-
Genes Sep 2023Esophageal atresia (EA) is the most common malformation of the upper gastrointestinal tract. The estimated incidence of EA is 1 in 3500 births. EA is more frequently...
Esophageal atresia (EA) is the most common malformation of the upper gastrointestinal tract. The estimated incidence of EA is 1 in 3500 births. EA is more frequently observed in boys and in twins. The exact cause of isolated EA remains unknown; a multifactorial etiology, including epigenetic gene expression modifications, is considered. The study included six pairs of twins (three pairs of monozygotic twins and three pairs of dizygotic twins) in which one child was born with EA as an isolated defect, while the other twin was healthy. DNA samples were obtained from the blood and esophageal tissue of the child with EA as well as from the blood of the healthy twin. The reduced representation bisulfite sequencing (RRBS) technique was employed for a whole-genome methylation analysis. The analyses focused on comparing the CpG island methylation profiles between patients with EA and their healthy siblings. Hypermethylation in the promoters of 219 genes and hypomethylation in the promoters of 78 genes were observed. A pathway enrichment analysis revealed the statistically significant differences in methylation profile of 10 hypermethylated genes in the Rho GTPase pathway, previously undescribed in the field of EA (, and ).
Topics: Male; Child; Humans; Esophageal Atresia; Twins, Monozygotic; Twins, Dizygotic; CpG Islands; Epigenesis, Genetic; Proto-Oncogene Proteins; Guanine Nucleotide Exchange Factors; Rho Guanine Nucleotide Exchange Factors
PubMed: 37761962
DOI: 10.3390/genes14091822 -
Can frailty scores predict the incidence of cancer? Results from two large population-based studies.GeroScience Jun 2023While chronological age is the single biggest risk factor for cancer, it is less clear whether frailty, an age-related state of physiological decline, may also predict...
While chronological age is the single biggest risk factor for cancer, it is less clear whether frailty, an age-related state of physiological decline, may also predict cancer incidence. We assessed the associations of frailty index (FI) and frailty phenotype (FP) scores with the incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, melanoma) in 453,144 UK Biobank (UKB) and 36,888 Screening Across the Lifespan Twin study (SALT) participants, who aged 38-73 years and had no cancer diagnosis at baseline. During a median follow-up of 10.9 and 10.7 years, 53,049 (11.7%) and 4,362 (11.8%) incident cancers were documented in UKB and SALT, respectively. Using multivariable-adjusted Cox models, we found a higher risk of any cancer in frail vs. non-frail UKB participants, when defined by both FI (hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 1.17-1.28) and FP (HR = 1.16; 95% CI = 1.11-1.21). The FI in SALT similarly predicted risk of any cancer (HR = 1.31; 95% CI = 1.15-1.49). Moreover, frailty was predictive of lung cancer in UKB, although this association was not observed in SALT. Adding frailty scores to models including age, sex, and traditional cancer risk factors resulted in little improvement in C-statistics for most cancers. In a within-twin-pair analysis in SALT, the association between FI and any cancer was attenuated within monozygotic but not dizygotic twins, indicating that it may partly be explained by genetic factors. Our findings suggest that frailty scores are associated with the incidence of any cancer and lung cancer, although their clinical utility for predicting cancers may be limited.
Topics: Humans; Male; Aged; Frailty; Frail Elderly; Incidence; Longevity; Lung Neoplasms
PubMed: 36997701
DOI: 10.1007/s11357-023-00783-9 -
Osteoarthritis and Cartilage Jul 2021To estimate the genetic contribution to traumatic and degenerative meniscus tears for men and women across the lifespan.
OBJECTIVE
To estimate the genetic contribution to traumatic and degenerative meniscus tears for men and women across the lifespan.
METHODS
We linked the Swedish Twin Register with individual-level national healthcare data to form a 30-year, population-wide, longitudinal twin cohort. To study genetic contribution to meniscus tears, we estimated the heritability and familial risk using incident traumatic and degenerative tear diagnostic codes in a cohort of 88,414 monozygotic and dizygotic twin-pairs, aged ≥17 years.
