Heritability of white matter in twins: A diffusion neuroimaging review.

Diffusion neuroimaging has emerged as an essential non-invasive technique to explore in vivo microstructural characteristics of white matter (WM), whose integrity allows complex behaviors and cognitive abilities. Studying the factors contributing to inter-individual variability in WM microstructure can provide valuable insight into structural and functional differences of brain among individuals. Genetic influence on this variation has been largely investigated in twin studies employing different measures derived from diffusion neuroimaging. In this context, we performed a comprehensive literature search across PubMed, Scopus and Web of Science of original twin studies focused on the heritability of WM. Overall, our results highlighted a consistent heritability of diffusion indices (i.e., fractional anisotropy, mean, axial and radial diffusivity), and network topology among twins. The genetic influence resulted prominent in frontal and occipital regions, in the limbic system, and in commissural fibers. To enhance the understanding of genetic influence on WM microstructure further studies in less heterogeneous experimental settings, encompassing all diffusion indices, are warranted.

Exploring the effects of family and life events on genetic and environmental architecture of schizotypal and hypomanic dimensions: Insights from a twin study.

BACKGROUND: Strategies of prevention for psychiatric disorders need a deep understanding of the aetiological factors involved in the psychopathological processes. Our twin study aims at disentangling the contributions of genes and environment to schizotypal and hypomanic dimensions, considering the role of stressful life events (LEs) and the quality of family relationships. METHODS: The Magical Ideation Scale (MIS) and Perceptual Aberration Scale (PAS) were used to assess positive schizotypy, while Hypomanic Personality Scale (HPS) and its sub-scales were used to investigate proneness to affective disorders. 268 twins (54.5 % female; aged 18.0 ± 6.68) were included. Participants filled out a questionnaire on LEs and their parents provided an evaluation of intra-family relationship (Relationship Quality Index, RQI). Classic univariate twin models for quantitative traits were fitted for scales, and the effects of covariates (LEs and RQI) were assessed. RESULTS: For MIS, HPS and its sub-scales, significant common and unique environmental effects were detected, with genetic factors affecting only HPS Social Vitality sub-scale. Unique environment was the only source of variance of PAS score. The number of recent LEs influenced MIS and PAS models, while RQI score affected MIS model. LIMITATIONS: The main limitation of the study is the small sample size, which reduces statistical power and may potentially lead to an underestimation of heritability. Additionally, the cross-sectional design limits the possibility to draw causal considerations. CONCLUSIONS: Findings provide preliminary evidence for a significant environmental role in modulating states of vulnerability. Moreover, the expression of positive schizotypy resulted influenced by recent stressors and intra-family relationships.

Connecting psychosocial and personality characteristics with mental health outcomes. An Italian co-twin control study.

Exposure to stressful life events is common, and it is linked to increased psychological issues. As most likely people respond to stressors depending on environmental and genetic factors, we assessed in a twin study the association of some personal characteristics such as resilience and self-perception with anxiety, depression and stress in the late Covid pandemic period, to verify the underlying genetic and shared familial components. With this design, the strength of the associations was compared between individual-level and intrapair-level analyses. From June 2020 to December 2021, the Italian Twin Registry conducted a three-wave longitudinal study among adult twins using validated questionnaires, and 1,763 adult twins participated in the study (mean age 46 years, 67 % females, 70 % monozygotic). A regression-based within-pair differences model was applied to control for genetic and shared environmental confounding. Results showed that anxiety was linked negatively with resilience, social support and perceived health, and positively with risk perception and hypochondria. Depression was associated negatively with resilience, social support and perceived health, and positively with financial concern and hypochondria. Stress was associated negatively with resilience and perceived health, and positively with financial concern, risk perception and hypochondria. These results suggest potential etiological effects of the above-mentioned risk factors. While our findings need to be confirmed by longitudinal studies, they propose potential etiological models for mental disorders, indicating that addressing in the clinical practice factors such as self-perception, personality traits (resilience), environmental resources (social support), and comorbid disorders (hypochondria) could have therapeutic benefits while treating certain common mental disorders.

