Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss.

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.

Association of cancer with functional decline at old age: a longitudinal study in Danish twins.

INTRODUCTION: There is evidence that older adults with cancer have a higher risk of functional decline than cancer-free older adults. However, few studies are longitudinal, and none are twin studies. Thus, we aimed to investigate the relationship between cancer and functional decline in older adult (aged 70+ years) twins. MATERIALS AND METHODS: Cancer cases in the Longitudinal Study of Aging Danish Twins were identified through the Danish Cancer Registry. Functional status was assessed using hand grip strength (6 years follow-up), and self-reported questions on mobility (10 years follow-up), and cut-offs were defined to assess functional decline. Cox regression models were performed for all the individual twins. In addition, we extended the analysis to discordant twin pairs (twin pairs with one having cancer and the other being cancer-free), to control to a certain extent for (unmeasured) shared confounders (genetic and environmental factors). RESULTS: The analysis based on individual twins showed that individual twins with cancer are at increased hazard of worsening hand grip strength (hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.04, 1.80) than cancer-free twins. Among the discordant twin pairs, twins with cancer had a higher hazard of worsening hand grip strength (HR 3.50, 95% CI 1.15, 10.63) than cancer-free cotwins. In contrast, there was no evidence of a difference between the hazard of experiencing mobility decline for twins with cancer compared with cancer-free twins, in both individual twins and discordant twin pairs analyses. DISCUSSION: Cancer was associated with hand grip strength functional decline in old individual twins and discordant pairs. Our results strengthen the importance of comprehensive geriatric assessment in older adults with cancer, as well as the importance of routine assessment of functional status. Promoting physical activity through exercise training programmes could enable the prevention of functional decline in older adults with cancer.

Identifying genetic variants regulating MGMT gene expression - A study in monozygotic Danish twins.

Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (p < 5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to p = 1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient's sensitivity to therapeutic alkylating agents.

A Mass Spectrometry-Based Proteome Study of Twin Pairs Discordant for Incident Acute Myocardial Infarction within Three Years after Blood Sampling Suggests Novel Biomarkers.

Acute myocardial infarction (AMI) is a major cause of mortality and morbidity worldwide, yet biomarkers for AMI in the short- or medium-term are lacking. We apply the discordant twin pair design, reducing genetic and environmental confounding, by linking nationwide registry data on AMI diagnoses to a survey of 12,349 twins, thereby identifying 39 twin pairs (48-79 years) discordant for their first-ever AMI within three years after blood sampling. Mass spectrometry of blood plasma identified 715 proteins. Among 363 proteins with a call rate > 50%, imputation and stratified Cox regression analysis revealed seven significant proteins (FDR < 0.05): FGD6, MCAM, and PIK3CB reflected an increased level in AMI twins relative to their non-AMI co-twins (HR > 1), while LBP, IGHV3-15, C1RL, and APOC4 reflected a decreased level in AMI twins relative to their non-AMI co-twins (HR < 1). Additional 50 proteins were nominally significant (p < 0.05), and bioinformatics analyses of all 57 proteins revealed biology within hemostasis, coagulation cascades, the immune system, and the extracellular matrix. A protein-protein-interaction network revealed Fibronectin 1 as a central hub. Finally, technical validation confirmed MCAM, LBP, C1RL, and APOC3. We put forward novel biomarkers for incident AMI, a part of the proteome field where markers are surprisingly rare and where additional studies are highly needed.

Stillbirth and early neonatal mortality rates may be underestimated using recall information: A comparison of demographic surveillance methodologies.

