Monozygotic Twin Pairs Research Articles

DNA Methylation Mediated the Association of Body Mass Index With Blood Pressure in Chinese Monozygotic Twins.

Obesity is an established risk factor for hypertension, but the mechanisms are only partially understood. We examined whether body mass index (BMI)-related DNA methylation (DNAm) variation would mediate the association of BMI with blood pressure (BP). We first conducted a genomewide DNA methylation analysis in monozygotic twin pairs to detect BMI-related DNAm variation and then evaluated the mediating effect of DNAm on the relationship between BMI and BP levels using the causal inference test (CIT) method and mediation analysis. Ontology enrichment analysis was performed for CpGs using the GREAT tool. A total of 60 twin pairs for BMI and systolic blood pressure (SBP) and 58 twin pairs for BMI and diastolic blood pressure (DBP) were included. BMI was positively associated with SBP (β = 1.86, p = .0004). The association between BMI and DNAm of 85 CpGs reached p < 1×10-4 level. Eleven BMI-related differentially methylated regions (DMRs) within LNCPRESS1, OGDHL, RNU1-44P, NPHS1, ECEL1P2, LLGL2, RNY4P15, MOGAT3, PHACTR3, and BAI2 were found. Of the 85 CpGs, 9 mapped to C10orf71-AS1, NDUFB5P1, KRT80, BAI2, ABCA2, PEX11G and FGF4 were significantly associated with SBP levels. Of the 9 CpGs, 2 within ABCA2 negatively mediated the association between BMI and SBP, with a mediating effect of -0.24 (95% CI [-0.65, -0.01]). BMI was also positively associated with DBP (β = 0.60, p = .0495). The association between BMI and DNAm of 193 CpGs reached p < 1×10-4 level. Twenty-five BMI-related DMRs within OGDHL, POU4F2, ECEL1P2, TTC6, SMPD4, EP400, TUBA1C and AGAP2 were found. Of the 193 CpGs, 33 mapped to ABCA2, ADORA2B, CTNNBIP1, KDM4B, NAA60, RSPH6A, SLC25A19 and STIL were significantly associated with DBP levels. Of the 33 CpGs, 12 within ABCA2, SLC25A19, KDM4B, PTPRN2, DNASE1, TFCP2L1, LMNB2 and C10orf71-AS1 negatively mediated the association between BMI and DBP, with a total mediation effect of -0.66 (95% CI [-1.07, -0.30]). Interestingly, BMI might also negatively mediate the association between the DNAm of most CpG mediators mentioned above and BP. The mediating effect of DNAm was also found when stratified by sex. In conclusion, DNAm variation may partially negatively mediate the association of BMI with BP. Our findings may provide new clues to further elucidate the pathogenesis of obesity to hypertension and identify new diagnostic biomarkers and therapeutic targets for hypertension.

A late-life neurogenetic signature of exposure to combat stress – A monozygotic discordant twin study

Animal models suggest that experiencing high-stress levels induces changes in amygdalar circuitry and gene expression. In humans, combat exposure has been shown to alter amygdalar responsivity and connectivity, but abnormalities have been indicated to normalize at least partially upon the termination of stress exposure. In contrast, other evidence suggests that combat exposure continues to exert influence on exposed individuals well beyond deployment and homecoming, as indicated by longitudinal psychosocial evidence from veterans, and observation of greater health decline in veterans late in life. Accordingly, the experience of combat stress early in life may affect amygdalar responsivity late in life, a possibility requiring careful consideration of the confounding effects of aging, genetic factors, and symptoms of post-traumatic stress disorder. Here, we investigated amygdalar responsivity in a unique sample of 16 male monozygotic (MZ) twin pairs in their sixties, where one but not the other sibling had been exposed to combat stress in early adulthood. Forty years after combat experience, a generally blunted amygdalar response was observed in combat-exposed veterans compared to their non-exposed twin siblings. Spatial associations between these phenotypical changes and patterns of gene expression in the brain were found for genes involved in the synaptic organization and chromatin structure. Protein-protein interactions among the set of identified genes pointed to histone modification mechanisms. We conclude that exposure to combat stress early in life continues to impact brain function beyond the termination of acute stress and appears to exert prolonged effects on amygdalar function later in life via neurogenetic mechanisms.

