and the United States. In all three samples, there were no differences in the number of children or age of first pregnancies in women from same sex pairs compared to those from opposite sex pairs. Similarly, there were no differences in psychological femininity between women from pairs of the same or opposite sex.

DNA methylation differences between identical twins could account for phenotypic twin discordance of behavioral traits and diseases. High throughput epigenomic microarray profiling can be a strategy of choice for identification of epigenetic differences in phenotypically different monozygotic (MZ) twins. Epigenomic profiling of a pair of MZ twins with quantified measures of psychometric discordance identified several DNA methylation differences, some of which may have developmental and behavioral implications and are consistent with the contrasting psychometric profiles of the twins. In particular, differential methylation of CpG islands proximal to the homeobox DLX1 gene could modulate stress responses and risk taking behavior, and deserve further attention as a potential marker of aversion to danger. The epigenetic difference detected at DLX1 of ∼1.2 fold change was used to evaluate experimental design issues such as the required numbers of technical replicates. It also enabled us to estimate the power this technique would have to detect a functionally relevant epigenetic difference given a range of 1 to 50 twin pairs. We found that use of epigenomic microarray profiling in a relatively small number (15–25) of phenotypically discordant twin pairs has sufficient power to detect 1.2 fold epigenetic changes.

The Human Genetics Society of Australasia is a vibrant professional society with more than 900 members that promotes and regulates the practice of human and medical genetics in Australia and New Zealand. The growth of human genetics was stimulated by the development of diagnostic clinical cytogenetics laboratories in the early to mid 1960s. This coincided with the recognition by medical specialists, mainly pediatricians, that genetic disorders, especially inborn errors of metabolism and birth defects, were of clinical interest and potentially challenging areas for their skills. The organization of professionals in human genetics was slow to evolve. There was an early Western Australian Human Genetics Society, and the cytogenetics community had begun to meet annually from about 1966 but was coordinated by a mailing list rather than as a formal organization. In 1976, as part of the celebrations of the Centenary Year of the Adelaide Children's Hospital, a clinical genetics meeting involving several high profile international speakers and most of the senior medical geneticists in Australia and New Zealand along with the annual meeting of the loose-knit cytogeneticists group agreed that a small working group be charged with setting up a Human Genetics Society. The society was formally incorporated in South Australia in 1977.

Hardy–Weinberg equilibrium (HWE) is the state of the genotypic frequency of two alleles of one autosomal gene locus after one discrete generation of random mating in an indefinitely large population: if the alleles are A and a with frequencies p and q(=1-p), then the equilibrium gene frequencies are simply p and q and the equilibrium genotypic frequencies for AA, Aa and aa are p2, 2pq and q2. It was independently identified in 1908 by G. H. Hardy and W. Weinberg after earlier attempts by W. E. Castle and K. Pearson. Weinberg, well known for pioneering studies of twins, made many important contributions to genetics, especially human genetics. Existence of this equilibrium provides a reference point against which the effects of selection, linkage, mutation, inbreeding and chance can be detected and estimated. Its discovery marked the initiation of population genetics.

The Thought–Problem scale (TP) of the CBCL assesses symptoms such as hallucinations and strange thoughts/behaviors and has been associated with other behavioral disorders. This study uses parental reports to examine the etiology of variation in TP, about which relatively little is known, in 7-year-old twins. Parental ratings on TP were collected in 8,962 7-year-old twin pairs. Because the distribution of TP scores was highly skewed scores were categorized into 3 classes. The data were analyzed under a threshold liability model with genetic structural equation modeling. Ratings from both parents were simultaneously analyzed to determine the rater agreement phenotype (or common phenotype [TPc]) and the rater specific phenotype [TPs] that represents rater disagreement caused by rater bias, measurement error and/or a unique view of the parents on the child's behavior. Scores on the TP-scale varied as a function of rater (fathers rated fewer problems), sex (boys scored higher) and zygosity (DZ twins scored higher). The TPc explained 67% of the total variance in the parental ratings. Variation in TPc was influenced mainly by the children's genotype (76%). Variance in TPs also showed a contribution of genetic factors (maternal reports: 61%, paternal reports: 65%), indicating that TPs does not only represent rater bias. Shared environmental influences were only found in the TPs. No sex differences in genetic architecture were observed. These results indicate an important contribution of genetic factors to thought problems in children as young as 7 years.