RESULTS
During follow-up, 3,372 (3.8%) of 88,414 twins were diagnosed with a traumatic or degenerative meniscus tear. The heritability was 0.39 (95% CI = 0.32-0.47) for men and 0.43 (95% CI = 0.36-0.50) for women, and did not vary by age. Environmental factors that were unique to each twin in a pair explained a greater proportion of the variance than genetic factors, both for men (0.61, 95% CI = 0.53-0.68) and women (0.57, 95% CI = 0.50-0.64). Separate analyses of traumatic vs degenerative meniscus tears yielded similar results.
CONCLUSION
For the first time, we have estimated the genetic contribution to doctor-diagnosed meniscus tears using a twin study design. We found a relatively low to modest heritability for meniscus tears (∼40%). The heritability was also fairly stable over the lifespan, and equal in both men and women. Our findings suggest that environmental risk factors are a more important contributor to both traumatic and degenerative doctor-diagnosed meniscus tears than genetic factors.
Topics: Adolescent; Adult; Cohort Studies; Female; Genetic Predisposition to Disease; Humans; Longitudinal Studies; Male; Middle Aged; Risk Factors; Sweden; Tibial Meniscus Injuries; Twins, Dizygotic; Twins, Monozygotic; Young Adult
PubMed: 33744431
DOI: 10.1016/j.joca.2021.03.005 -
BMC Medicine Nov 2023Emerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders (i.e.,...
BACKGROUND
Emerging research suggests that attention-deficit/hyperactivity disorder (ADHD) increases the risk for cardiovascular (CVDs) and metabolic disorders (i.e., cardiometabolic disorders) in adulthood. Yet, available studies are scarce and have mainly been focused on individuals receiving clinical ADHD diagnoses. We aimed to investigate the prospective associations of ADHD symptoms in young and mid-adulthood with subsequent cardiometabolic disorders and the underlying mechanisms.
METHODS
We studied 10,394 twins from the Swedish Twin Registry (STR), born between 1958 and 1985 without previous medical history of cardiometabolic disorders. They provided self-assessment of ADHD symptoms (score range 0-36) via a validated, DSM-IV-based scale in a web-based questionnaire/telephone interview within the Study of Twin Adults: Genes and Environment (STAGE), in 2005-2006 (aged 19-47 years), and were followed until the end of 2018 (33-59 years) to identify incident clinical diagnoses/medication prescriptions for cardiometabolic disorders acquired from Swedish national registers. We used Cox regression models to investigate the associations between ADHD symptoms score and cardiometabolic outcomes, with and without adjustment for relevant covariates, and a co-twin control design to study familial confounding.
RESULTS
A one-unit increase in the level of ADHD symptoms was associated with a 2% increase in the rate of CVDs (hazard ratio [HR] = 1.02, 95% confidence interval 1.01-1.04) and a 3% increase in the rate of metabolic disorders (HR = 1.03, 1.02-1.05), after adjusting for birth year and sex. The associations were no longer significant after adjusting for educational attainment, lifestyle factors, and comorbid psychiatric disorders. The associations remained significant after adjusting for familial factors shared by dizygotic twin pairs but became nonsignificant after adjusting for factors shared by monozygotic twin pairs. However, the strength of the associations attenuated significantly in monozygotic twins compared to dizygotic twins for CVDs only, suggesting genetic confounding.
CONCLUSIONS
ADHD symptom score is associated with a higher risk for cardiometabolic disorders, which may be explained by lower educational attainment, adverse lifestyle factors, and psychiatric comorbidities. Moreover, the associations appear to be partly confounded by shared genetic factors, especially for CVDs. Further research is needed to investigate the identified associations at the level of individual cardiometabolic disorders and to follow-up participants until a more advanced older age.
Topics: Female; Humans; Adult; Attention Deficit Disorder with Hyperactivity; Twins; Longitudinal Studies; Metabolic Diseases; Cardiovascular Diseases
PubMed: 37993878
DOI: 10.1186/s12916-023-03174-1 -
Journal of Child Psychology and... Apr 2020Autism Spectrum Disorder (ASD) is associated with altered global and local visual processing. However, the nature of these alterations remains controversial, with...
BACKGROUND
Autism Spectrum Disorder (ASD) is associated with altered global and local visual processing. However, the nature of these alterations remains controversial, with contradictory findings and notions ranging from a reduced drive to integrate information into a coherent 'gestalt' ("weak central coherence" = WCC) to an enhanced perceptual functioning (EPF) in local processing.
