Pioneer factor Pax7 initiates two-step cell-cycle-dependent chromatin opening.

Pioneer transcription factors direct cell differentiation by deploying new enhancer repertoires through their unique ability to target and initiate remodelling of closed chromatin. The initial steps of their action remain undefined, although pioneers have been shown to interact with nucleosomal target DNA and with some chromatin-remodeling complexes. We now define the sequence of events that enables the pioneer Pax7 with its unique abilities. Chromatin condensation exerted by linker histone H1 is the first constraint on Pax7 recruitment, and this establishes the initial speed of chromatin remodeling. The first step of pioneer action involves recruitment of the KDM1A (LSD1) H3K9me2 demethylase for removal of this repressive mark, as well as recruitment of the MLL complex for deposition of the activating H3K4me1 mark. Further progression of pioneer action requires passage through cell division, and this involves dissociation of pioneer targets from perinuclear lamin B. Only then are the SWI-SNF remodeling complex and the coactivator p300 recruited, leading to nucleosome displacement and enhancer activation. Thus, the unique features of pioneer actions are those occurring in the lamin-associated compartment of the nucleus. This model is consistent with previous work that showed a dependence on cell division for establishment of new cell fates.

An exemplary model of genetic counselling for highly specialised services.

With genomic testing being increasingly integrated into every day clinical practice and a wide range of practitioners ordering genetic tests, it is important that the scope of the genetic counselling role continues to evolve alongside these changes. We present an exemplary role for genetic counsellors in a highly specialised service within England's National Health Service for people who have or are suspected to have rare genetic types of Ehlers Danlos syndrome. The service employs genetic counsellors and consultants from the fields of genetics and dermatology. The service also works closely with other specialists and related charities and patient organisations. The genetic counsellors in the service provide routine genetic counselling such as diagnostic and predictive testing, but their role also includes the writing of patient literature and emergency and well-being resources, delivering workshops and talks, and the development of qualitative and quantitative research on the patient experience. Data from such research has informed the development of patient self-advocacy and supportive resources, raised awareness amongst healthcare professionals and enhanced the standard of care and outcomes for patients. The service aims to be an example of innovation and accessibility and provides a model that can be potentially adopted by other highly specialised services of rare genetic diseases.

A collaborative genetic carrier screening model for the British Ashkenazi Jewish community.

We present a unique model of a British genetic carrier screening programme for individuals with Ashkenazi Jewish ancestry that exemplifies a partnership between a publicly funded healthcare service (the NHS) and a charity, Jnetics. This model provides affordable access to carrier screening for severe autosomal recessive diseases increased in this community. Prior to the development of this programme, the British healthcare system only provided Tay Sachs' screening for this community, leaving them at higher risk of having a child with a serious autosomal recessive disease. The Jnetics screening programme is promoted through community and social media campaigns, involves educational outreach, a pre-test genetic counselling service by a dedicated NHS-based genetic counsellor, saliva-based DNA testing, comprehensive reporting and, where required, post-test genetic counselling. The charity raises funds to subsidise the screening. In 6 years, the model has been successfully implemented in hospital and community settings and in schools and universities, aiming to reach those pre-conception. In response to the COVID-19 pandemic, the programme adapted by offering genetic screening virtually and has subsequently expanded in its outreach. Furthermore, the screening panel is currently being expanded to include other conditions increased in the Ashkenazi and also the Sephardi and Mizrahi Jewish communities. An example of innovation and accessibility, providing free screening to all students and disadvantaged individuals, the programme aims to provide a model that can potentially be adopted by other genetically at-risk communities.

MECHANISMS IN ENDOCRINOLOGY: Pioneer transcription factors in pituitary development and tumorigenesis.

Pioneer transcription factors have key roles in development as master regulators of cell fate specification. Only a small fraction of all transcription factors have the pioneer ability that confers access to target genomic DNA sites embedded in so-called 'closed' heterochromatin. This ability to seek and bind target sites within the silenced portion of the epigenome is the basis for their role in changing cell fate. Upon binding heterochromatin sites, pioneer factors trigger remodeling of chromatin from a repressed into an active organization. This action is typically exerted at enhancer regulatory sequences, thus allowing activation of new gene subsets. During pituitary development, the only pioneer with a well-documented role is Pax7 that specifies the intermediate lobe melanotrope cell fate. In this review, a particular focus is placed on this Pax7 function but its properties are also considered within the general context of pioneer factor action. Given their potent activity to reprogram gene expression, it is not surprising that many pioneers are associated with tumor development. Overexpression or chromosomal translocations leading to the production of chimeric pioneers have been implicated in different cancers. We review here the current knowledge on the mechanism of pioneer factor action.