Although life events are often conceptualized as reflecting exogenous risk factors for psychopathology, twin studies have suggested they are heritable. We undertook a mixed twin/adoption study to further explore genetic and environmental contributions to individual differences in the experience of life events. Specifically, a sample of 618 pairs of like-sex adolescent twins, 244 pairs of like-sex adopted adolescent and young adult siblings, and 128 pairs of like-sex biological siblings completed a life events interview. Events were classified as independent (not likely to have been influenced by respondent's behavior), dependent (likely to have been influenced by respondent's behavior), or familial (experienced by a family member), and then summed to form three life event scales. Variance on the scales was assumed to be a function of four factors: additive genetic effects (a2), shared environmental effects (c2), twin-specific effects (t2), and nonshared environmental effects (e2). Data were analyzed using standard biometrical models. Shared environmental effects were found to be the largest contributor to variance in familial events (c2 = .71; 95% confidence interval of .65, .76); additive genetic effects were the largest contributor to dependent events (a2 = .45; CI = .31, .58); and nonshared environmental effects were found to be the largest contributor independent events (e2 = .57; CI = .51, .64). A significant twin-specific effect was also found for independent life events, indicating that twins are more likely to be exposed to such events than non-twin biological siblings. Findings are discussed in terms of their implication for understanding the nature of psychosocial risk.

Human height is a highly heritable trait, with genetic factors explaining up to 90% of phenotypic variation. Vitamin D levels are known to influence several physiological processes, including skeletal growth. The vitamin D receptor (VDR) gene has been reported as contributing to variation in height. A meta-analysis of 13607 adult individuals found a small but significant association with the rs1544410 (BsmI) polymorphism. In contrast, the meta-analysis found no effect in a sample of 550 children. Two recent studies reported variants with large effect on height elsewhere in VDR (rs10735810 [FokI] and rs7139166 [-1521] polymorphisms). We genotyped large Caucasian samples from Australia (N = 3906) and the Netherlands (N = 1689) for polymorphisms in VDR. The Australian samples were twin families with height measures from 3 time points throughout adolescence. The Dutch samples were adult twins. We use the available family data to perform both within and between family tests of association. We found no significant associations for any of the genotyped variants after multiple testing correction. The (non-significant) effect of rs1544410 in the Australian adolescent cohort was in the same direction and of similar magnitude (additive effect 0.3cm) to the effect observed in the published adult meta-analysis. An effect of this size explains ~0.1% of the phenotypic variance in height — this implies that many, probably hundreds, of such variants are responsible for the observed genetic variation. Our results did not support any role for two other regions (rs10735810, rs7139166) of VDR in explaining variation in height.

Recent clinic-based and population-based studies have shown evidence of association between ADHD and autistic symptoms in children and adolescents as well as evidence for genetic overlap between these disorders. The objective of the current study was to confirm the association between autistic and ADHD symptoms in a young adult twin sample assessed by self-report, and investigate whether shared genetic and/or environmental factors can explain the association. We performed twin-based structural equation modeling using self-report data from 11 Social Responsiveness Scale (SRS) items and 12 DSM-IV ADHD inattentive and impulsive symptom items obtained from 674 young adult Australian twins. Phenotypic correlation between autistic and ADHD symptoms was moderate. The most parsimonious univariate models for SRS and ADHD included additive genetic effects and unique environmental effects, without sex differences. ADHD and autistic traits were both moderately heritable. In a bivariate model, genetic correlation (rg) between SRS and ADHD was 0.72. Our results suggest that in young adults, a substantial proportion of the genetic influences on self-reported autistic and ADHD symptoms may be shared between the two disorders.

