Corrado Fagnani

Sex Differences in Heritability of BMI: A Comparative Study of Results from Twin Studies in Eight Countries

Body mass index (BMI), a simple anthropometric measure, is the most frequently used measure of adiposity and has been instrumental in documenting the worldwide increase in the prevalence of obesity witnessed during the last decades. Although this increase in overweight and obesity is thought to be mainly due to environmental changes, i.e., sedentary lifestyles and high caloric diets, consistent evidence from twin studies demonstrates high heritability and the importance of genetic differences for normal variation in BMI. We analysed self-reported data on BMI from approximately 37,000 complete twin pairs (including opposite sex pairs) aged 20-29 and 30-39 from eight different twin registries participating in the GenomEUtwin project. Quantitative genetic analyses were conducted and sex differences were explored. Variation in BMI was greater for women than for men, and in both sexes was primarily explained by additive genetic variance in all countries. Sex differences in the variance components were consistently significant. Results from analyses of opposite sex pairs also showed evidence of sex-specific genetic effects suggesting there may be some differences between men and women in the genetic factors that influence variation in BMI. These results encourage the continued search for genes of importance to the body composition and the development of obesity. Furthermore, they suggest that strategies to identify predisposing genes may benefit from taking into account potential sex specific effects.

Concordance, disease progression, and heritability of coeliac disease in Italian twins

Background and aims: We adopted the twin method to disentangle the genetic and environmental components of susceptibility to coeliac disease (CD). We estimated disease concordance rate by zygosity and HLA genotypes, discordance times, progression rates to disease, and heritability. Methods: We crosslinked the Italian Twin Registry with the membership lists of the Italian Coeliac Disease Association and recruited 23 monozygotic (MZ) and 50 dizygotic (DZ) twin pairs with at least one affected member. Zygosity was assigned by DNA fingerprinting, and HLA-DQ and DR alleles were genotyped. Disease status was ascertained by antiendomysial, anti-human tissue transglutaminase antibodies, and bowel biopsy. Results: Concordance was significantly higher in MZ (83.3% probandwise, 71.4% pairwise) than in DZ (16.7% probandwise, 9.1% pairwise) pairs. Concordance was not affected by sex or HLA genotype of the co-twin and being MZ was significantly associated with the occurrence of CD (Cox adjusted hazard ratio 14.3 (95% confidence interval 4.0–50.3)). In 90% of concordant pairs the discordance time was ⩽2 years. MZ and DZ co-twins had 70% and 9% cumulative probability of having symptomatic or silent forms of CD, respectively, within five years. Under ACE (additive genetic, common, and unshared environmental factors) models, with CD population prevalences of 1/91 and 1/1000, heritability estimates were 87% and 57%, respectively. Conclusion: MZ pairs have a high probability of being concordant, regardless of sex or HLA genotype. Most of the affected co-twins receive a diagnosis within two years. A remarkable proportion of phenotypic variance is due to genetic factors.

Genetic influences on growth traits of BMI: a longitudinal study of adult twins.

Objective: To investigate the interplay between genetic factors influencing baseline level and changes in BMI in adulthood.

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells

In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors.

Genetic influences on alexithymia and their relationship with depressive symptoms.

OBJECTIVE The factors involved in the etiology of alexithymia are still unclear. While a few studies suggested substantial genetic influences on alexithymia, it remains to be determined if these influences are independent of genetic influences on other mental health variables correlated with alexithymia, such as depression. This study is aimed at confirming previous findings of a genetic contribution to alexithymia, examining whether there are genetic or environmental influences common to alexithymia facets, and investigating whether genetic influences on alexithymia are independent of genetic influences on depression. METHODS The 20-item Toronto Alexithymia Scale and a validated measure of depression were administered to a sample of 729 twins (45% males) aged 23-24 years drawn from the population-based Italian Twin Register. Genetic structural equation modeling was performed with the Mx program. RESULTS Genetic factors accounted for 42% of individual differences in alexithymia. Unshared environmental factors explained the remaining proportion of variance. There was a substantial (0.65) genetic correlation between alexithymia and depression. The inclusion of depression as a covariate in the genetic models reduced the heritability estimate for alexithymia to 33%. CONCLUSIONS Despite some limitations, this study corroborates the notion that genetic factors contribute substantially to individual differences in alexithymia, with unshared environmental factors also playing an important role. Also, it suggests a genetic link between alexithymia and depression.

Heritability and shared genetic effects of asthma and hay fever: an Italian study of young twins.

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.