Fifteen Years of Iodine Prophylaxis in Italy: Results of a Nationwide Surveillance (Period 2015-2019).

CONTEXT: In 2005, a nationwide program of iodine prophylaxis on a voluntary basis was implemented in Italy by law. However, recent data on iodine status are lacking. OBJECTIVE: The aim of this study was to evaluate efficiency, effectiveness, and possible adverse effects (increased occurrence of thyroid autoimmunity and hyperthyroidism) of the Italian iodine prophylaxis program. METHODS: From 2015 to 2019, a nationwide survey was performed. The use of iodized salt was evaluated in a sample of 164 593 adults and in 998 school canteens. A sample of 4233 schoolchildren (aged 11-13 years) was recruited to assess urinary iodine concentration, prevalence of goiter, and thyroid hypoechogenicity on ultrasound, with the latter being an indirect indicator of thyroid autoimmunity. Neonatal TSH values of 197 677 infants screened in regions representative of Northern, Central, and Southern Italy were analyzed to investigate the percentage of TSH values >5.0 mIU/L. Data on methimazole prescriptions were analyzed as indirect indicators of new cases of hyperthyroidism. RESULTS: The prevalence of the use of iodized salt was 71.5% in adult population and 78% in school canteens. A median urinary iodine concentration of 124 µg/L, a prevalence of goiter of 2.2%, and a prevalence of thyroid hypoechogenicity of 5.7% were observed in schoolchildren. The percentage of neonatal TSH values >5.0 mIU/L resulted still higher (5.1%) than the World Health Organization threshold of 3.0%, whereas the prescriptions of methimazole showed a reduction of 13.5%. CONCLUSION: Fifteen years of iodine prophylaxis have led to iodine sufficiency in Italy, although there still is concern about iodine nutritional status during pregnancy.

Investigating Genetic and Environmental Substrates of the Relationship between Positive Mental Health and Biological Aging-A Study Protocol.

BACKGROUND: The Italian National Institute of Health (Istituto Superiore di Sanità) funded a 30-month project (July 2021-January 2024) to conduct a twin study of the relationships between Positive Mental Health (PMH) and cellular longevity. Only a few previous studies have focused on the biomarkers of aging in relation to psychological well-being, and none of them exploited the potential of the twin design. METHOD: In this project, following the standard procedures of the Italian Twin Registry (ITR), we aim to recruit 200 adult twin pairs enrolled in the ITR. They are requested to complete a self-report questionnaire battery on PMH and to undergo a blood withdrawal for the assessment of aging biomarkers, i.e., telomere length and mitochondrial DNA functionality. The association between psychological and aging biomarker measures will be assessed, controlling for genetic and familial confounding effects using the twin study design. RESULTS AND CONCLUSIONS: Biomarker assays are underway. Once data are available for the total study sample, statistical analyses will be performed. The project's results may shed light on new mechanisms underlying the mind-body connection and may prove helpful to promote psychological well-being in conjunction with biological functioning.

Reduction in the use of green spaces during the COVID-19 pandemic and its impact on mental health.

Our study examined the use of green spaces before and during the pandemic in a large cohort of Italian twins and evaluated its impact on measures of mental health (depressive, anxiety, stress symptoms). Twins were analysed as individuals and as pairs. A twin design approach was applied to minimize confounding by genetic and shared environmental factors. Questionnaires from 2,473 twins enrolled in the Italian Twin Registry were screened. Reduced green space use was associated with significantly higher levels of depression, anxiety and distress. Being a woman, residing in urban areas, and having a high perceived risk of the outbreak resulted in a higher likelihood to modify green space use, with a negative impact on mental health.

Stability and change in genetic and environmental influences on depressive symptoms in response to COVID-19 pandemic.