METHODS
This study assessed the association between autism and global/local visual processing, using a large sample of monozygotic (MZ) and dizygotic (DZ) twins (N = 290, 48% females, age = 8-31 years). The Fragmented Pictures Test (FPT) assessed global processing, whereas local processing was estimated with the Embedded Figures Test (EFT) and the Block Design Test (BDT). Autism was assessed both categorically (clinical diagnosis), and dimensionally (autistic traits). Associations between visual tasks and autism were estimated both across the cohort and within-twin pairs where all factors shared between twins are implicitly controlled.
RESULTS
Clinical diagnosis and autistic traits predicted a need for more visual information for gestalt processing in the FPT across the cohort. For clinical diagnosis, this association remained within-pairs and at trend-level even within MZ twin pairs alone. ASD and higher autistic traits predicted lower EFT and BDT performance across the cohort, but these associations were lost within-pairs.
CONCLUSIONS
In line with the WCC account, our findings indicate an association between autism and reduced global visual processing in children, adolescents and young adults (but no evidence for EPF). Observing a similar association within MZ twins suggests a non-shared environmental contribution.
Topics: Adolescent; Adult; Autism Spectrum Disorder; Child; Female; Humans; Male; Twins, Dizygotic; Twins, Monozygotic; Visual Perception; Young Adult
PubMed: 31452200
DOI: 10.1111/jcpp.13120 -
Alzheimer's & Dementia : the Journal of... Mar 2024Dementia predicts increased mortality. We used case-control and co-twin control models to investigate genetic and shared environmental influences on this association.
INTRODUCTION
Dementia predicts increased mortality. We used case-control and co-twin control models to investigate genetic and shared environmental influences on this association.
METHODS
Case-control design, including 987 twins with dementia and 2938 age- and sex-matched controls in the Swedish Twin Registry. Co-twin control design, including 90 monozygotic (MZ) and 288 dizygotic (DZ) twin pairs discordant for dementia. To test for genetic and environmental confounding, differences were examined in mortality risk between twins with dementia and their matched or co-twin controls.
RESULTS
Twins with dementia showed greater mortality risk than age- and sex-matched controls (HR = 2.02 [1.86, 2.18]). Mortality risk is significantly elevated but attenuated substantially in discordant twin pairs, for example, comparing MZ twins with dementia to their co-twin controls (HR = 1.48 [1.08, 2.04]).
DISCUSSION
Findings suggest that genetic factors partially confound the association between dementia and mortality and provide an alternative hypothesis to increased mortality due to dementia itself. Highlights We studied dementia and mortality in twin pairs discordant for dementia. People without dementia outlived people with dementia. Identical twins with dementia and their co-twin controls had similar survival time. Findings suggest genotype may explain the link between dementia and mortality.
Topics: Aged; Humans; Dementia; Genotype; Sweden; Twins, Dizygotic; Twins, Monozygotic; Male; Female
PubMed: 38078564
DOI: 10.1002/alz.13553 -
Neurobiology of Aging Dec 2021We studied the association between episodic memory and cortical fibrillar β-amyloid pathology within twin pairs. Using telephone-administered cognitive screening of...
We studied the association between episodic memory and cortical fibrillar β-amyloid pathology within twin pairs. Using telephone-administered cognitive screening of 1415 twin pairs in a population-based older Finnish Twin Cohort study, we identified 45 (mean [SD] age 72.9 [4.0] years, 40% women) cognitively discordant same-sex twin pairs (24 dizygotic and 21 monozygotic) without neurological or psychiatric disorders other than AD or mild cognitive impairment. In-person neuropsychological testing was conducted. Cortical amyloid was measured with carbon 11-labelled Pittsburgh compound B ([C]PiB) positron emission tomography imaging and quantified as the average standardized uptake value ratio in cortical regions affected in AD. Larger within-twin pair differences in verbal immediate (r = -0.42) and delayed free recall (r = -0.41), and visual delayed free recall (r = -0.46) were associated with larger within-twin pair differences in [C]PiB uptake (p's < 0.01). Correlations were not significantly different in dizygotic and monozygotic pairs suggesting that the episodic memory-cortical amyloid relationship is not confounded by genetic effects. However, larger samples are needed to draw more definitive conclusions.