Pioneer and nonpioneer factor cooperation drives lineage specific chromatin opening.

Pioneer transcription factors are characterized by having the unique property of enabling the opening of closed chromatin sites, for implementation of cell fates. We previously found that the pioneer Pax7 specifies melanotrope cells through deployment of an enhancer repertoire, which allows binding of Tpit, a nonpioneer factor that determines the related lineages of melanotropes and corticotropes. Here, we investigate the relation between these two factors in the pioneer mechanism. Cell-specific gene expression and chromatin landscapes are defined by scRNAseq and chromatin accessibility profiling. We find that in vivo deployment of the melanotrope enhancer repertoire and chromatin opening requires both Pax7 and Tpit. In cells, binding of heterochromatin targets by Pax7 is independent of Tpit but Pax7-dependent chromatin opening requires Tpit. The present work shows that pioneer core properties are limited to the ability to recognize heterochromatin targets and facilitate nonpioneer binding. Chromatin opening per se may be provided through cooperation with nonpioneer factors.

Association of the resolvin precursor 17-HDHA, but not D- or E- series resolvins, with heat pain sensitivity and osteoarthritis pain in humans.

Resolvins are omega-3 fatty acid derived potent bioactive lipids that resolve inflammation and modulate transient receptor potential channels. Exogenous administration of the resolvin precursor 17-HDHA shows a strong analgesic effect in animal models of osteoarthritis and acute inflammatory pain, but has not been studied in humans. Our aim was to assess the role of 17-HDHA and resolvins in heat pain sensitivity and in osteoarthritis pain in humans. Resolvins D1, D2, D3, D5, E1 and 17-HDHA, were measured by liquid chromatography-mass spectrometry and tested for association with heat pain thresholds in 250 healthy volunteers who had undergone quantitative sensory testing. Resolvins D1, D2 and 17-HDHA were then tested in 62 individuals affected with knee osteoarthritis and 52 age matched controls and tested for association with knee pain. Circulating levels of docosahexaenoic acid (DHA) were also measured. Levels of 17-HDHA, but not those of the other 5 resolvins tested, were associated with increased heat pain thresholds (beta = 0.075; 95% CI 0.024, 0.126; p < 0.0046). 17-HDHA was associated with lower pain scores in OA patients (beta -0.41; 95% CI-0.69, -0.12; p < 0.005; adjusted for covariates) but not with radiographic osteoarthritis. The associations of 17-HDHA with heat pain sensitivity and osteoarthritis pain were independent of DHA levels.

Evaluating the consent preferences of UK research volunteers for genetic and clinical studies.

OBJECTIVES: To establish the views of research volunteers on the consent process; to explore their views on the consent process in different research scenarios; to inform debate on emerging models of consent for participation in research. DESIGN, SETTING AND PARTICIPANTS: 2,308 adult volunteers from the TwinsUK Registry (www.twinsuk.ac.uk) completed an online survey about their views on the consent process for use of their DNA and medical information in research. Their views on the re-consenting process in different scenarios were assessed. RESULTS: The majority of volunteers preferred to be informed of the identity of the main researcher of a study in which they are participating, which is contrary to current practice. Over 80% were willing to complete the consent process online instead of face to face. On the whole, respondents did not view their DNA differently from their medical information with regard to the consent process. Research participants were more willing to give broad consent to cover future research if their DNA was to be used by the original researcher than by another researcher, even if the disease under investigation varied, in contrast to the traditional 'gold standard' whereby specific consent is required for all new research projects. DISCUSSION: In some scenarios, research participants reported that they would be comfortable with not signing a new consent form for future research uses of their data and DNA, and are comfortable with secure, online consent processes rather than traditional face-to-face consent processes. Our findings indicate that the perceived relationship between research participants and researchers plays an important role in shaping preferences regarding the consent process and suggest that this relationship is not captured by traditional consent processes. We argue that the development of new formats of consent should be informed by empirical research on volunteers' perceptions and preferences regarding the consent process.

How do emotional restrictions affect the use of humor? A behavior genetic analysis of alexithymia and humor styles.

This article reports the first behavioral genetic study of relationships between alexithymia and four styles of humor: affiliative, self-enhancing, self-defeating, and aggressive. A total of 509 MZ pairs and 264 DZ pairs of twins completed the Toronto Alexithymia Scale-20 (TAS-20) and the Humor Styles Questionnaire (HSQ). Consistent with our predictions, alexithymia correlated negatively with affiliative and self-enhancing humor and positively with self-defeating and aggressive humor. All but one of the 16 phenotypic correlations that we report are significant at the 0.01 level. Also consistent with our predictions, the phenotypic correlations between alexithymia and humor styles were primarily attributable to correlated genetic factors and to a lesser extent to correlated non-shared environmental factors. Correlated shared environmental factors had no significant effect. Implications and limitations of this study are discussed.