Technical strategy for monozygotic twin discrimination by single-nucleotide variants.

Monozygotic (MZ) twins are theoretically genetically identical. Although they are revealed to accumulate mutations after the zygote splits, discriminating between twin genomes remains a formidable challenge in the field of forensic genetics. Single-nucleotide variants (SNVs) are responsible for a substantial portion of genetic variation, thus potentially serving as promising biomarkers for the identification of MZ twins. In this study, we sequenced the whole genome of a pair of female MZ twins when they were 27 and 33years old to approximately 30 × coverage using peripheral blood on an Illumina NovaSeq 6000 Sequencing System. Potentially discordant SNVs supported by whole-genome sequencing were validated extensively by amplicon-based targeted deep sequencing and Sanger sequencing. In total, we found nine bona fide post-twinning SNVs, all of which were identified in the younger genomes and found in the older genomes. None of the SNVs occurred within coding exons, three of which were observed in introns, supported by whole-exome sequencing results. A double-blind test was employed, and the reliability of MZ twin discrimination by discordant SNVs was endorsed. All SNVs were successfully detected when input DNA amounts decreased to 0.25ng, and reliable detection was limited to seven SNVs below 0.075ng input. This comprehensive analysis confirms that SNVs could serve as cost-effective biomarkers for MZ twin discrimination.

Familial Transmission of Developmental Prosopagnosia: New Case Reports from an Extended Family and Identical Twins.

Existing evidence suggests that developmental prosopagnosia (DP) is a surprisingly prevalent condition, with some individuals describing lifelong difficulties with facial identity recognition. Together with case reports of multiple family members with the condition, this evidence suggests that DP is inherited in at least some instances. Here, we offer some novel case series that further support the heritability of the condition. First, we describe five adult siblings who presented to our lab with symptoms of DP. Second, for the first known time in the literature, we describe a pair of adult identical twins who contacted us in the belief that they both experience DP. The condition was confirmed in three of the five siblings (with minor symptoms observed in the remaining two) and in both twins. Supplementary assessments suggested that all individuals also experienced some degree of difficulty with facial identity perception, but that object recognition was preserved. These findings bolster the evidence supporting the heritability of DP and suggest that it can be a specific impairment in some cases.

Spatial Similarity of MRI-Visible Perivascular Spaces in Healthy Young Adult Twins.

This study aimed to determine whether genetic factors affect the location of dilated perivascular spaces (dPVS) by comparing healthy young twins and non-twin (NT) siblings. A total of 700 healthy young adult twins and NT siblings [138 monozygotic (MZ) twin pairs, 79 dizygotic (DZ) twin pairs, and 133 NT sibling pairs] were collected from the Human Connectome Project dataset. dPVS was automatically segmented and normalized to standard space. Then, spatial similarity indices [mean squared error (MSE), structural similarity (SSIM), and dice similarity (DS)] were calculated for dPVS in the basal ganglia (BGdPVS) and white matter (WMdPVS) between paired subjects before and after propensity score matching of dPVS volumes between groups. Within-pair correlations for the regional volumes of dVPS were also assessed using the intraclass correlation coefficient. The spatial similarity of dPVS was significantly higher in MZ twins [higher DS (median, 0.382 and 0.310) and SSIM (0.963 and 0.887) and lower MSE (0.005 and 0.005) for BGdPVS and WMdPVS, respectively] than in DZ twins [DS (0.121 and 0.119), SSIM (0.941 and 0.868), and MSE (0.010 and 0.011)] and NT siblings [DS (0.106 and 0.097), SSIM (0.924 and 0.848), and MSE (0.016 and 0.017)]. No significant difference was found between DZ twins and NT siblings. Similar results were found even after the subjects were matched according to dPVS volume. Regional dPVS volumes were also more correlated within pairs in MZ twins than in DZ twins and NT siblings. Our results suggest that genetic factors affect the location of dPVS.

Twin Study: The Factors Affecting the Serum LDL-C and HDL-C Levels and an RNA-Seq Analysis in Mononuclear Cells in Monozygotic Twins.

