Explore the vast range of titles available.

Monozygotic (MZ) twins do not show complete concordance for many complex diseases; for example, discordance rates for autoimmune diseases are 20%-80%. MZ discordance indicates a role for epigenetic or environmental factors in disease. We used MZ twins discordant for psoriasis to search for genome-wide differences in DNA methylation and gene expression in CD4(+) and CD8(+) cells using Illumina's HumanMethylation27 and HT-12 expression assays, respectively. Analysis of these data revealed no differentially methylated or expressed genes between co-twins when analyzed separately, although we observed a substantial amount of small differences. However, combined analysis of DNA methylation and gene expression identified genes where differences in DNA methylation between unaffected and affected twins were correlated with differences in gene expression. Several of the top-ranked genes according to significance of the correlation in CD4(+) cells are known to be associated with psoriasis. Further, gene ontology (GO) analysis revealed enrichment of biological processes associated with the immune response and clustering of genes in a biological pathway comprising cytokines and chemokines. These data suggest that DNA methylation is involved in an epigenetic dysregulation of biological pathways involved in the pathogenesis of psoriasis. This is the first study based on data from MZ twins discordant for psoriasis to detect epigenetic alterations that potentially contribute to development of the disease.

Although substantial progress has been made in managing COVID-19, it is still difficult to predict a patient’s prognosis. We explored the epigenetic signatures of COVID-19 in peripheral blood using data from an ongoing prospective observational study of COVID-19 called the Norwegian Corona Cohort Study. A series of EWASs were performed to compare the DNA methylation profiles between COVID-19 cases and controls three months post-infection. We also investigated differences associated with severity and long-COVID. Three CpGs—cg22399236, cg03607951, and cg09829636—were significantly hypomethylated (FDR < 0.05) in COVID-19 positive individuals. cg03607951 is located in IFI44L which is involved in innate response to viral infection and several systemic autoimmune diseases. cg09829636 is located in ANKRD9 , a gene implicated in a wide variety of cellular processes, including the degradation of IMPDH2. The link between ANKRD9 and IMPDH2 is striking given that IMPDHs are considered therapeutic targets for COVID-19. Furthermore, gene ontology analyses revealed pathways involved in response to viruses. The lack of significant differences associated with severity and long-COVID may be real or reflect limitations in sample size. Our findings support the involvement of interferon responsive genes in the pathophysiology of COVID-19 and indicate a possible link to systemic autoimmune diseases.

Background and aims Poor quality of life is a main complaint among individuals with irritable bowel syndrome (IBS). Self-rated health (SRH) is a powerful predictor of clinical outcomes, and also reflects psychological and social aspects of life and an overall sense of well-being. This population-based twin study evaluates how IBS affects ratings of physical and mental health, and influences perceptions of hindrance of daily activity by physical or mental health. Further, we examine how IBS is related to these SRH measures. Methods The sample included 5288 Norwegian twins aged 40–80, of whom 575 (10.9%) suffer from IBS. Hierarchical regressions were used to estimate the impact of IBS on perceptions of health, before and after accounting for other chronic physical and mental health conditions. Two dimensions of SRH, physical and mental, and two aspects of functional limitations, the extent to which physical or mental health interferes with daily activities, were included as outcomes in separate models. Co-twin control analyses were used to explore whether the relationships between IBS and the four measures of SRH are causal, or due to shared genetic or shared environment effects. Results IBS was an independent predictor of poor self-rated physical health (OR = 1.82 [1.41; 2.33]), the size of this effect was comparable to that predicted by chronic somatic conditions. However, in contrast to somatic diseases, IBS was associated with the perception that poorer ratings of mental health (OR = 1.45 [1.02; 2.06]), but not physical health (OR = 1.23 [0.96; 1.58]), interfered with daily activity. The co‐twin control analyses suggest that causal mechanisms best explain the relationships between IBS with self-rated physical health and with hindrance of daily activities. In contrast, the relationship between IBS and self-rated mental health was consistent with shared genetic effects. Conclusion IBS is predictive of poor self-rated physical health. The relationship between IBS and self-rated mental health is best explained by shared genetic effects which might partially explain why mental health interferes with daily activity to a larger degree among those with IBS.

Despite a well-known inverse association between education and dementia risk, the mediating mechanisms are not well understood. We explored how lifestyle and health risk factors across the life-course mediate the relationship between education and dementia among adults aged 70 + years. We included 7,655 participants with dementia diagnoses and education information, using a historical cohort design linking prospective exposure data across the life course from the HUNT4 70 + Study with registry data from Statistics Norway and earlier HUNT surveys. We conducted causal mediation analysis to assess the mediating roles of occupational characteristics, lifestyle factors (smoking, physical inactivity), and health risk factors (obesity, hypertension, diabetes, hearing impairment, cardiovascular diseases, LDL cholesterol, depression, anxiety) assessed during early, middle, and late adulthood in the relationship between education and dementia in later life. Participants with lower education were more likely to have dementia with odds ratios of 1.99, 1.88, 1.83 for the model’s accounting exposure to mediators during early, middle, and late adulthood, respectively. These associations were partially mediated by the joint effect of health and lifestyle risk factors from early through late adulthood (mediated 11.55–19.50%). Health risk factors from early to late adulthood jointly mediated 6.85–13.06% of the effect of low education on dementia risk later in life. Additionally, lifestyle factors during middle and late adulthood jointly mediated 4.11–4.96% of the total effect of low education on dementia risk later in life. Educational differences in dementia risk can partly mediated by lifestyle and health factors across the life course. These findings suggest potential targets to address varying dementia risks linked to education levels.