OBJECTIVE: Child mortality and stillbirth rates (SBR) remain high in low-income countries but may be underestimated due to incomplete reporting of child deaths in retrospective pregnancy/birth histories. The aim of this study is to compare stillbirth and mortality estimates derived using two different methods: the method assuming full information and the prospective method. METHODS: Bandim Health Project's Health and Demographic Surveillance Systems (HDSS) follows women of reproductive age and children under five through routine home visits every 1, 2 or 6 months. Between 2012 and 2020, we estimated and compared early neonatal (ENMR, <7 days), neonatal (NMR, <28 days), and infant mortality (IMR, <1 year) per 1000 live births and SBR per 1000 births. Risk time for children born to registered women was calculated from birth (the method assuming full information) versus date of first observation in the HDSS (the prospective method), either at birth (for pregnancy registration) or registration. Rates were calculated using the Kaplan-Meier estimator and compared in generalised linear models allowing for within-child correlation obtaining relative risks (RR). RESULTS: We registered and followed 29,413 infants (1380 deaths; 1459 stillbirths) prospectively. An additional 164 infant deaths and 129 stillbirths were registered retrospectively and included in the method assuming full information. The ENMR was 24.5 (95%CI: 22.6-26.4) for the method assuming full information and 25.8 (23.7-27.8) for the prospective method, RR = 0.96 (0.93-0.99). Differences were smaller for the NMRs and IMRs. For SBRs, the estimates were 53.5 (50.9-56.0) and 58.6 (55.7-61.5); RR = 0.91 (0.90-0.93). The difference between methods became more pronounced when the analysis was limited to areas visited every 6 months: RR for ENMR: 0.91 (0.86-0.96) and RR for SBR: 0.85 (0.83-0.87). CONCLUSIONS: Assuming full information underestimates SBR and ENMR. Accounting for omissions of stillbirths and early neonatal deaths may lead to more accurate estimates and improved ability to monitor mortality.

A robust and fast two-sample test of equal correlations with an application to differential co-expression.

A robust and fast two-sample test for equal Pearson correlation coefficients (PCCs) is important in solving many biological problems, including, for example, analysis of differential co-expression. However, few existing methods for this test can achieve robustness against deviation from normal distributions, accuracy under small sample sizes, and computational efficiency simultaneously. Here, we propose a new method for testing differential correlation using a saddlepoint approximation of the residual bootstrap (DICOSAR). To achieve robustness, accuracy, and efficiency, DICOSAR combines the ideas underlying the pooled residual bootstrap, the signed root of a likelihood ratio statistic, and a multivariate saddlepoint approximation. Through a comprehensive simulation study and a real data analysis of gene co-expression, we demonstrate that DICOSAR is accurate and robust in controlling the type I error rate for detecting differential correlation and provides a faster alternative to the bootstrap and permutation methods. We further show that DICOSAR can also be used for testing differential correlation matrices. These results suggest that DICOSAR provides an analytical approach to facilitate rapid testing for the equality of PCCs in large-scale analysis.

Socioeconomic differences in expected discomfort from colonoscopy and colon capsule endoscopy.

Individual income and educational level are associated with participation rates in colorectal cancer screening. We aimed to investigate the expected discomfort from the endoscopic diagnostic modalities of colonoscopy and colon capsule endoscopy in different socioeconomic groups as a potential barrier for participation. In a randomized clinical trial within the Danish colorectal cancer screening program, we distributed questionnaires to 2031 individuals between August 2020 and December 2022 to investigate the expected procedural and overall discomfort from investigations using visual analogue scales. Socioeconomic status was determined by household income and educational level. Multivariate continuous ordinal regressions were performed to estimate the odds of higher expected discomfort. The expected procedural and overall discomfort from both modalities were significantly higher with increasing educational levels and income, except for procedural discomfort from colon capsule endoscopy between income quartiles. The odds ratios for higher expected discomfort increased significantly with increasing educational level, whereas the differences between income groups were less substantial. Bowel preparation contributed most to expected discomfort in colon capsule endoscopy, whereas in colonoscopy, the procedure itself was the largest contributor. Individuals with prior experiences of colonoscopy reported significantly lower expected overall but not procedural discomfort from colonoscopy. The threshold for acceptable discomfort between subgroups is unknown, but the expected discomfort in colon capsule endoscopy and colonoscopy was higher in higher socioeconomic subgroups, suggesting that expected discomfort is not a significant contributor to the inequalities in screening uptake.

Cancer in twin pairs discordant for smoking: The Nordic Twin Study of Cancer.