A twin study is a valuable tool for elucidating the acquired factors against lifestyle diseases such as dyslipidemia, diabetes mellitus, and obesity. We aimed 1. to investigate the factors that affect low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in monozygotic (MZ) twins, and 2. to identify genes which expression levels changed in pairs with large differences in LDL-C or HDL-C levels. The registered database at the Center for Twin Research, Osaka University, containing 263 pairs of MZ twins, was analyzed. 1. The effects of smoking, exercise, nutritional factors, and anthropometric and biochemical parameters on LDL-C or HDL-C levels were examined in MZ twins. 2. RNA sequencing in the peripheral blood mononuclear cells of 59 pairs was analyzed for large differences of LDL-C or HDL-C groups. 1. The ΔLDL-C levels were significantly associated with an older age, the ΔTG levels, and ΔBMI. ΔHDL-C levels were associated with the ΔBMI, ΔTG, ΔTP, and ΔLDL-C levels. The HDL-C levels were affected by smoking and exercise habits. The intakes of cholesterol and saturated fatty acids were not associated with the LDL-C or HDL-C levels. 2. An RNA sequencing analysis revealed that the expression of genes related to the TLR4 and IFNG pathways was suppressed in accordance with the HDL-C levels in the larger ΔHDL-C group among the 59 pairs. We identified the factors affecting the LDL-C or HDL-C levels in monozygotic twins. In addition, some types of inflammatory gene expression in peripheral blood mononuclear cells were suppressed in accordance with the HDL-C levels, thus suggesting the importance of weight management and exercise habits in addition to dietary instructions to control the LDL-C or HDL-C levels.

The Colombo Twin and Singleton Study (COTASS): Piloting the Feasibility of Collecting Nutritional Data and Extension of the Sample to Include Children of Twins

Nutrition and diet are key modifiable risk factors for the rising burden of non-communicable diseases like cardio-vascular diseases and diabetes in low- and middle- income countries (LMICs). The nutritional transition in dietary behaviours in LMICs has most likely contributed to this problem. Although traditionally assumed to be environmental, dietary choices are also genetically influenced. Twin study designs can be used to investigate the relative influence of genes and environment on nutrition intake, eating behaviours and associated psychological health. The overall aim of this project is to: provide proof-of-concept for the feasibility of using dietary (biomarker) data within the Children-of-Twin design in nutrition studies, develop laboratory skills and statistical genetic skills and establish a Sri Lankan-specific food composition database. Currently, a pilot study is being conducted with 304 individuals (38 Monozygotic twin pairs, 38 Dizygotic twin pairs and their male or female adult offspring). Questionnaire data on nutritional intake, eating behaviours, psychological well-being, physical health, and bio-specimens are being collected. A Sri Lankan-specific food composition database was developed, training sessions on macro and micro element analysis in biological samples and statistical genetics skills development were conducted and Community Engagement and Involvement programs were carried out in two districts of Sri Lanka.

Association Between Accelerometer-Measured Physical Activity and Mobility Limitations in Twins.

The associations between mobility limitations and device-measured physical activity are sparsely studied. In this study, these associations are studied among community-dwelling older twins. This cross-sectional study utilized data gathered in 2014-2016 for the MOBILETWIN study. Participants were twins born in Finland between 1940 and 1944 (774 participants, mean age 73years). Physical activity was measured with a hip-worn accelerometer. Mobility limitations were assessed with a questionnaire. Individual-level analyses revealed that physical activity was associated with mobility limitations. Participants with severe mobility limitations took 2,637 (SD = 1,747) steps per day, those with some mobility limitations 4,437 (SD = 2,637) steps, and those without mobility limitations 7,074 (SD = 2,931) steps (p < .05). The within-twin pair analyses revealed the same pattern for the 144 dizygotic twin pairs, but no associations were seen for the 117 monozygotic twin pairs. Accelerometer-measured physical activity and mobility limitations were associated in community-dwelling older adults. Genetic factors may explain some of the variations in physical activity. A personalized exercise program to promote increased physical activity should be provided for older adults who report mobility difficulties. Future research is needed to examine causality between physical activity and mobility limitations.