Background Rheumatoid arthritis (RA), particularly seronegative disease, is difficult to diagnose early, which can delay treatment initiation. This study aims to develop a binary DNA methylation (DNAm)-based algorithm to diagnose RA. Methods Three datasets (discovery, training, holdout) were constructed from DNAm profiles from 1366 persons (treatment-naïve RA, other inflammatory/autoimmune diseases, healthy individuals). DNAm features that differentiate RA from other inflammatory/autoimmune diseases and healthy individuals were identified using the discovery set. Our classification algorithm was developed using machine learning techniques in the training set. Its diagnostic performance, with and without serological status, was evaluated in the holdout set containing RA cases (15 seropositive, 6 seronegative) and controls (14 other arthritides, 11 healthy individuals). Results Our algorithm included 391 DNAm features. Combined with serological status, it classified RA from controls in the holdout set with the following performance: sensitivity 0.90 [95% CI: 0.70–0.99], specificity 0.88 [95% CI: 0.69–0.97], and AUC 0.96 [95% CI: 0.91–1.00]. Its performance in classifying patients with seronegative RA versus those with other arthritides was: sensitivity 0.83 [95% CI: 0.36–1.00], specificity 0.79 [95% CI: 0.49–0.95], and AUC 0.81 [95% CI: 0.61–1.00]. Conclusions The present DNAm-based classification algorithm may be clinically useful for the early diagnosis of RA, especially in seronegative patients, which currently often poses a diagnostic challenge.

Twin pairs discordant for disease may help elucidate the epigenetic mechanisms and causal environmental factors in disease development and progression. To obtain the numbers of pairs, especially monozygotic (MZ) twin pairs, necessary for in-depth studies while also allowing for replication, twin studies worldwide need to pool their resources. The Discordant Twin (DISCOTWIN) consortium was established for this goal. Here, we describe the DISCOTWIN Consortium and present an analysis of type 2 diabetes (T2D) data in nearly 35,000 twin pairs. Seven twin cohorts from Europe (Denmark, Finland, Norway, the Netherlands, Spain, Sweden, and the United Kingdom) and one from Australia investigated the rate of discordance for T2D in same-sex twin pairs aged 45 years and older. Data were available for 34,166 same-sex twin pairs, of which 13,970 were MZ, with T2D diagnosis based on self-reported diagnosis and medication use, fasting glucose and insulin measures, or medical records. The prevalence of T2D ranged from 2.6% to 12.3% across the cohorts depending on age, body mass index (BMI), and national diabetes prevalence. T2D discordance rate was lower for MZ (5.1%, range 2.9–11.2%) than for same-sex dizygotic (DZ) (8.0%, range 4.9–13.5%) pairs. Across DISCOTWIN, 720 discordant MZ pairs were identified. Except for the oldest of the Danish cohorts (mean age 79), heritability estimates based on contingency tables were moderate to high (0.47–0.77). From a meta-analysis of all data, the heritability was estimated at 72% (95% confidence interval 61–78%). This study demonstrated high T2D prevalence and high heritability for T2D liability across twin cohorts. Therefore, the number of discordant MZ pairs for T2D is limited. By combining national resources, the DISCOTWIN Consortium maximizes the number of discordant MZ pairs needed for in-depth genotyping, multi-omics, and phenotyping studies, which may provide unique insights into the pathways linking genes to the development of many diseases.

Background Chromatin immunoprecipitation coupled with high-throughput DNA sequencing (ChIP-seq) offers high resolution, genome-wide analysis of DNA-protein interactions. However, current standard methods require abundant starting material in the range of 1–20 million cells per immunoprecipitation, and remain a bottleneck to the acquisition of biologically relevant epigenetic data. Using a ChIP-seq protocol optimised for low cell numbers (down to 100,000 cells / IP), we examined the performance of the ChIP-seq technique on a series of decreasing cell numbers. Results We present an enhanced native ChIP-seq method tailored to low cell numbers that represents a 200-fold reduction in input requirements over existing protocols. The protocol was tested over a range of starting cell numbers covering three orders of magnitude, enabling determination of the lower limit of the technique. At low input cell numbers, increased levels of unmapped and duplicate reads reduce the number of unique reads generated, and can drive up sequencing costs and affect sensitivity if ChIP is attempted from too few cells. Conclusions The optimised method presented here considerably reduces the input requirements for performing native ChIP-seq. It extends the applicability of the technique to isolated primary cells and rare cell populations (e.g. biobank samples, stem cells), and in many cases will alleviate the need for cell culture and any associated alteration of epigenetic marks. However, this study highlights a challenge inherent to ChIP-seq from low cell numbers: as cell input numbers fall, levels of unmapped sequence reads and PCR-generated duplicate reads rise. We discuss a number of solutions to overcome the effects of reducing cell number that may aid further improvements to ChIP performance.