The structure of genetic and environmental risk factors for dimensional representations of DSM-5 obsessive-compulsive spectrum disorders.

IMPORTANCE: The new DSM-5 "Obsessive-Compulsive and Related Disorders" chapter contains a series of conditions thought to be etiologically related to obsessive-compulsive disorder (OCD). However, the evidence to support this relatedness remains incomplete. OBJECTIVE: To estimate the degree to which genetic and environmental risk factors are shared and/or unique to dimensionally scored OCD, body dysmorphic disorder (BDD), hoarding disorder (HD), trichotillomania (hair-pulling disorder) (TTM), and excoriation (skin-picking) disorder (SPD). DESIGN, SETTING, AND PARTICIPANTS: Multivariate twin modeling methods involving 5409 female members of the TwinsUK adult population-based twin register. MAIN OUTCOMES AND MEASURES: Scores on the Obsessive-Compulsive Inventory-Revised, the Dysmorphic Concern Questionnaire, the Hoarding Rating Scale, the Massachusetts General Hospital Hairpulling Scale, and the Skin Picking Scale. RESULTS: A 2-latent factor common pathway model fitted the data best; the first latent factor loaded on all 5 phenotypes, particularly on OCD, BDD, and HD. A second factor loaded exclusively on TTM and SPD. Disorder-specific genetic (for OCD, BDD, and HD only) and particularly nonshared environmental risk factors were also evident. Shared environmental influences were negligible. CONCLUSIONS AND RELEVANCE: Obsessive-compulsive and related disorders may be influenced by 2 distinct liability factors rather than a single liability factor. One of these factors was common to all disorders, and another was exclusive to TTM and SPD. Disorder-specific genetic factors unique to OCD, BDD, and HD were also apparent, whereas TTM and SPD were largely influenced by the same latent genetic factor. Environmental influences were largely disorder specific. The results help explain the apparent similarities as well as some important differences between the disorders included in the new Obsessive-Compulsive and Related Disorders chapter.

Relationship between dry eye symptoms and pain sensitivity.

IMPORTANCE: Dry eye disease (DED) is common, but little is known about factors contributing to symptoms of dry eye, given the poor correlation between these symptoms and objective signs at the ocular surface. OBJECTIVE: To explore whether pain sensitivity plays a role in patients' experience of DED symptoms. DESIGN, SETTING, AND PARTICIPANTS: A population-based cross-sectional study of 1635 female twin volunteers, aged 20 to 83 years, from the TwinsUK adult registry. MAIN OUTCOMES AND MEASURES: Dry eye disease was diagnosed if participants had at least 1 of the following: (1) a diagnosis of DED by a clinician, (2) the prescription of artificial tears, and/or (3) symptoms of dry eyes for at least 3 months. A subset of 689 women completed the Ocular Surface Disease Index (OSDI) questionnaire. Quantitative sensory testing using heat stimulus on the forearm was used to assess pain sensitivity (heat pain threshold [HPT]) and pain tolerance (heat pain suprathreshold [HPST]). RESULTS: Of the 1622 participants included, 438 (27.0%) were categorized as having DED. Women with DED showed a significantly lower HPT (P = .03) and HPST (P = .003)--and hence had higher pain sensitivity--than those without DED. A strong significant association between the presence of pain symptoms on the OSDI and the HPT and HPST was found (P = .008 for the HPT and P = .003 for the HPST). In addition, participants with an HPT below the median had DED pain symptoms almost twice as often as those with an HPT above the median (31.2% vs 20.5%; odds ratio, 1.76; 95% CI, 1.15-2.71; P = .01). CONCLUSIONS AND RELEVANCE: High pain sensitivity and low pain tolerance are associated with symptoms of DED, adding to previous associations of the severity of tear insufficiency, cell damage, and psychological factors. Management of DED symptoms is complex, and physicians need to consider the holistic picture, rather than simply treating ocular signs.

Heritability of acquiescence bias and item keying response style associated with the HEXACO personality scale.

The current research investigates the heritability of two of the most common response styles: acquiescence bias (tendency to agree or disagree with survey items regardless of the items' actual content) and item keying (differential responding related to the use of regular- and reverse-keyed items). We estimated response styles from a common personality measure (HEXACO) and examined the heritability of each with univariate genetics analyses. The results show item keying effect was heritable but acquiescence bias was not. Neither response style was strongly influenced by the shared environment of the twins. Unique environmental effects were found to be substantial for response styles. The current findings have important implications for future research of response behaviors that are often overlooked by behavioral geneticists.