Topics: Aged; Amyloid beta-Peptides; Cerebral Cortex; Cognitive Dysfunction; Cohort Studies; Diseases in Twins; Female; Humans; Male; Memory, Episodic; Neuropsychological Tests; Positron-Emission Tomography; Twins, Dizygotic; Twins, Monozygotic
PubMed: 34607247
DOI: 10.1016/j.neurobiolaging.2021.08.016 -
Hormones and Behavior Nov 2021Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes...
Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (β = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (β = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.
Topics: Cohort Studies; Educational Status; Female; Humans; Male; Sex Characteristics; Testosterone; Twins, Dizygotic
PubMed: 34488063
DOI: 10.1016/j.yhbeh.2021.105054 -
JCPP Advances Dec 2021Studies have reported significant associations between asthma and attention-deficit/hyperactivity disorder (ADHD), but whether the association is due to shared etiology...
BACKGROUND
Studies have reported significant associations between asthma and attention-deficit/hyperactivity disorder (ADHD), but whether the association is due to shared etiology such as shared genetic risk factors remains unclear. We aimed to investigate patterns of familial co-aggregation of asthma and ADHD and also to quantify the relative contribution of genetic and environmental influences.
METHODS
Through Swedish register linkages, we obtained a cohort of 927,956 individuals born 1992-2001 and identified monozygotic twins (MZ), dizygotic twins (DZ), full- and half-siblings, and full- and half-cousins. Clinical diagnosis of asthma and ADHD were identified from the Swedish national registers. We used logistic regressions to investigate the within-individual association and familial co-aggregation between asthma and ADHD. We then used bivariate twin modeling to quantify the genetic and environmental correlations and their contributions to the familial liability.
RESULTS
Individuals with asthma had significantly higher risk of ADHD (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.47-1.54). Relatives of individuals with asthma had an increased risk of ADHD compared to relatives of individuals without asthma; in familial co-aggregation analysis, the association was strongest in MZ twins (OR, 1.67; 95% CI, 0.99-2.84) and attenuated with degree of genetic relatedness. In the twin modeling, the phenotypic and genetic correlations between asthma and ADHD estimated from the ACE model were 0.09 (95% CI, 0.05-0.14) and 0.12 (95% CI, 0.02-0.21), respectively. The bivariate heritability was 0.88 (95% CI, 0.30-1.46). Estimates for contributions from shared and non-shared environment factors were not statistically significant.
CONCLUSIONS
Asthma and ADHD co-aggregate in families primarily due to shared genetic risk factors. Within-individual and family history of either disorder should prompt clinical assessment of the other condition. Future studies should further investigate genetic variants underlying the co-occurrence of ADHD and asthma.
PubMed: 37431403
DOI: 10.1002/jcv2.12044 -
Brain Structure & Function Jan 2022Quantitative neuroimaging studies in twin samples can investigate genetic contributions to brain structure and microstructure. Diffusion tensor imaging (DTI) studies...
Quantitative neuroimaging studies in twin samples can investigate genetic contributions to brain structure and microstructure. Diffusion tensor imaging (DTI) studies with twin samples have shown moderate to high heritability in white matter microstructure. This study investigates the genetic and environmental contributions of another widely used diffusion MRI model not yet applied to twin studies, neurite orientation dispersion and density imaging (NODDI). The NODDI model is a multicompartment model of the diffusion-weighted MRI signal, providing estimates of neurite density (ND) and the orientation dispersion index (ODI). A cohort of monozygotic (MZ) and same-sex dizygotic (DZ) twins (N = 460 individuals) between 13 and 24 years of age were scanned with a multi-shell diffusion weighted imaging protocol. Select white matter (WM) regions of interest (ROI) were extracted. Biometric structural equation modeling estimated the relative contributions from additive genetic (A) and common (C) and unique environmental (E) factors. Genetic factors for the NODDI measures accounted for 91% and 65% of the variation of global ND and ODI, respectively, compared with 83% for FA. We observed higher heritability for ND than both FA and ODI in 25 of 30 discrete white matter regions that we examined, suggesting ND may be more sensitive to underlying genetic sources of variation. This study demonstrated that genetic factors play a key role in the development of white matter microstructure using both DTI and NODDI.
Topics: Brain; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Humans; Neurites; White Matter
PubMed: 34585302
DOI: 10.1007/s00429-021-02393-7