Background Longitudinal cohort studies are pivotal to understand how socioeconomic, environmental, biological, and lifestyle factors influence health and disease. The added value of cohort studies increases as they accumulate life course data and expand across generations. Ensuring that participants stay motivated to contribute over decades of follow-up is, however, challenging. Participant engagement and involvement (PEI) aims to secure the long-term commitment of participants and promote researcher-participant interaction. This study explored PEI practices in a selection of pregnancy and birth, twin, and family-based population cohort studies. Methods Purposive sampling was used to identify cohorts in Europe, Australia and New Zealand. Fourteen semi-structured digital interviews were conducted with cohort study representatives to explore strategies for participant recruitment, informed consent, communication of general and individual information to participants, data collection, and participant involvement. Experiences, resources allocated to PEI, and reflections on future PEI, were discussed. The interview data were analyzed using a content analysis approach and summary results were reviewed and discussed by the representatives. Results The cohort studies used various strategies to recruit participants including support from health professionals and organizations combined with information on the studies’ web sites and social media. New approaches such as intra-cohort recruitment, were being investigated. Most cohorts transitioned from paper-based to digital solutions to collect the participants’ consent and data. While digital solutions increased efficiency, they also brought new challenges. The studies experimented with the use of participant advisory panels and focus groups to involve participants in making decisions, although their success varied across age and socio-economic background. Most representatives reported PEI resources to be limited and called for more human, technical, educational and financial resources to maximize the positive effects of PEI. Conclusions This study of PEI among well-established cohort studies underscores the importance of PEI for project sustainability and highlights key factors to consider in developing PEI. Our analysis shows that knowledge gaps exist regarding which approaches have highest impact on retention rates and are best suited for different participant groups. Research is needed to support the development of best practices for PEI as well as knowledge exchange between cohorts through network building.

Background Epigenetic clocks have been recognized for their precise prediction of chronological age, age-related diseases, and all-cause mortality. Existing epigenetic clocks are based on CpGs from the Illumina HumanMethylation450 BeadChip (450 K) which has now been replaced by the latest platform, Illumina MethylationEPIC BeadChip (EPIC). Thus, it remains unclear to what extent EPIC contributes to increased precision and accuracy in the prediction of chronological age. Results We developed three blood-based epigenetic clocks for human adults using EPIC-based DNA methylation (DNAm) data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Gene Expression Omnibus (GEO) public repository: 1) an Adult Blood-based EPIC Clock (ABEC) trained on DNAm data from MoBa ( n  = 1592, age-span: 19 to 59 years), 2) an extended ABEC (eABEC) trained on DNAm data from MoBa and GEO ( n  = 2227, age-span: 18 to 88 years), and 3) a common ABEC (cABEC) trained on the same training set as eABEC but restricted to CpGs common to 450 K and EPIC. Our clocks showed high precision (Pearson correlation between chronological and epigenetic age (r) > 0.94) in independent cohorts, including GSE111165 ( n  = 15), GSE115278 ( n  = 108), GSE132203 ( n  = 795), and the Epigenetics in Pregnancy (EPIPREG) study of the STORK Groruddalen Cohort ( n  = 470). This high precision is unlikely due to the use of EPIC, but rather due to the large sample size of the training set. Conclusions Our ABECs predicted adults’ chronological age precisely in independent cohorts. As EPIC is now the dominant platform for measuring DNAm, these clocks will be useful in further predictions of chronological age, age-related diseases, and mortality.

The association between birth weight and later life outcomes is of considerable interest in life-course epidemiology. Research often relies on self-reported measures of birth weight, and its validity is consequently of importance. We assessed agreement between self-reported birth weight and official birth records for Norwegian twins born 1967–1974. The intraclass correlation between self-reported birth weight and register-based birth weight was 0.91 in our final sample of 363 twins. It could be expected that 95% of self-reported birth-weight values will deviate from official records within a maximum of +446 grams and a minimum of −478 grams — around a mean deviation of 16 grams. Self-reported birth weight had a sensitivity of 0.78–0.89 and a positive predictive value of 0.59–0.85, and an overall weighted kappa of 0.71. We further assessed agreement by conducting two linear regression models where we respectively regressed self-reported birth weight and register-based birth weight on adult body mass index, a known association. The two models were not significantly different; however, there were different levels of significance in parameter estimates that warrant some caution in using self-reported birth weight. Reliability of self-reported birth weight was also assessed, based on self-reports in another sample of twins born 1935–1960 who had reported their birth weight in two questionnaires 34 years apart. The intraclass correlation was 0.86, which indicates a high degree of reliability. In conclusion, self-reported birth weight, depending on context and age when birth weight was reported, can be cautiously used.