The genetics of asthma and atopy has been studied frequently in twin populations from various parts of the world. However, emphasis has been put on univariate analysis of questionnaire data, whereas clinical and intermediate traits only sporadically have been studied, especially in multivariate settings. This review focuses on multivariate twin studies of atopy and related traits. We conclude that the genetic liability to most atopic traits is significantly correlated but that trait-specific genes also play a role. Previous studies have estimated the genetic correlation between upper and lower respiratory allergic symptoms, that is, asthma and hay fever, to be between .47 and .95. Furthermore, atopic traits share a portion of their genetic determinants with other complex disorders like obesity and behavioral traits. A correlation of about .3 and .34 has been reported between genes associated with asthma and obesity, and between genes associated with asthma and depression, respectively. We emphasize that multivariate methods applied to twin studies, especially when genetic marker information is available, provide a valuable framework within which complex etiological mechanisms underlying atopy can be disentangled.

There have been incredible advances made in human genetics over the past 40 years. I have set out in the next few pages to describe just some of these changes and to illustrate how they unfolded through my own experiences.

We examine the heritability of psychological resilience among US adults aged 25 to 74 years. Using monozygotic and same sex dizygotic twin pairs from the National Survey of Mid-Life Development in the United States (MIDUS) we show that positive affect is equally heritable among men (h2 = .60) and women (h2 = .59). We then estimate the heritability of positive affect after controlling for an exhaustive list of social and inter-personal stressors, and we operationalize the residual for positive affect as resilience. According to this specification, the heritability of resilience is higher among men (h2 = .52) compared to women (h2 = .38). We show that self-acceptance is one of the most important aspects of psychological functioning that accounts for the heritability of resilience among both men and women. However, compared to women, men appear to derive additional benefits from environmental mastery that may enable otherwise sex-neutral resilient tendencies to manifest.

Twin studies of diabetes mellitus can help elucidate genetic and environmental factors in etiology and can provide valuable biological samples for testing functional hypotheses, for example using expression and methylation studies of discordant pairs. We searched the volunteer Australian Twin Registry (19,387 pairs) for twins with diabetes using disease checklists from nine different surveys conducted from 1980–2000. After follow-up questionnaires to the twins and their doctors to confirm diagnoses, we eventually identified 46 pairs where one or both had type 1 diabetes (T1D), 113 pairs with type 2 diabetes (T2D), 41 female pairs with gestational diabetes (GD), 5 pairs with impaired glucose tolerance (IGT) and one pair with MODY. Heritabilities of T1D, T2D and GD were all high, but our samples did not have the power to detect effects of shared environment unless they were very large. Weight differences between affected and unaffected cotwins from monozygotic (MZ) discordant pairs were large for T2D and GD, but much larger again for discordant dizygotic (DZ) pairs. The bivariate genetic analysis (under the multifactorial threshold model) estimated the genetic correlation between body mass index (BMI) and T2D to be 0.46, and the environmental correlation at only 0.06.

A number of studies have provided evidence of a significant familial aggregation for both asthma and hay fever, and have reported a substantial comorbidity between the two conditions. However, far fewer, especially in Italy, have aimed at clarifying the origins of such comorbidity. The main aims of the present study were (a) to estimate heritability of asthma and hay fever, (b) to measure the association between asthma and hay fever at the individual level, and (c) to assess the extent to which genetic and environmental factors, shared by the two conditions, mediate this association. The twin method was used. The study sample was derived from the Italian Twin Registry, and included 392 twin pairs aged 8 to 17 years. Data collection was performed through parent self-administered questionnaire. Bivariate structural equation twin modeling was applied to asthma and hay fever. Genetic factors accounted for 92% and 78% of the variance in liability to asthma and hay fever, respectively, with the remaining contributions due to unique environmental influences. The within-individual association between asthma and hay fever was substantial. The genetic correlation between the two conditions was .58, whereas no evidence of overlapping unique environmental effects was found. In conclusion, this study showed a high heritability of asthma and hay fever in the Italian child and adolescent population. It also indicated that asthma and hay fever share, to a large extent, a common genetic background, and environmental factors are not relevant to explain the comorbidity.