The discordant twin pair study design is powerful to control for familial confounding. We employed this approach to investigate the associations of smoking with several cancers. The NorTwinCan study combines data from the Danish, Finnish, Norwegian and Swedish twin and cancer registries. Follow-up started when smoking status was determined and ended at cancer diagnosis confirmed by information in the cancer registry, death or end of follow-up. We classified the participants as never (n = 59 093), former (n = 21 168) or current (n = 47 314) smokers. We pooled data from twin pairs where one co-twin was diagnosed with any of the following tobacco-related cancers: esophagus, kidney, larynx, liver, oral cavity, pancreas, pharynx or urinary bladder, while their co-twin had none of those. Lung cancer was included in further analysis. We used Cox regression allowing for pair-specific baseline functions to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). For tobacco-related cancer sites, we recorded 7379 cases during median 27 years of follow-up. The analyses based on individual twins showed that former (HR 1.31, 95% CI: 1.17-1.48) and current (HR 2.14 [1.95-2.34]) smokers are at increased risk to develop one of cancers listed above, compared to never smokers. Among 109 monozygotic twin pairs discordant for cancer and smoking, the HR was 1.85 (95% CI: 1.15-2.98) among current smokers and 1.69 (1.00-2.87) among former smokers when compared to their never smoking co-twin. Thus, associations of smoking with several cancers were replicated for discordant identical twin pairs. Analyses based on genetically informative data provide evidence consistent with smoking causing multiple cancers.

The heritability of BMI varies across the range of BMI-a heritability curve analysis in a twin cohort.

BACKGROUND: The heritability of traits such as body mass index (BMI), a measure of obesity, is generally estimated using family and twin studies, and increasingly by molecular genetic approaches. These studies generally assume that genetic effects are uniform across all trait values, yet there is emerging evidence that this may not always be the case. METHOD/SUBJECTS: This paper analyzes twin data using a recently developed measure of heritability called the heritability curve. Under the assumption that trait values in twin pairs are governed by a flexible Gaussian mixture distribution, heritability curves may vary across trait values. The data consist of repeated measures of BMI on 1506 monozygotic (MZ) and 2843 like-sexed dizygotic (DZ) adult twin pairs, gathered from multiple surveys in older Finnish Twin Cohorts. RESULTS: The heritability curve and BMI value-specific MZ and DZ pairwise correlations were estimated, and these varied across the range of BMI. MZ correlations were highest at BMI values from 21 to 24, with a stronger decrease for women than for men at higher values. Models with additive and dominance effects fit best at low and high BMI values, while models with additive genetic and common environmental effects fit best in the normal range of BMI. CONCLUSIONS: We demonstrate that twin and molecular genetic studies need to consider how genetic effects vary across trait values. Such variation may reconcile findings of traits with high heritability and major differences in mean values between countries or over time.

Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality.

Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is defined by mutations in myeloid cancer-associated genes with a variant allele frequency of at least 2%. Recent studies have suggested a possible genetic predisposition to CH. To further explore this phenomenon, we conducted a population-based study of 594 twins from 299 pairs aged 73 to 94 years, all with >20 years' follow-up. We sequenced DNA from peripheral blood with a customized 21-gene panel at a median coverage of 6179X. The casewise concordance rates for mutations were calculated to assess genetic predisposition. Mutations were identified in 214 (36%) of the twins. Whereas 20 twin pairs had mutations within the same genes, the exact same mutation was only observed in 2 twin pairs. No significant difference in casewise concordance between monozygotic and dizygotic twins was found for any specific gene, subgroup, or CHIP mutations overall, and no significant heritability could be detected. In pairs discordant for CHIP mutations, we tested if the affected twin died before the unaffected twin, as a direct measurement of the association of having CH when controlling for familial factors. A total of 127 twin pairs were discordant for carrying a mutation, and in 61 (48%) cases, the affected twin died first (P = .72). Overall, we did not find a genetic predisposition to CHIP mutations in this twin study. The previously described negative association of CHIP mutations on survival could not be confirmed in a direct comparison among twin pairs that were discordant for CHIP mutations.

Multivariate Generalized Linear Models for Twin and Family Data.