Female interpersonal dependency: genetic and environmental components and its relationship to depression as a function of age.

OBJECTIVES: Research has shown that female interpersonal dependency is significantly associated with clinical depression but is only marginally related to childhood environmental factors. This study replicates the finding of O'Neill and Kendler that such dependency has a significant genetic component and no shared environmental component and extends this by examining the effect of age and the relationship between interpersonal dependency and depression. METHOD: A genetic model analysis for female twin pairs was made incorporating a scale from the Interpersonal Dependency Inventory, and the association between dependency quartiles and depression for both sexes determined. Dependency data were obtained by questionnaire from 4427 monozygotic and dizygotic twins, 90% female and this was combined with lifetime incidence of depression data in three categories of severity. RESULTS: Additive genetic variance components of 49% and 41% were estimated for those females between 19-64 and 65-87 years, respectively, with no significant effect for the shared family environment for either age group. Only female dependency was found to be associated with the incidence of depression. Incidence levels of severe depression for older females in the highest quartile of dependency were 26% compared to 43% for the younger females. CONCLUSION: The investigation has estimated that nearly half of the variance in female interpersonal dependency is genetic in origin. It has also confirmed that high levels of such dependency are associated with the incidence of severe depression and this effect reduces with age. The possible reasons for this age-related effect are discussed.

Overlap and specificity of genetic and environmental influences on excessive acquisition and difficulties discarding possessions: Implications for hoarding disorder.

A reluctance to discard items, leading to severely cluttered living spaces, is the landmark feature of hoarding disorder (HD). Many, but not all, individuals with HD also excessively acquire, buy or even steal items that they do not need and for which no space is available. In DSM-5, "excessive acquisition" can be coded as a specifier of HD. Despite their consistent co-occurrence, the question of whether excessive acquisition and difficulties discarding possessions share a common etiology remains unanswered. The current study sought to flesh out this relationship by examining the extent of shared genetic and environmental influences on the association between excessive acquisition and difficulties discarding in a community sample of adult, female twins. A total of 5,022 female twins (2,529 pairs; mean age = 55.5 years) completed a self-report measure of hoarding symptoms, including items assessing excessive acquisition and difficulties discarding. The data were analyzed using bivariate twin modeling methods in the statistical program Mx. As expected, we found a strong phenotypic correlation (0.63) between excessive acquisition and difficulty discarding items. Both traits were moderately heritable. The genetic correlation between the traits was estimated to be 0.77 (95% CI: 0.69-0.85), indicating a substantial but imperfect genetic overlap. The non-shared environmental correlation (0.50 [95% CI: 0.42-0.57]), though lower, was also significant. The findings demonstrate a substantial genetic, and more modest environmental, etiological overlap between the excessive acquisition of possessions and difficulties discarding them, providing a possible explanation for their frequent co-occurrence in HD. However, given that the etiological overlap is not perfect, unique etiological influences, particularly environmental, on each phenotype seem plausible.

A behavior genetic analysis of trait emotional intelligence and alexithymia: a replication.

This replication study examines relations between alexithymia and trait emotional intelligence (trait EI) at the phenotypic, genetic, and environmental levels. A sample of 1,444 same-sex twin pairs (850 MZ pairs and 594 DZ pairs) completed the Toronto Alexithymia Scale-20. A subset of 494 same-sex twin pairs (287 MZ pairs and 207 DZ pairs) had earlier completed the Trait Emotional Intelligence Questionnaire. Individual differences in alexithymia were attributable to genetic, non-shared environmental, and shared environmental factors. All but one of the facets of alexithymia were negatively and significantly correlated with the factors of trait EI, and these phenotypic correlations were entirely attributable to correlated genetic and correlated non-shared environmental factors. These bivariate results provide a valuable replication of those of Baughman et al. (Twin Research and Human Genetics, Vol. 14, 2011, pp. 539-543), which was conducted with substantially smaller samples of twins.

Genome-wide association analysis of eating disorder-related symptoms, behaviors, and personality traits.

Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P < 10(-5) . Genetic variants that showed suggestive evidence of association were previously associated with several psychiatric disorders and ED-related phenotypes. Our study indicates that larger-scale collaborative studies will be needed to achieve the necessary power to detect loci underlying ED-related traits.

Prevalence and heritability of skin picking in an adult community sample: a twin study.