Multiparametric Analysis of Speaking Fundamental Frequency in Genetically Related Speakers Using Different Speech Materials: Some Forensic Implications.

To assess the speaker-discriminatory potential of a set of fundamental frequency estimates in intraidentical twin pair comparisons and cross-pair comparisons (i.e., among all speakers). A total of 20 Brazilian Portuguese speakers of the same dialect, namely 10 male identical twin pairs aged between 19 and 35, were recruited. The participants were recorded directly through professional microphones while taking part in a spontaneous dialogue over mobile phones. Acoustic measurements were performed in connected speech samples, and in lengthened vowels, at least 160ms long produced during spontaneous speech. f0 baseline, central tendency, and extreme values were found mostly discriminatory in intra-twin pair and cross-pair comparisons. These were also the estimates displaying the largest effect sizes. Overall, only three identical twins were found statistically different regarding their f0 patterns in connected speech, but not for lengthened vowel-based f0 metrics. Estimates of f0 variation and modulation were found the least discriminatory across speakers, which may signal the control of speaking style and dialect on dynamic patterns of f0. Concerning system performance, the base value of f0 (f0 baseline) was found the most reliable metric, displaying the lowest equal error rate (EER). The outcomes suggest that, although identical twins were very closely related regarding their f0 patterns, some pairs could still be differentiated acoustically, only in connected speech. Such findings reinforce the relevance of analyzing long-term f0 metrics for speaker comparison purposes, with particular consideration to f0 baseline. Furthermore, f0 differences across subjects were suggested as more expressive in connected speech than in lengthened vowels.

A study of forensic genetics: ITO index distribution and kinship judgment between two individuals.

According to Mendel's law of genetic separation, there must be a certain blood relationship between members of the same family, and two individuals with blood relations must have the following three situations, that is, there are two homologous genes (I denotes), one homologous gene (T denotes), and no homologous genes (O denotes), which is the ITO index for calculating the blood relationship between two individuals. The AGGU Expressmarker 22 kit, ABI 3500 genetic analyzer, and GeneMapper ID-X v1.5 software were used to statistically analyze the ITO index of the gene locus of 5 kinds of samples, 28 pairs of monozygotic twins (MT), 4,000 pairs of parent-offspring (PO), 392 pairs of full sibling (FS), 138 pairs of half-siblings (HS) (including grandchildren, uncles, and nephews) and 3,500 pairs of unrelated individuals (UI). Observing the median distribution of ITO index found that from MT, PO, FS, HS to UI, the more distant the kinship, the smaller the ITO index. Full sibling index (FSI)/half-sibling index (HSI) ≥ 1 can be used as the FS discriminant standard, FSI/HSI < 1 can be used as the HS discriminant standard. According to the distance of kinship, from the direction of MT, PO, FS, HS, and UI, the proportion of the maximum ITO index of the same type of sample in the true kinship index item showed a decreasing trend. ITO index is an important statistical means to identify the kinship between two individuals, according to which the ITO index can accurately determine the kinship between individuals, which has high application value. MT index is not 0 to identify relatives as MT, PO index is an important indicator to distinguish between relatives as PO and FS. The critical values of ITO index discriminant values for UI and HS need to be further studied.

EPIGENETIC AGE ACCELERATION AND IMMUNE CELL COUNT: A TWIN STUDY

Abstract Accelerated aging, as measured by epigenetic clocks, is associated with declines in immune system functioning. Investigating the causal basis of this association may provide mechanistic insight into the link between DNA methylation, on which epigenetic clocks are based, and age-related changes in immune cell composition. Using preliminary data from the Louisville Twin Study, this study examined the genetic and environmental sources of covariation between immune cell count (neutrophils, lymphocytes) and GrimAge Acceleration. GrimAge is a composite biomarker derived from 7 DNA methylation-based surrogates associated with mortality and smoking pack years. GrimAge Acceleration is the residual of GrimAge regressed onto chronological age. Participants consisted of 43 monozygotic twin pairs and 30 (18 same-sex) dizygotic twin pairs with a mean age of 54.5 years (sd = 5.27). Phenotypic analyses revealed that GrimAge Acceleration was significantly associated with neutrophil and lymphocyte count (r = 0.45 and -0.49, respectively). To examine the sources of covariation between these variables, biometric regression models were used to decompose the covariance between GrimAge Acceleration and neutrophils (and lymphocytes) into genetic and environmental components. Bivariate analyses revealed moderate, marginally significant genetic correlations between GrimAge Acceleration and immune cell count (rg = 0.32 and -0.38 for neutrophils and lymphocytes, respectively) and large, significant nonshared environmental correlations (re = .58 and -.54 for neutrophils and lymphocytes, respectively). Common genetic factors accounted for 39% of the phenotypic correlation in neutrophils and 43% in lymphocytes, whereas common nonshared environmental factors accounted for 61% and 57% of the correlation in these cell types, respectively.