The human ACTN3 gene encodes the protein α-actinin-3, a component of the contractile apparatus in fast skeletal muscle fibers. In 1999, we identified a common polymorphism in ACTN3 (R577X) that results in absence of α-actinin-3 in more than one billion people worldwide, despite the ACTN3 gene being highly conserved during human evolution. In 2003, we demonstrated that ACTN3 genotype influences elite athletic performance, and the association between ACTN3 genotype and skeletal muscle performance has since been replicated in athletes and non-athlete cohorts. We have also studied the evolution of the R577X allele during human evolution and demonstrated that the null (X) allele has undergone strong, recent positive selection in Europeans and Asian populations. We have developed an Actn3 knockout mouse model that replicates α-actinin-3 deficiency in humans and has already provided insight into the role of α-actinin-3 in the regulation of skeletal muscle metabolism, fibre size, muscle mass and contractile properties. In particular, mouse muscle lacking α-actinin-3 uses energy more efficiently, with the fast fibers displaying metabolic and contractile properties of slow oxidative fibers. While this favors endurance activities, the trade off is that the muscle cannot generate the rapid contractions needed to excel in sprinting. We propose that the shift towards more efficient aerobic muscle metabolism associated with α-actinin-3 deficiency also underlies the adaptive benefit of the 577X allele. Our future studies will focus on the effect of ACTN3 genotype on response to exercise and ageing, and the onset and severity of muscle disease phenotype.

Do genetically identical children experience the same classroom differently? Are nonshared classroom experiences associated with differences in achievement? We designed a telephone diary measure which we administered every school day for 2 weeks to 122 10-year-olds in 61 monozygotic (MZ) twin pairs. Each pair shared genes, a classroom, peers and a teacher. We found that MZ twins did experience their classrooms differently (rMZ < 0.65 for all measures of classroom experience). Furthermore, MZ differences in peer problems were significantly associated with MZ differences in Mathematics achievement (ES = 8%); differences in positivity about school were significantly associated with differences in Mathematics (ES = 15%) and Science (ES = 8%) achievement; and differences in ‘flow’ in Science lessons were associated with differences in Science achievement (ES = 12%). In a multiple regression analysis, MZ differences in positivity about school significantly predicted MZ differences in Mathematics achievement (R2 = 0.16, p < .01) and MZ differences in ‘flow’ in Science significantly predicted MZ differences in Science achievement (R2 = 0.10, p < .05). These results indicate that MZ twins experience the classroom differently and that differences in their experience are associated with differences in their achievement.

Circulating levels of leptin and adiponectin are closely associated with obesity. However, it is not known whether there are common shared genes or environment exerting influences on the levels of leptin, adiponectin, and BMI. We aimed to assess the relative contribution of genes and environment to adiponectin, leptin, and BMI individually as well as simultaneously to the three measures. Our subjects included a total of 228 twin/sibling pairs aged 12 to 18 (130 monozygotic twins, 68 dizygotic twins and 30 sibling pairs) were recruited from the middle schools. Multivariate analyses were applied to twin/sibling data using structural equation modeling. The results showed that intraclass correlations for adiponectin, leptin and BMI were higher in the MZ twins than those in the DZ/SP group. The relative contribution of genes to adiponectin (39%) was comparable to those of shared environment (40%). In contrast, leptin and BMI were influenced mostly by genes (74% and 89%, respectively). The multivariate genetic analyses showed that a latent factor underlying the three measures was identified, with BMI being equivalent to this latent factor. The BMI-dependent genetic factor explains only 15% and 34% of variation of adiponectin and leptin, respectively. These data indicate a differential contribution of genetic factors for the variation of adiponectin, leptin and BMI. More importantly, only a small portion of the genetic influences on adiponectin and leptin was attributed to BMI. Our findings provided more insight into the complex regulation of adiponectin and leptin in obesity.