Background: The rapid spread of the new Coronavirus and the consequent restrictions to contain transmission generated an unprecedented psychological impact on the general population. The Italian Twin Registry performed a longitudinal study to investigate to what extent genetic and environmental influences contributed to changes in depressive symptoms. Methods: Data from adult twins were collected. All participants completed an online questionnaire including the 2-item Patient Health Questionnaire (PHQ-2) just before (February 2020) and immediately after the Italian lockdown (June 2020). Genetic modeling based on Cholesky decomposition was used to estimate the role of genetic (A) and both shared (C) and unshared (E) environmental factors in the observed longitudinal course of depressive symptoms. Results: Longitudinal genetic analysis was based on 348 twin pairs (215 monozygotic and 133 dizygotic pairs) with a mean age of 42.6 years (range 18-93 years). An AE Cholesky model provided heritability estimates for depressive symptoms of 0.24 and 0.35 before and after the lockdown period, respectively. Under the same model, the observed longitudinal trait correlation (0.44) was approximately equally contributed by genetic (46%) and unshared environmental (54%) influences, while longitudinal environmental correlation was lower than genetic correlation (0.34 and 0.71, respectively). Conclusions: Although the heritability of depressive symptoms was rather stable across the targeted time window, different environmental as well as genetic factors seemed to act before and after the lockdown, which suggests possible gene-environment interaction.

A Twin Study of the Relationships between Cognitive Disengagement Syndrome and Anxiety Phenotypes in Childhood and Adolescence.

Data on the etiological factors underlying the co-occurrence of Cognitive Disengagement Syndrome (CDS) with anxiety symptoms are very limited. The present study investigated the nature of latent shared etiological elements in 400 Italian twin pairs aged 8-18, explaining the covariation between CDS and anxiety symptoms. Preliminary analysis demonstrated significant correlations between Child Behaviour Checklist/6-18 Sluggish Cognitive Tempo Scale and two (Somatic Anxiety, Generalized Anxiety) out of five Screen for Child Anxiety Related Disorders anxiety subscales. Results from causal analysis seem to exclude the hypothesis that co-occurrence between CDS and Anxiety Symptoms could be due to a direct phenotypic effect of one trait upon the other. Model fitting-analysis indicated that the aforementioned associations were partially explained by shared genetic and environmental factors influencing a common liability factor. A latent variable capturing the covariation between CDS and anxiety problems can be considered as a unifying (patho)physiological mechanism/system common to these constructs. Our results support the adoption of a broader view of the relationships between CDS and anxiety phenotypes in childhood and adolescence for both clinicians and educators.

Age-Related Variations of Genetic and Environmental Contributions to the Covariation of Fear, Distress and Externalizing Symptoms: A Twin Study in Childhood and Adolescence.

The frequency with which Internalizing and Externalizing symptoms co-occur suggests that, behind both domains, there may be a common susceptibility represented by a general psychopathology factor. However, it's still unclear whether this common susceptibility is affected by age-related variations. Internalizing (i.e., Fear and Distress) and Externalizing symptoms were evaluated in 803 twin pairs from the population-based Italian Twin Registry. Model-fitting analysis was performed separately in the 6-14 and 15-18 age groups to estimate genetic and environmental contributions to the covariance among symptoms. For the 6-14 group, a multivariate Cholesky model best fitted the data, while, for the 15-18 group, the best fit was provided by a Common Pathway model in which nearly 50% of total variance of each trait was mediated by common genetic factors. Our findings support a common susceptibility behind Internalizing and Externalizing symptoms, mainly genetic in origin, that becomes more evident at the beginning of puberty.

A multi-marker integrative analysis reveals benefits and risks of bariatric surgery.

Bariatric surgery (BS) is an effective intervention for severe obesity and associated comorbidities. Although several studies have addressed the clinical and metabolic effects of BS, an integrative analysis of the complex body response to surgery is still lacking. We conducted a longitudinal data study with 36 patients with severe obesity who were tested before, 6 and 12 months after restrictive BS for more than one hundred blood biomarkers, including clinical, oxidative stress and metabolic markers, peptide mediators and red blood cell membrane lipids. By using a synthetic data-driven modeling based on principal component and correlation analyses, we provided evidence that, besides the early, well-known glucose metabolism- and weight loss-associated beneficial effects of BS, a tardive, weight-independent increase of the hepatic cholesterol metabolism occurs that is associated with potentially detrimental inflammatory and metabolic effects. Canonical correlation analysis indicated that oxidative stress is the most predictive feature of the BS-induced changes of both glucose and lipids metabolism. Our results show the power of multi-level correlation analysis to uncover the network of biological pathways affected by BS. This approach highlighted potential health risks of restrictive BS that are disregarded with the current practice to use weight loss as surrogate of BS success.