Genetic and Environmental Factors Shape Infant Sleep Patterns: A Study of 18-Month-Old Twins

OBJECTIVE: Between 25% and 30% of children and adolescents experience sleep disorders. These disorders are complex phenotypes that are regulated by many genes, the environment, and gene-environment interactions. The objective of this study was to evaluate the contribution of genetic and environmental factors to sleep behaviors in early childhood and to contribute to the knowledge on appropriate therapeutic approaches, using a twin design. PATIENTS AND METHODS: Data on sleeping behavior were collected from 314 18-month-old twin pairs (127 monozygotic and 187 dizygotic)using a parent-rated questionnaire. We used structural equation modeling to estimate genetic and environmental variance components for different sleep behaviors (cosleeping, sleep duration, and night awakenings). RESULTS: Shared environment explained almost all (98.3%) of the total variance in cosleeping. Sleep duration was substantially influenced by shared environmental factors (64.1% nocturnal sleep and 61.2% diurnal sleep), with a moderate contribution of additive genetic effects (30.8% and 36.3% for nocturnal and diurnal sleep, respectively). For nocturnal waking episodes, we found a shared environmental contribution of 63.2% and a heritability estimate of 35.3%. CONCLUSIONS: Most sleep disturbances during early childhood are explained by common shared environmental factors, and behavioral interventions adopted by parents and focused on modifying sleep behavior could contribute to solving sleep disturbances in this age group. However, the influence of genetic factors should not be underestimated, and research in this area could clarify the physiologic architecture of sleeping and contribute to selecting appropriate personalized therapeutic approaches.

The co-occurrence between internalizing and externalizing behaviors

Although Internalized and Externalized problem behaviors are described as separate phenomena at the psychometric and clinical levels, they frequently co-occur. Only few studies, however, have investigated the causes of such covariation. In a sample of 398 twin pairs aged 8–17 drawn from the general population-based Italian Twin Registry, we applied bivariate genetic analyses to parent-rated CBCL/6–18 Internalization and Externalization scores. Covariation of Internalizing and Externalizing problem behaviors was best explained by genetic and common environmental factors, while the influence of unique environmental factors upon covariance appeared negligible. Odds ratio values showed that a borderline/clinical level of Externalization is a robust predictor of co-existing Internalizing problems in the same child, or within a sibship. Our findings help to approximate individual risks (e.g., in clinical practice, predicting the presence of Internalization in an externalizing child, and vice-versa), and to recognize that several shared environmental and genetic factors can simultaneously affect a child’s proneness to suffer from both types of problem behaviors.

An update on the Italian Twin Register: advances in cohort recruitment, project building and network development.

The Italian Twin Register has been in place for more than 10 years. Since its establishment, it has been focusing, on the one hand, on a continuous update of the existing information, and on the other hand, on new phenotypes and sample collection. Demographic data on about 140,000 twins have been updated using the municipality registries. The Italian Twin Register has been carrying out several new studies during the last few years. A birth cohort of twins, Multiple Births Cohort Study, has been started and the enrollment is ongoing. For this cohort, data on pregnancy and birth are collected, and periodical follow-ups are made. DNA is being collected for the twins and their parents. In the area of behavioral genetics, most efforts have been directed to psychological well being assessed with self-reported tools. Research on age-related traits continues with studies on arteriosclerosis development, early biomarkers in mild cognitive impairment, and the relation between lifestyle habits and mutagen sensitivity. The Italian Twin Register biobanking has grown in its size and in its know-how in terms of both technical issues and ethical procedures implementation. Furthermore, attitudes toward biobank-based research, together with willingness and motivation for donation, are being investigated. A valuable key resource for the Italian Twin Register is the possibility of linking twin data with disease registries. This approach has been yielding several important results, such as the recent study on the heritability of type 1 diabetes.

The association between arterial hypertension and rotator cuff tear: the influence on rotator cuff tear sizes

BACKGROUND This study was conducted to establish whether hypertension increases the risk of occurrence of rotator cuff tear and influences its size. MATERIALS AND METHODS A case-control design was used. We studied 408 consecutive patients (228 men, 180 women) who underwent arthroscopic rotator cuff repair. Tear size was determined during surgery. The control group included 201 individuals. For the study purpose, participants were divided into 2 groups by presence or absence of hypertension. We applied a logistic regression model to investigate if hypertension affects the risk of cuff tear. A multinomial logistic regression model was applied to explore the association between hypertension and tear size. We used the analysis of covariance method to determine if the duration of hypertension influences the severity of the tear; finally, we compared mean duration of antihypertensive therapy in patients with small, large, and massive tears. All analyses were adjusted for age and sex. RESULTS Hypertension was associated with a 2-fold higher risk of tear occurrence (odds ratio [OR], 2.05; 95% confidence interval [CI], 41-2.98). No association was detected between hypertension and the probability of a small tear (OR, 0.63, 95% CI, 0.33-1.19). Hypertensive individuals were 2 times more likely to experience large tear (OR, 02.09; 95% CI, 1.39-3.16) and 4 times more likely to experience massive tear (OR, 04.30; 95% CI, 2.44-7.58) than normotensive individuals. Mean duration of antihypertensive therapy significantly increased from small tear (1.08 years) to large tear (3.20 years) to massive tear (6.34 years) patients (analysis of covariance: F((2,403)) = 16.357, P = 1.48 × 10(-7)). CONCLUSIONS Our data provide evidence that hypertension is a significant risk factor for the occurrence and severity of rotator cuff tears.