Differences of circular RNA expression profiles between monozygotic twins' blood, with the forensic application in bloodstain and saliva

Monozygotic twins (MZTs) possess identical genomic DNA sequences and are usually indistinguishable through routine forensic DNA typing methods, which can be relevant in criminal and paternity cases. Recently, novel epigenetic methods involving DNA methylation and microRNA analysis have been introduced to differentiate MZTs. In this study, we explore the potential of using epigenetic markers, specifically circular RNAs (circRNAs), a type of non-coding RNA (ncRNA), to identify MZTs, and investigate the unique expression patterns of circRNAs within pairs of MZTs, enabling effective differentiation. Epigenetics regulates gene expression at the post-transcriptional level and plays a crucial role in cell growth and aging. CircRNAs, a recently characterized subclass of ncRNA, have a distinct covalent loop structure without the typical 5′ cap or 3′ tail. They have been reported to modulate various cellular processes and play roles in embryogenesis and eukaryotic development. To achieve this, we conducted a comprehensive circRNA sequencing analysis (circRNA-seq) using total RNA extracted from the blood samples of five pairs of MZTs. We identified a total of 15,257 circRNAs in all MZTs using circRNA-seq. Among them, 3, 21, 338, and 2967 differentially expressed circRNAs (DEcircRNAs) were shared among five, four, three, and two pairs of MZTs, respectively. Subsequently, we validated twelve selected DEcircRNAs using real-time quantitative polymerase chain reaction (RT-qPCR) assays, which included hsa_circ_0004724, hsa_circ_0054196, hsa_circ_004964, hsa_circ_0000591, hsa_circ_0005077, hsa_circ_0054853, hsa_circ_0054716, hsa_circ_0002302, hsa_circ_0004482, hsa_circ_0001103, novel_circ_0030288 and novel_circ_0056831. Among them, hsa_circ_0005077 and hsa_circ_0004482 exhibited the best performance, showing differences in 7 out of 10 pairs of MZTs. These twelve differentially expressed circRNAs also demonstrated strong discriminative power when tested on saliva samples from 10 pairs of MZTs. Notably, hsa_circ_0004724 displayed differential expression in 8 out of 10 pairs of MZTs in their saliva. Additionally, we evaluated the detection sensitivity, longitudinal temporal stability, and suitability for aged bloodstains of these twelve DEcircRNAs in forensic scenarios. Our findings highlight the potential of circRNAs as molecular markers for distinguishing MZTs, emphasizing their suitability for forensic application.

DNA identification of monozygotic twins

This study details the differentiation of identical twins based on single mutational base differences. There were three pairs of male monozygotic (MZ) twins in this study. DNA samples from blood, a buccal swab or saliva from each individual were all initially genotyped using 22 autosomal STR and 27 Y-STR loci. Preliminary screening confirmed there were no differences in the STR data between each pair of MZ twins. Whole Genome Sequence (WGS) data were generated from DNA extracted from the three body fluids from each individual. Kinship coefficients with 0.4254, 0.4557 and 0.4543 from 3 twins were generated based on WGS data to further confirm that their relationship was that of MZ twins. The fastq data generated by the Illumina Hiseq 2000 between MZ twins were then treated as “normal” as opposed to “tumor” using commercially available software tools to identify mutational single base changes. Sanger DNA sequencing confirmed there were 1, 5 and 9 single base changes found in WGS data from each of the three MZ twin sets. There was individual variation in the mutational base changes when comparing data from the three body fluids. The methods used in this study to differentiate MZ twins based on WGS data can readily be performed in many operational forensic DNA laboratories using user friendly software.