Multivariate twin and family studies are one of the most important tools to assess diseases inheritance as well as to study their genetic and environment interrelationship. The multivariate analysis of twin and family data is in general based on structural equation modelling or linear mixed models that essentially decomposes sources of covariation as originally suggested by  Fisher. In this paper, we propose a flexible and unified statistical modelling framework for analysing multivariate Gaussian and non-Gaussian twin and family data. The non-normality is taken into account by actually modelling the mean and variance relationship, while the covariance structure is modelled by means of a linear covariance model including the option to model the dispersion components as functions of known covariates in a regression model fashion. The marginal specification of our models allows us to extend classic models and biometric indices such as the bivariate heritability, genetic, environmental and phenotypic correlations to non-Gaussian data. We illustrate the proposed models through simulation studies and six data analyses and provide computational implementation in R through the package mglm4twin.

The familial and genetic contribution to the association between depression and cardiovascular disease: a twin cohort study.

Depression and cardiovascular disease (ischemic heart disease and stroke) are associated in a bidirectional manner. Their relatively high heritability has led to the hypothesis that this co-occurrence is related to shared familial and genetic factors; this study aims to test this hypothesis. We included 23,498 monozygotic and 39,540 same-sex dizygotic twins from the Danish Twin Registry followed from January 1977 until December 2011 in nationwide Danish registries. We used survival analyses accounting for censoring and competing risk of death to estimate cumulative incidence, casewise concordance, relative recurrence risk, and heritability of the co-occurrence of depression and cardiovascular disease by age using monozygotic and same-sex dizygotic twin pairs. The casewise concordance of ischemic heart disease or stroke in twins whose co-twin was diagnosed with depression was at all ages similar for the monozygotic and dizygotic twin pairs and to the cumulative incidence of ischemic heart disease or stroke, respectively, in the entire twin population. A similar pattern was seen in analyses of depression risk given the co-twin being diagnosed with ischemic heart disease or stroke. Relative recurrence risk and heritability estimates were also of modest size and with confidence intervals including unity. Results were similar after stratification by gender as well as when redefining depression to include the use of antidepressant medication from 1995. Our findings do not support that co-occurrence between depression and cardiovascular disease is explainable by shared genetic factors, nor did we find strong evidence of a familial effect.

Familial risk and heritability of ischemic heart disease and stroke in Danish twins.

Aim: Our aim was to explore whether familial factors influence the risk of ischemic heart disease, stroke, and their co-occurrence. Methods: In total, 23,498 monozygotic and 39,540 same-sex dizygotic twins from the Danish Twin Registry were followed from 1977 to 2011 in the Danish National Patient Registry for ischemic heart disease and stroke. Time-to-event analyses accounting for censoring and competing risk of death were used to estimate familial risk (casewise concordance relative to the cumulative incidence) and heritability of ischemic heart disease, stroke, and the co-occurrence by age. Results: During follow-up, we observed 5561 and 4186 twin individuals with ischemic heart disease and stroke respectively, with 936 twin pairs concordant for ischemic heart disease and stroke. Familial risks were significant for both, with higher cumulative risks in monozygotic than in dizygotic twins. Estimates for heritability were significant for ischemic heart disease as well as for stroke diagnosed after the age of 80. The casewise concordance of ischemic heart disease in twins whose co-twin was diagnosed with stroke did not differ for monozygotic and dizygotic twins; however, from age 55 it was 10% higher than the cumulative risk in the overall twin cohort and was 25% higher at age 90. A similar pattern was seen for stroke following the co-twin's ischemic heart disease. Conclusions: As in previous studies, we found a higher heritability of ischemic heart disease than of stroke. There was a significant familial risk but no heritability for the co-occurrence of ischemic heart disease and stroke. The co-occurrence is therefore likely due to other shared familial than genetic factors, highlighting that preventive initiatives should target families rather than individuals.

Heritability and Risk Factors of Incident Small and Large Drusen in the Copenhagen Twin Cohort Eye Study: A 20-Year Follow-Up.