An Italian Twin Study of Non-Cancer Chronic Pain as a Wide Phenotype and Its Intensity.

Background and Objectives: Non-cancer chronic pain (CP) results from the interaction between genetic and environmental factors. Twin studies help to estimate genetic and environmental contributions to complex traits such as CP. To date, twin studies on the heritability of pain phenotypes have relied almost exclusively on specific diagnoses, neglecting pain intensity. This study aims to estimate the genetic and environmental contributions to CP occurrence as a wide phenotype and its intensity among a non-clinical population. Materials and Methods: A nationwide online survey was conducted in February 2020 on 6000 adult twins enrolled in the Italian Twin Registry. A five-item questionnaire, designed and validated by our study group, was administered to detect the CP condition along with its intensity, underlying causes or triggers, treatments, and self-perceived efficacy. The twin study design was used to infer the relative weight of genes and environment on CP occurrence and intensity, and biometrical modelling was applied to these phenotypes. Results: A total of 3258 twins, aged ≥18, replied to the online survey (response rate 54%). These included 762 intact pairs (mean age: 39 years; age range: 18-82 years; 34% male; CP prevalence: 24%), of whom 750 pairs were subjected to biometrical modelling after the exclusion of pairs with either unknown zygosity or cancer-associated CP. Broad-sense heritability estimates were driven by non-additive genetic effects and were 0.36 (0.19-0.51) for CP occurrence and 0.31 (0.16-0.44) for CP intensity. No evidence emerged for either sex differences in genetic and environmental variance components or interactions of these components with age. Conclusions: Moderate non-additive genetic components were suggested for non-cancer CP occurrence and its intensity. These results encourage further research on the gene-gene interactions underlying CP liability and associated phenotypes, and also strengthen the need for prevention strategies to avoid CP occurrence or to decrease pain intensity.

Association of Assisted Reproductive Technology With Offspring Growth and Adiposity From Infancy to Early Adulthood.

Importance: People conceived using assisted reproductive technology (ART) make up an increasing proportion of the world's population. Objective: To investigate the association of ART conception with offspring growth and adiposity from infancy to early adulthood in a large multicohort study. Design, Setting, and Participants: This cohort study used a prespecified coordinated analysis across 26 European, Asia-Pacific, and North American population-based cohort studies that included people born between 1984 and 2018, with mean ages at assessment of growth and adiposity outcomes from 0.6 months to 27.4 years. Data were analyzed between November 2019 and February 2022. Exposures: Conception by ART (mostly in vitro fertilization, intracytoplasmic sperm injection, and embryo transfer) vs natural conception (NC; without any medically assisted reproduction). Main Outcomes and Measures: The main outcomes were length / height, weight, and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared). Each cohort was analyzed separately with adjustment for maternal BMI, age, smoking, education, parity, and ethnicity and offspring sex and age. Results were combined in random effects meta-analysis for 13 age groups. Results: Up to 158 066 offspring (4329 conceived by ART) were included in each age-group meta-analysis, with between 47.6% to 60.6% females in each cohort. Compared with offspring who were NC, offspring conceived via ART were shorter, lighter, and thinner from infancy to early adolescence, with differences largest at the youngest ages and attenuating with older child age. For example, adjusted mean differences in offspring weight were -0.27 (95% CI, -0.39 to -0.16) SD units at age younger than 3 months, -0.16 (95% CI, -0.22 to -0.09) SD units at age 17 to 23 months, -0.07 (95% CI, -0.10 to -0.04) SD units at age 6 to 9 years, and -0.02 (95% CI, -0.15 to 0.12) SD units at age 14 to 17 years. Smaller offspring size was limited to individuals conceived by fresh but not frozen embryo transfer compared with those who were NC (eg, difference in weight at age 4 to 5 years was -0.14 [95% CI, -0.20 to -0.07] SD units for fresh embryo transfer vs NC and 0.00 [95% CI, -0.15 to 0.15] SD units for frozen embryo transfer vs NC). More marked differences were seen for body fat measurements, and there was imprecise evidence that offspring conceived by ART developed greater adiposity by early adulthood (eg, ART vs NC difference in fat mass index at age older than 17 years: 0.23 [95% CI, -0.04 to 0.50] SD units). Conclusions and Relevance: These findings suggest that people conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.

Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts.

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

Development and Validation of the Italian "Brief Five-Item Chronic Pain Questionnaire" for Epidemiological Studies.

Background: Chronic pain (CP) prevalence estimates addressing a wide phenotype are still quite fragmented and may vary widely due to the lack of standardized tools of investigation. There is an urgent need to update general population CP estimates. Methods: For this purpose, the Brief Five-item Chronic Pain Questionnaire was developed through experts' consultations for design and content validity assessment; literature analysis of measures used to investigate CP for general population surveys; understandability evaluation through a survey on a convenience sample of affected and non-affected individuals; reliability assessment by means of two double-wave online surveys carried out by the Italian Twin Registry; criterion and construct validity assessment through the third wave of the 2019 European Health Interview Survey (Ehis). Results: Key dimensions were defined to describe CP main aspects from a public health perspective. Literature analysis showed that validated questionnaires were rarely used to address important public health CP aspects. Understandability of the measure was good. Test-retest analyses showed adequate reliability of the measure: k values were at least "moderate" with highest values regarding CP "occurrence" and "intensity". Correlations of CP with well-known comorbidities (cancer, depression), and specific traits (age, education) as well as of CP and its intensity with "physical pain occurrence and intensity" detected in the Ehis 2019, confirmed, respectively, a good construct and criterion validity. Construct validity was also evaluated through the correlation between "perceived treatment effectiveness" and "interference of pain in daily life activities" as recorded in the Ehis 2019. Conclusion: The designed questionnaire is a brief self-administered measure, particularly suitable to detect persistent states of pain and related intensity in large-scale general population surveys by means of a first filtering item followed by four further items. It is, in fact, designed to detect CP possible underlying causes/triggers, drugs/treatments taking and frequency, and self-perceived effectiveness among CP sufferers. Further validation of the measure in different social and cultural contexts is desirable.

Genetic and environmental contributions to psychopathological symptoms stability and change across the COVID-19 pandemic.

Several longitudinal studies investigated changes in mental health related to the pandemic event. However, little research has focused on the mediating role of environmental and genetic factors. The current prospective study aimed to evaluate the genetic and environmental contributions to the stability of symptoms of depression, anxiety and stress during the COVID-19 crisis. A total of 798 adult twins, previously enrolled in the Italian Twin Register, participated in the study and completed on-line questionnaires sent out on June 2020 and December 2020. The nine-item Patient Health Questionnaire (PHQ-9), the six-item State-Trait Anxiety Inventory (STAI-6), and the Impact of Event Scale - Revised (IES-R) were administered to assess depressive and anxiety symptoms, and pandemic-related subjective distress, respectively. A considerable longitudinal stability was observed for each trait (range: 0.57, STAI-6 - 0.67, PHQ-9). Bivariate Cholesky decomposition indicated that genetic factors explained from 53% (IES-R) to 61% (STAI-6) of between-wave covariance and that genetic overlap between the two waves was almost complete (range: 0.91, STAI-6 - 0.99, PHQ-9). Our findings support the hypothesis, at least over the 6-month period examined, of a genetic stability between waves and of an environmental discontinuity due to changes in life conditions during the pandemic.

Inflammation, underweight, malignancy and a marked catabolic state as predictors for worse outcomes in COVID-19 patients with moderate-to-severe disease admitted to Internal Medicine Unit.