Evaluating functional brain organization in individuals and identifying contributions to network overlap

Abstract Individual differences in the spatial organization of resting-state networks have received increased attention in recent years. Measures of individual-specific spatial organization of brain networks and overlapping network organization have been linked to important behavioral and clinical traits and are therefore potential biomarker targets for personalized psychiatry approaches. To better understand individual-specific spatial brain organization, this paper addressed three key goals. First, we determined whether it is possible to reliably estimate weighted (non-binarized) resting-state network maps using data from only a single individual, while also maintaining maximum spatial correspondence across individuals. Second, we determined the degree of spatial overlap between distinct networks, using test-retest and twin data. Third, we systematically tested multiple hypotheses (spatial mixing, temporal switching, and coupling) as candidate explanations for why networks overlap spatially. To estimate weighted network organization, we adopt the Probabilistic Functional Modes (PROFUMO) algorithm, which implements a Bayesian framework with hemodynamic and connectivity priors to supplement optimization for spatial sparsity/independence. Our findings showed that replicable individual-specific estimates of weighted resting-state networks can be derived using high-quality fMRI data within individual subjects. Network organization estimates using only data from each individual subject closely resembled group-informed network estimates (which was not explicitly modeled in our individual-specific analyses), suggesting that cross-subject correspondence was largely maintained. Furthermore, our results confirmed the presence of spatial overlap in network organization, which was replicable across sessions within individuals and in monozygotic twin pairs. Intriguingly, our findings provide evidence that overlap between 2-network pairs is indicative of coupling. These results suggest that regions of network overlap concurrently process information from both contributing networks, potentially pointing to the role of overlapping network organization in the integration of information across multiple brain systems.

Genetic and Environmental Causes of Variation in an Automated Breast Cancer Risk Factor Based on Mammographic Textures.

Cirrus is an automated risk predictor for breast cancer that comprises texture-based mammographic features and is mostly independent of mammographic density. We investigated genetic and environmental variance of variation in Cirrus. We measured Cirrus for 3,195 breast cancer-free participants, including 527 pairs of monozygotic (MZ) twins, 271 pairs of dizygotic (DZ) twins, and 1,599 siblings of twins. Multivariate normal models were used to estimate the variance and familial correlations of age-adjusted Cirrus as a function of age. The classic twin model was expanded to allow the shared environment effects to differ by zygosity. The SNP-based heritability was estimated for a subset of 2,356 participants. There was no evidence that the variance or familial correlations depended on age. The familial correlations were 0.52 (SE, 0.03) for MZ pairs and 0.16(SE, 0.03) for DZ and non-twin sister pairs combined. Shared environmental factors specific to MZ pairs accounted for 20% of the variance. Additive genetic factors accounted for 32% (SE = 5%) of the variance, consistent with the SNP-based heritability of 36% (SE = 16%). Cirrus is substantially familial due to genetic factors and an influence of shared environmental factors that was evident for MZ twin pairs only. The latter could be due to nongenetic factors operating in utero or in early life that are shared by MZ twins. Early-life factors, shared more by MZ pairs than DZ/non-twin sister pairs, could play a role in the variation in Cirrus, consistent with early life being recognized as a critical window of vulnerability to breast carcinogens.

Mental, physical, and social well-being and quality of life in healthy young adult twin pairs discordant and concordant for body mass index.