INTRODUCTION: The transition from a normal fundus to one with early drusen (≥20 small hard drusen) to age-related macular degeneration (AMD) in the form of drusen ≥63 µm in diameter is of interest, because small hard drusen may be precursors of large drusen. Study of AMD precursor lesions may provide valuable insight into factors that initiate AMD. Here, the progression of drusen was studied over an interval of 20 years in a population-based twin cohort. METHODS: Single-center, 20-year follow-up of 138 twins include biometry, fundus optical coherence tomography, and fundus photography. Macular characteristics were hierarchically classified as (per eye) (1) <20 small hard drusen, (2) ≥20 small hard drusen, (3) drusen ≥63 µm, or (4) ≥20 small hard drusen combined with drusen ≥63 µm. Additive and dominant genetic effects as well as shared and nonshared environmental effects were analyzed in a bivariate biprobit model with a classic liability-threshold approach and polygenic modeling with random effects. RESULTS: Median participant age was 59 (range 41-66) years. Of 25 (18%) cases of incident macular drusen, 7 had ≥20 small hard drusen, and 18 had drusen ≥63 µm at follow-up, whereas no participant had developed both traits simultaneously. Smoking was associated with incident ≥20 small hard drusen (p = 0.04) and incident drusen ≥63 µm (p = 0.003). Having ≥20 small hard drusen at baseline was associated with incident drusen ≥63 µm at follow-up (p = 0.02). Development of drusen ≥63 µm was attributable to 49% genetic effects and 51% environmental effects. CONCLUSION: The risk of progressing from 0 to 19 small hard macular drusen per eye to having ≥20 small hard drusen or drusen ≥63 µm at follow-up was associated with smoking and genetic predisposition. Having ≥20 small hard drusen in the absence of drusen ≥63 µm at baseline was associated with incident drusen ≥63 µm when examined 20 years later. The study confirms that small hard macular drusen is a forewarning of AMD and that progression to AMD may be hindered by avoidance of smoking.

Efficacy and cost-effectiveness of a therapist-assisted web-based intervention for depression and anxiety in patients with ischemic heart disease attending cardiac rehabilitation [eMindYourHeart trial]: a randomised controlled trial protocol.

BACKGROUND: One in five patients with ischaemic heart disease (IHD) develop comorbid depression or anxiety. Depression is associated with risk of non-adherence to cardiac rehabilitation (CR) and dropout, inadequate risk factor management, poor quality of life (QoL), increased healthcare costs and premature death. In 2020, IHD and depression are expected to be among the top contributors to the disease-burden worldwide. Hence, it is paramount to treat both the underlying somatic disease as well as depression and anxiety. eMindYourHeart will evaluate the efficacy and cost-effectiveness of a therapist-assisted eHealth intervention targeting depression and anxiety in patients with IHD, which may help fill this gap in clinical care. METHODS: eMindYourHeart is a multi-center, two-armed, unblinded randomised controlled trial that will compare a therapist-assisted eHealth intervention to treatment as usual in 188 CR patients with IHD and comorbid depression or anxiety. The primary outcome of the trial is symptoms of depression, measured with the Hospital Anxiety and Depression Scale (HADS) at 3 months. Secondary outcomes evaluated at 3, 6, and 12 months include symptoms of depression and anxiety (HADS), perceived stress, health complaints, QoL (HeartQoL), trial dropout (number of patients dropped out in either arm at 3 months) and cost-effectiveness. DISCUSSION: To our knowledge, this is the first trial to evaluate both the efficacy and cost-effectiveness of a therapist-assisted eHealth intervention in patients with IHD and comorbid psychological distress as part of CR. Integrating screening for and treatment of depression and anxiety into standard CR may decrease dropout and facilitate better risk factor management, as it is presented as "one package" to patients, and they can access the eMindYourHeart program in their own time and at their own convenience. The trial holds a strong potential for improving the quality of care for an increasing population of patients with IHD and comorbid depression, anxiety or both, with likely benefits to patients, families, and society at large due to potential reductions in direct and indirect costs, if proven successful. Trial registration The trial was prospectively registered on https://clinicaltrials.gov/ct2/show/NCT04172974 on November 21, 2019 with registration number [NCT04172974].