The negative social attributes associated with drug use and abuse/dependence may arise as a result of shared genetic or environmental factors rather than through causal pathways. To evaluate this possibility, structured interviews were conducted for 3969 male and female twins from the Mid-Atlantic Twin Registry and evaluations of their socioeconomic status (SES), social interactions, and use of drugs were obtained. Drug involvement was categorized as never used, tried, or met criteria for abuse or dependence. A co-twin control design was implemented using hierarchical linear modeling to assess whether twins who used drugs experienced lower SES and social support than non-using co-twins. Poorer social functioning in the drug-exposed twin is consistent with a causal relationship, while similar functioning in the drug exposed versus naive twins imply shared genetic or common environmental factors. Use of drugs was not significantly related to any SES measures. However, education and job status appear to share genetic influences with drug abuse/dependence. Lower income was not related to abuse/dependence of drugs. Negative interactions with friends and relatives share genetic factors with use of drugs, but the escalation from trying drugs to abusing them appears to generate discord between the abuser and friends and relatives in a causal fashion. These results indicate that presumptive causal influences of drug abuse/dependence on low SES may actually be mediated by shared genes. Drug use and social discord also appear to have shared genetic factors, but increased levels of drug involvement seem to causally influence social interactions.

Insulin resistance and obesity are underlying causes of type 2 diabetes and therefore much interest is focused on the potential genes involved. A series of anthropometric and metabolic characteristic were measured in 240 MZ and 112 DZ twin pairs recruited from the East Flanders Prospective Twin Survey. Microsatellite markers located close to ABCC8, ADIPOQ, GCK, IGF1, IGFBP1, INSR, LEP, LEPR, PPARγ and the RETN gene were genotyped. Univariate single point variance components linkage analyses were performed using two methods: (1) the standard method, only comprising the phenotypic and genotypic data of the DZ twin pairs and (2) the extended method, also incorporating the phenotypic data of the MZ twin pairs. Suggestive linkages (LOD > 1) were observed between the ABCC8 marker and waist-to-hip ratio and HDL-cholesterol levels. Both markers flanking ADIPOQ showed suggestive linkage with triglycerides levels, the upstream marker also with body mass and HDL-cholesterol levels. The IGFBP1 marker showed suggestive linkage with fat mass, fasting insulin and leptin levels and the LEP marker showed suggestive linkage with birth weight. This study suggests that DNA variants in ABCC8, ADIPOQ, IGFBP1 and LEP gene region may predispose to type 2 diabetes. In addition, the two methods used to perform linkage analyses yielded similar results. This was however not the case for birth weight where chorionicity seems to be an important confounder.

The present study assessed the prevalence of asthma and allergy, and estimated the importance of genetic and environmental influences on asthma and allergy liability and their association. Longitudinal data on self-reported, doctor-diagnosed asthma and allergy were collected in over 14,000 individuals registered with the Netherlands Twin Register. Structural equation modeling was used for univariate and bivariate genetic analyses on data from twins, their siblings, and parents. Results showed no sex, age, and minimal birth cohort effects for asthma prevalence (11.8%). For allergy, prevalence was higher in women (19.8%) than in men (13.9%). Allergy prevalence at ages 22, 23, and 24 years increased from the 1970 to the 1980 birth cohort. The prevalence of allergy, but not of asthma, was higher in nontwin siblings than in twins. No assortative mating was observed. High (broad-sense) heritabilities were found for asthma (75%) and allergy (66%), with evidence for nonadditive genetic effects in asthma. The association between asthma and allergy (correlation = .65) was largely due to common genes (70%). No sex differences in genetic architecture were found. In conclusion, the prevalence of allergy but not of asthma increased in recent years. Individual differences in the liability to asthma, allergy and their co-occurrence are for a large part accounted for by differences in genetic background. Nonadditive gene action is important, which may have consequences for gene hunting strategies.