The relationship between obesity and mental health is complex and is moderated by the level of obesity, age, sex, and social and genetic factors. In the current study, we used a unique co-twin control design, with twin pairs discordant for body mass index (BMI), to control for shared genetic and environmental effects between obesity and several dimensions of mental health. We studied 74 monozygotic (MZ) twin pairs, of whom 36 were BMI-discordant (intra-pair difference in BMI ≥ 3 kg/m2), and 77 dizygotic (DZ) twin pairs (46 BMI-discordant). We assessed subjective health, especially mental health and mental well-being (depression, anxiety, self-esteem, health-related quality of life, life satisfaction, and social well-being) through questionnaires. Heavier MZ co-twins from BMI-discordant pairs had poorer general health (58.8±3.0 vs. 72.4±3.8, P = 0.001, FDR = 0.017 on a scale from 0 to 100 where higher scores indicate more positive results), physical functioning (90.3±1.1 vs. 95.5±2.2, P = 0.024, FDR = 0.122), energy levels (55.6±3.4 vs. 66.6±3.3, P = 0.013, FDR = 0.109), and emotional well-being (65.9±3.2 vs. 75.4±2.9, P = 0.031, FDR = 0.122), as well as a tendency for depressive symptoms (8.4±1.3 vs. 5.6±0.9, P = 0.071, FDR = 0.166) compared to their leaner co-twins. Heavier DZ co-twins had poorer total physical well-being (91.6±1.9 vs. 95.6±1.0, P = 0.035, FDR = 0.356) and more depressive symptoms (4.3±0.9 vs. 2.4±0.5, P = 0.016, FDR = 0.345 on a scale from 0 to 63 where lower scores indicate fewer depressive symptoms) than their leaner co-twins. Association analyses, using all twin pairs, confirmed that higher BMI within pairs linked to general health, physical functioning and depressive symptoms. No association was found between BMI and anxiety, self-esteem, life satisfaction, or social well-being. In conclusion, this study underscores the notable association between elevated BMI and physical well-being and to a lesser extent between elevated BMI and depressive symptoms, while revealing no discernible connections with anxiety, self-esteem, life satisfaction, or social well-being.

Educational Attainment and Risk of All‐Cause Dementia, Vascular Dementia, and Alzheimer’s Disease – A Population‐Based Twin Study

AbstractBackgroundMost studies on the association between educational attainment and dementia have been conducted in unrelated individuals. Dementia‐discordant twin pairs can inform if the protective effect of education on dementia is evident when controlling for environmental and genetic effects. We investigated the association of educational attainment on all‐cause dementia, vascular dementia (VaD), and Alzheimer’s disease (AD) mortality in a population‐based sample of dizygotic (DZ) and monozygotic (MZ) pairs.MethodParticipants were from a population‐based longitudinal older Finnish Twin Cohort study with baseline questionnaire in 1975 (N = 29,784; mean age = 36.9±14.9years). Education was coded as &lt;12 years versus ≥12 years. Registry‐based cause of death data until year 2020 was based on the International Classification of Diseases. We ran individual‐level cox proportional hazard models with sex as a covariate and conditional within‐twin‐pair models for education predicting all‐cause dementia, VaD, and AD mortality. We report hazard ratios (HR) with 95% confidence intervals (CI).ResultIn individual‐level analyses higher education was associated with a decreased risk of all‐cause dementia (HR = .935, 95%CI = .934;.936, p&lt;.001) and VaD (HR = .638, 95%CI = .637;.640, p&lt;.001), but with an increased risk of AD (HR = 1.276, 95%CI = 1.275;1.277, p&lt;.001). In co‐twin analyses of discordant DZ and MZ twin pairs, co‐twins with higher education had lower – although non‐significant – risk of all‐cause dementia (N = 52, HR = .688, 95%CI = .319;1.481, p = .339) or AD (N = 36, HR = .600, 95%CI: .218;1.651, p = .323). Co‐twin analyses were not done for VaD due to small number of discordant pairs (N = 6).ConclusionThis large population‐based sample showed that higher education is related to lower risk of all‐cause dementia and VaD mortality. Unexpectedly, higher education was related to higher AD mortality, but discordant twin pair analyses were informative regarding this counterintuitive result. This case‐control design, controlling for genetic and environmental effects, did not support any causality from higher education to higher AD risk. Despite the large sample, twin pairs – especially MZ twins – discordant for dementia are rare. Meta‐ or mega‐analysis of multiple large twin studies is needed to clarify if secondary education is related to lower risk of dementia, VaD, and AD mortality when controlling for genetic effects.