A Prospective Observational Feasibility Study of Jugular Bulb Microdialysis in Subarachnoid Hemorrhage.

BACKGROUND: Cerebral metabolic perturbations are common in aneurysmal subarachnoid hemorrhage (aSAH). Monitoring cerebral metabolism with intracerebral microdialysis (CMD) allows early detection of secondary injury and may guide decisions on neurocritical care interventions, affecting outcome. However, CMD is a regional measuring technique that is influenced by proximity to focal lesions. Continuous microdialysis of the cerebral venous drainage may provide information on global cerebral metabolism relevant for the care of aSAH patients. This observational study aimed to explore the feasibility of jugular bulb microdialysis (JBMD) in aSAH and describe the output characteristics in relation to conventional multimodal monitoring. METHODS: Patients with severe aSAH were included at admission or after in-house deterioration when local clinical guidelines prompted extended multimodal monitoring. Non-dominant frontal CMD, intracranial pressure (ICP), partial brain tissue oxygenation pressure (PbtO2), and cerebral perfusion pressure (CPP) were recorded every hour. The dominant jugular vein was accessed by retrograde insertion of a microdialysis catheter with the tip placed in the jugular bulb under ultrasound guidance. Glucose, lactate, pyruvate, lactate/pyruvate ratio, glycerol, and glutamate were studied for correlation to intracranial measurements. Modified Rankin scale was assessed at 6 months. RESULTS: Twelve adult aSAH patients were monitored during a mean 4.2 ± 2.6 days yielding 22,041 data points for analysis. No complications related to JBMD were observed. Moderate or strong significant monotonic CMD-to-JBMD correlations were observed most often for glucose (7 patients), followed by lactate (5 patients), and pyruvate, glycerol, and glutamate (3 patients). Moderate correlation for lactate/pyruvate ratio was only seen in one patient. Analysis of critical periods defined by ICP > 20, CPP < 65, or PbtO2 < 15 revealed a tendency toward stronger CMD-to-JBMD associations in patients with many or long critical periods. Possible time lags between CMD and JBMD measurements were only identified in 6 out of 60 patient variables. With the exception of pyruvate, a dichotomized outcome was associated with similar metabolite patterns in JBMD and CMD. A nonsignificant tendency toward greater differences between outcome groups was seen in JBMD. CONCLUSIONS: Continuous microdialysis monitoring of the cerebral drainage in the jugular bulb is feasible and safe. JBMD-to-CMD correlation is influenced by the type of metabolite measured, with glucose and lactate displaying the strongest associations. JBMD lactate correlated more often than CMD lactate to CPP, implying utility for detection of global cerebral metabolic perturbations. Studies comparing JBMD to other global measures of cerebral metabolism, e.g., PET CT or Xenon CT, are warranted.

On the power of epigenome-wide association studies using a disease-discordant twin design.

Motivation: Many studies have investigated the association between DNA methylation alterations and disease occurrences using two design paradigms, traditional case-control and disease-discordant twins. In the disease-discordant twin design, the affected twin serves as the case and the unaffected twin serves as the control. Theoretically the twin design takes advantage of controlling for the shared genetic make-up, but it is still highly debatable if and how much researchers may benefit from such a design over the traditional case-control design. Results: In this study, we investigate and compare the power of both designs with simulations. A liability threshold model was used assuming that identical twins share the same genetic contribution with respect to the liability of complex human diseases. Varying ranges of parameters have been used to ensure that the simulation is close to real-world scenarios. Our results reveal that the disease-discordant twin design implies greater statistical power over the traditional case-control design. For diseases with moderate and high heritability (>0.3), the disease-discordant twin design allows for large sample size reductions compared to the ordinary case-control design. Our simulation results indicate that the discordant twin design is indeed a powerful tool for epigenetic association studies. Availability and implementation: Computer scripts are available at https://github.com/zickyls/EWAS-Twin-Simulation. Supplementary information: Supplementary data are available at Bioinformatics online.

Migraine with visual aura associated with thicker visual cortex.