Skin-picking disorder (SPD) is a disabling psychiatric condition that can lead to skin damage and other medical complications. Epidemiological data is scarce and its causes are unknown. The present study examined the prevalence and heritability of skin-picking symptoms in a large sample of twins. A total of 2,518 twins completed a valid and reliable self-report measure of skin-picking behavior. The prevalence of clinically significant skin picking was established using empirically derived cut-offs. Twin modeling methods were employed to decompose the variance in the liability to skin picking into additive genetic and shared and non-shared environmental factors. A total of 1.2% of twins scored above the cut-off, indicative of clinically significant skin picking. All these participants were women. Univariate model-fitting analyses (female twins only, N = 2,191) showed that genetic factors accounted for approximately 40% (95% CI 19-58%) of the variance in skin picking, with non-shared environmental factors and measurement error accounting for the remaining variance (60% [95% CI 42-81%]). Shared environmental factors were negligible. It is concluded that pathological skin picking is relatively prevalent problem, particularly among women, and that it tends to run in families primarily due to genetic factors. Non-shared environmental factors are also likely to play an important role in its etiology.

Genes contributing to pain sensitivity in the normal population: an exome sequencing study.

Sensitivity to pain varies considerably between individuals and is known to be heritable. Increased sensitivity to experimental pain is a risk factor for developing chronic pain, a common and debilitating but poorly understood symptom. To understand mechanisms underlying pain sensitivity and to search for rare gene variants (MAF<5%) influencing pain sensitivity, we explored the genetic variation in individuals' responses to experimental pain. Quantitative sensory testing to heat pain was performed in 2,500 volunteers from TwinsUK (TUK): exome sequencing to a depth of 70× was carried out on DNA from singletons at the high and low ends of the heat pain sensitivity distribution in two separate subsamples. Thus in TUK1, 101 pain-sensitive and 102 pain-insensitive were examined, while in TUK2 there were 114 and 96 individuals respectively. A combination of methods was used to test the association between rare variants and pain sensitivity, and the function of the genes identified was explored using network analysis. Using causal reasoning analysis on the genes with different patterns of SNVs by pain sensitivity status, we observed a significant enrichment of variants in genes of the angiotensin pathway (Bonferroni corrected p = 3.8×10(-4)). This pathway is already implicated in animal models and human studies of pain, supporting the notion that it may provide fruitful new targets in pain management. The approach of sequencing extreme exome variation in normal individuals has provided important insights into gene networks mediating pain sensitivity in humans and will be applicable to other common complex traits.

A survey of UK public interest in internet-based personal genome testing.

BACKGROUND: In view of the increasing availability of commercial internet-based Personal Genome Testing (PGT), this study aimed to explore the reasons why people would consider taking such a test and how they would use the genetic risk information provided. METHODOLOGY/PRINCIPAL FINDINGS: A self-completion questionnaire assessing public awareness and interest in PGT and motivational reasons for undergoing PGT was completed by 4,050 unselected adult volunteers from the UK-based TwinsUK register, aged 17 to 91 (response rate 62%). Only 13% of respondents were aware of the existence of PGT. After reading a brief summary about PGT, one in twenty participants (5%) were potentially interested at current prices (£250), however this proportion rose to half (50%) if the test was free of charge. Nearly all respondents who were interested in free PGT reported they would take the test to encourage them to adopt a healthier lifestyle if found to be at high genetic risk of a disease (93%). Around 4 in 5 respondents would have the test to convey genetic risk information to their children and a similar proportion felt that having a PGT would enable their doctor to monitor their health more closely. A TwinsUK research focus group also indicated that consumers would consult their GP to help interpret results of PGT. CONCLUSIONS/SIGNIFICANCE: This hypothetical study suggests that increasing publicity and decreasing costs of PGT may lead to increased uptake, driven in part by the general public's desire to monitor and improve their health. Although the future extent of the clinical utility of PGT is currently unknown, it is crucial that consumers are well informed about the current limitations of PGT. Our results suggest that health professionals will inevitably be required to respond to individuals who have undergone PGT. This has implications for health service providers regarding both cost and time.

Risk of Parkinson disease in carriers of parkin mutations: estimation using the kin-cohort method.

OBJECTIVE: To estimate the risk of Parkinson disease (PD) in individuals with mutations in the Parkin gene. DESIGN: We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset < or =50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband. SETTING: Tertiary care movement disorders center. Patients Cases, controls, and their first-degree relatives were enrolled in the GEPD study. MAIN OUTCOME MEASURES: Estimated age-specific penetrance in first-degree relatives. RESULTS: Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52). CONCLUSIONS: The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study.