Traumatic Brain Injury and Cognitive Aging Among Older Veteran Men – A Twin Study Accounting for Genetics and Medical Conditions

AbstractBackgroundTraumatic brain injury (TBI) is associated with increased risk of dementia, but whether TBI influences cognitive trajectories in later life is less clear. Identifying those at high‐risk of cognitive decline creates intervention opportunities to delay dementia. Since twins share many genes and environmental factors, we capitalize on the twin‐study design to investigate the association between lifetime TBI and cognitive decline.MethodParticipants (n = 8,662) members of the National Academy of Sciences‐National Research Council’s Twins Registry of World‐War‐II Male Veterans born between 1917‐1927 with self or proxy‐reported history of TBI and from one to four assessments over 12 years using the modified‐Telephone Interview for Cognitive Status (TICS‐m). We used linear random‐effects‐mixed models to examine the association between TBI and TICS‐m in the full sample and among co‐twins discordant for TBI. Additional TBI predictor variables included: number and severity (with/without loss‐of‐consciousness[LOC]) of TBI; and age of first TBI (age &lt;25 vs 25+). Models were adjusted for age (centered‐at‐70‐years), age‐squared, education, wave, twin pairs and for lifestyle behaviors and medical conditions. In a subset, we assessed the impact of APOE on TICS‐m.ResultHistory of any TBI, TBI with LOC, and older age of TBI were associated with lower TICS‐m scores at 70‐years (p‐values&lt;0.001). TBI with LOC, more than one TBI, and older age of TBI were associated with faster cognitive decline (p‐values&lt;0.05). Among monozygotic twin pairs discordant for TBI (589 pairs), a history of TBI and having TBI at older age was associated with lower TICS‐m scores (p‐values&lt;0.01); those with more than one TBI and TBI at older age showed greater cognitive decline (p‐values&lt;0.05) compared to their cotwin without TBI. Across all twins, APOE‐e4 carriers with TBI, more than one TBI, TBI with LOC, and older age of TBI had lower TICS‐m scores and greater cognitive decline compared to APOE‐e4 non‐carriers.ConclusionThese findings support an association between TBI and lower cognitive score and more rapid cognitive decline in later life. The results in the monozygotic pairs, who share all genes and many exposures particularly in early life, provide evidence of a causal relationship between TBI and poorer late life cognitive outcomes.

Attention-deficit/hyperactivity disorder symptoms and subsequent cardiometabolic disorders in adults: investigating underlying mechanisms using a longitudinal twin study

BackgroundEmerging 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.MethodsWe 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.ResultsA 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.ConclusionsADHD 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.

Genetic and environmental influences on early-age susceptibility and initiation of nicotine-containing product use: A twin-pairs study.

Nicotine-containing products (NCPs) such as electronic nicotine delivery systems (ENDS) are increasingly common throughout the landscape of youth use of nicotine-containing products (NCP), and have overtaken traditional cigarette smoking modalities. This study seeks to examine the genetic and environmental influences on liability for susceptibility and initiation of ENDS and other NCPs among US children. Data were drawn from 886 monozygotic (MZ) and dizygotic (DZ) twin pairs aged 9-10 years in the Adolescent Brain & Cognitive Development (ABCD) study at the baseline during 2016-2018. Heritability (h2) measured the proportion of the total phenotypic variation attributable to genes. Variance component models were utilized to analyze influences from the common environment (c2) and unique environmental factors (e2), taking into account correlations within twin pairs. The national sample included 50% females, 69.5% of non-Hispanic Whites, 12.8% of non-Hispanic Blacks, and 11.6% of Hispanics, with a mean age of 121.5 months. The twin sets were 60% DZ and 40% MZ. Heritability was low for NCP susceptibility (h2=0) and moderate for NCP initiation (h2=39%, p=0.02). The variance associated with NCP susceptibility was primarily influenced by environmental factors, especially one's unique factors (c2=37%, p<0.0001 vs e2=63%, p<0.0001). In contrast, the variance associated with NCP initiation was split across common and unique environmental factors (c2=32%, p=0.02 vs e2=29%, p=0.02). In the era with ENDS use surging among youth, NCP initiation remains to be a heritable trait with joint influence from the environment. NCP susceptibility is largely influenced by environmental factors, especially unique environments. Continued assessment of gene × environment interaction can better inform future youth NCP interventions.