Until recent years it was believed that migraine with aura was a disorder causing intermittent neurological symptoms, with no impact on brain structure. However, recent MRI studies have reported increased cortical thickness of visual and somatosensory areas in patients with migraine with aura, suggesting that such structural alterations were either due to increased neuronal density in the areas involved, or a result of multiple episodes of cortical spreading depression as part of aura attacks. Subsequent studies have yielded conflicting results, possibly due to methodological reasons, e.g. small number of subjects. In this cross-sectional study, we recruited females aged 30-60 years from the nationwide Danish Twin Registry. Brain MRI of females with migraine with aura (patients), their co-twins, and unrelated migraine-free twins (controls) were performed at a single centre and assessed for cortical thickness in predefined cortical areas (V1, V2, V3A, MT, somatosensory cortex), blinded to headache diagnoses. The difference in cortical thickness between patients and controls adjusted for age, and other potential confounders was assessed. Comparisons of twin pairs discordant for migraine with aura were also performed. Comparisons were based on 166 patients, 30 co-twins, and 137 controls. Compared with controls, patients had a thicker cortex in areas V2 [adjusted mean difference 0.032 mm (95% confidence interval 0.003 to 0.061), V3A [adjusted mean difference 0.037 mm (95% confidence interval 0.008 to 0.067)], while differences in the remaining areas examined were not statistically significant [adjusted mean difference (95% confidence interval): V1 0.022 (-0.007 to 0.052); MT: 0.018 (-0.011 to 0.047); somatosensory cortex: 0.020 (-0.009 to 0.049)]. We found no association between the regions of interest and active migraine, or number of lifetime aura attacks. Migraine with aura discordant twin pairs (n = 30) only differed in mean thickness of V2 (0.039 mm, 95% CI 0.005 to 0.074). In conclusion, females with migraine with aura have a thicker cortex corresponding to visual areas and our results indicate this may be an inherent trait rather than a result of repeated aura attacks.

A Major Limitation of the Direction of Causation Model: Non-Shared Environmental Confounding.

Determining (1) the direction of causation and (2) the size of causal effects between two constructs is a central challenge of the scientific study of humans. In the early 1990s, researchers in behavioral genetics invented what was termed the direction of causation (DoC) model to address exactly these two concerns. The model claims that for any two traits whose mode of inheritance is sufficiently different, the direction of causation can be ascertained using a sufficiently large genetically informative sample. Using a series of simulation studies, we demonstrate a major challenge to the DoC model, namely that it is extremely sensitive to even tiny amounts of non-shared confounding. Even under ideal conditions for the DoC model (a large sample, N = 10,000), a large causal relationship (e.g., a causal correlation of .50) with very different modes of inheritance between the two traits (e.g., a pure AE model for one trait and a pure CE model for another trait) and a modest degree (correlation of .10) of non-shared confounding between the two traits results in the choice of the wrong causal models and estimating the wrong causal effects.

The Nordic Twin Study on Cancer - NorTwinCan.

Nordic twin studies have played a critical role in understanding cancer etiology and elucidating the nature of familial effects on site-specific cancers. The NorTwinCan consortium is a collaborative effort that capitalizes on unique research advantages made possible through the Nordic system of registries. It was constructed by linking the population-based twin registries of Denmark, Finland, Norway and Sweden to their country-specific national cancer and cause-of-death registries. These linkages enable the twins to be followed many decades for cancer incidence and mortality. To date, two major linkages have been conducted: NorTwinCan I in 2011-2012 and NorTwinCan II in 2018. Overall, there are 315,413 eligible twins, 57,236 incident cancer cases and 58 years of follow-up, on average. In the initial phases of our work, NorTwinCan established the world's most comprehensive twin database for studying cancer, developed novel analytical approaches tailored to address specific research considerations within the context of the Nordic data and leveraged these models and data in research publications that provide the most accurate estimates of heritability and familial risk of cancers reported in the literature to date. Our findings indicate an excess familial risk for nearly all cancers and demonstrate that the incidence of cancer among twins mirrors the rate in the general population. They also revealed that twin concordance for cancer most often manifests across, rather than within, cancer sites, and we are currently focusing on the analysis of these cross-cancer associations.