INTRODUCTION: During COVID-19 pandemic, Internal Medicine Units (IMUs) accounted for about 70% of patients hospitalized. Although a large body of data has been published regarding the so-called first wave of the pandemic, little is known about the characteristics and predictors of worse outcomes of patients managed in IMUs during the second wave. METHODS: We prospectively assessed demographics, comorbidities, treatment and outcomes, including ventilation support (VS) and death, in patients admitted to our IMU for SARS-CoV-2 between October 13th, 2020 and January 21st, 2021. Clinical evolution and biochemical testing 1, 7 and 14 days after COVID-19 diagnosis were recorded. RESULTS: We studied 120 patients (M/F 56/64, age 71±14.5 years) admitted to our IMU. Most of them had at least one comorbidity (80%). Patients who died were older, more frequently underweight, affected by malignant neoplasms and on statin therapy compared to patients eventually discharged. Both worse outcome groups (VS and death) presented higher neutrophils, ferritin, IL-6 and lower total proteins levels than controls. Age was significantly associated with mortality but not with VS need. The multivariate analysis showed age and gender independent association of mortality with underweight, malignancy and antibiotics use at the admission. With regard to biochemical parameters, both unfavourable outcomes were positively associated with high WBC count, neutrophils, blood urea nitrogen and low serum total proteins. CONCLUSIONS: Our study identified inflammation, underweight, malignancy and a marked catabolic state as the main predictors for worse outcomes in COVID-19 patients admitted to IMU during the so-called second wave of the pandemic.

Adolescent pain, anxiety, and depressive problems: a twin study of their co-occurrence and the relationship to substance use.

ABSTRACT: Data on the etiological factors underlying the co-occurrence of common adolescent pain with anxiety and depression symptoms are very limited. Opioid prescriptions for adolescent pain problems are on the rise in North America and constitute a risk factor for diversion, misuse, and substance use. In this study, we aimed to investigate the phenotypic and etiological association among pain, depression, and anxiety and to test their link to substance use in adolescents. By taking advantage of the Italian National Twin Registry and of the relatively low incidence of opioid prescriptions in Italy, we applied multivariate modelling analyses to 748 Italian adolescent twins (374 pairs, mean age 16 ± 1.24 years). Twins' responses to the Achenbach Youth Self-Report questionnaire were used to build a composite adolescent pain index and to measure anxiety, depression, and substance use. All monozygotic within-pair correlations were higher than the dizygotic correlations, indicating genetic influences for adolescent pain, anxiety, and depressive problems. A common latent liability factor influenced by genetic and environmental elements shared among pain, depression, and anxiety provided the best fit to explain the co-occurrence of adolescent pain, anxiety, and depression problems. A common phenotypic factor capturing all 3 phenotypes was positively associated (ß = 0.19, P < 0.001, confidence interval: 0.10-0.27) with substance use. These findings indicate that several intertwined mechanisms, including genetic factors, can explain a shared liability to common adolescent pain, anxiety, and depression problems. Their association with substance use remains traceable even in societies with relatively low prevalence of opioid prescriptions.

The COVID-19 pandemic in Italy: Depressive symptoms immediately before and after the first lockdown.

BACKGROUND: Italy was one of the first countries to be heavily hit by the spread of the new Coronavirus. Longitudinal studies are needed to investigate the real effect of COVID-19 on adult mental health. The Italian Twin Registry carried out a study to investigate, over time, the course of depressive symptoms in the general population. METHODS: The study relies on data collected just before the beginning (February 2020) and the end (June 2020) of the first lockdown. Symptoms of depression were assessed using the Patient Health Questionnaire, and total scores or categorized depression scores were considered in the analyzes. RESULTS: A total of 1690 adult twins were recruited. The study showed a mean depression score of 1.11 immediately before lockdown and 1.20 immediately after, with an overall prevalence of depressive symptoms increasing from 33.6 to 38.9%. Depressive symptoms immediately after the restriction period were associated with Covid-19 symptoms affecting households, financial problems due to the pandemic and poor social support. Independently of the baseline risk of depressive symptoms, we observed an increased risk among younger and less educated people. Compared to the pre-lockdown period, women and middle-aged people also were found to be at greater risk of developing depressive symptoms. LIMITATIONS: Possible participation bias and residual selection bias. CONCLUSIONS: The study shows that the COVID-19 pandemic was associated with an increased depressive symptomatology and that, in such health emergency times, the most vulnerable persons are young adults, women, and those living in a socially, culturally, or economically disadvantaged environment.