GWAS Identifies Risk Locus for Erectile Dysfunction and Implicates Hypothalamic Neurobiology and Diabetes in Etiology.

Erectile dysfunction (ED) is a common condition affecting more than 20% of men over 60 years, yet little is known about its genetic architecture. We performed a genome-wide association study of ED in 6,175 case subjects among 223,805 European men and identified one locus at 6q16.3 (lead variant rs57989773, OR 1.20 per C-allele; p = 5.71 × 10-14), located between MCHR2 and SIM1. In silico analysis suggests SIM1 to confer ED risk through hypothalamic dysregulation. Mendelian randomization provides evidence that genetic risk of type 2 diabetes mellitus is a cause of ED (OR 1.11 per 1-log unit higher risk of type 2 diabetes). These findings provide insights into the biological underpinnings and the causes of ED and may help prioritize the development of future therapies for this common disorder.

Correction: The Gen-Equip Project: evaluation and impact of genetics e-learning resources for primary care in six European languages.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.

The Gen-Equip Project: evaluation and impact of genetics e-learning resources for primary care in six European languages.

PURPOSE: Genetic advances mean patients at risk of genetic conditions can be helped through testing, clinical screening, and preventive treatment, but they must first be identified to benefit. Ensuring quality of genetic care for patients requires genetic expertise in all health services, including primary care. To address an educational shortfall, a series of e-learning resources was developed in six languages to equip primary care professionals with genetic skills relevant for practice. The purpose of the study was to evaluate these resources using Kirkpatrick's framework for educational outcomes. METHODS: Mixed methods (qualitative and quantitative) were used over four phases of the study. RESULTS: A high level of satisfaction with the resources was reported. Knowledge and skills improved significantly after using the education material. Participants reported changes in confidence and practice behavior, including family history taking, seeking advice from specialists and referring patients. The resources helped users to learn how to explain genetics. Many visited the resources repeatedly and some used them to educate colleagues or students. CONCLUSION: Gen-Equip modules are effective in improving genetic knowledge, skills, and attitudes for primary care professionals. They provide both continuing professional development and just-in-time learning for a potentially large global audience at a practical level.

A systematic review of interventions to provide genetics education for primary care.

BACKGROUND: At least 10 % of patients seen in primary care are said to have a condition in which genetics has an influence. However, patients at risk of genetic disease may not be recognised, while those who seek advice may not be referred or managed appropriately. Primary care practitioners lack knowledge of genetics and genetic testing relevant for daily practice and feel inadequate to deliver genetic services. The aim of this systematic review was to evaluate genetics educational interventions in the context of primary care. METHODS: Following the process for systematic reviews developed by the Centre for Reviews and Dissemination, we conducted a search of five relevant electronic databases. Primary research papers were eligible for inclusion if they included data on outcomes of interventions regarding genetics education for primary care practitioners. The results from each paper were coded and grouped under themes. RESULTS: Eleven studies were included in the review. The five major themes identified inductively (post hoc) were: prior experience, changes in confidence, changes in knowledge, changes in practice, satisfaction and feedback. In five of the studies, knowledge of practitioners was improved following the educational programmes, but this tended to be in specific topic areas, while practitioner confidence improved in six studies. However, there was little apparent change to practice. CONCLUSIONS: There are insufficient studies of relevant quality to inform educational interventions in genetics for primary care practitioners. Educational initiatives should be assessed using changes in practice, as well as in confidence and knowledge, to determine if they are effective in causing significant changes in practice in genetic risk assessment and appropriate management of patients.

Non-invasive prenatal testing for aneuploidy: a systematic review of Internet advertising to potential users by commercial companies and private health providers.

BACKGROUND: The development of non-invasive prenatal testing has increased accessibility of fetal testing. Companies are now advertising prenatal testing for aneuploidy via the Internet. OBJECTIVES: The aim of this systematic review of websites advertising non-invasive prenatal testing for aneuploidy was to explore the nature of the information being provided to potential users. METHODS: We systematically searched two Internet search engines for relevant websites using the following terms: 'prenatal test', 'antenatal test', 'non-invasive test', 'noninvasive test', 'cell-free fetal DNA', 'cffDNA', 'Down syndrome test' or 'trisomy test'. We examined the first 200 websites identified through each search. Relevant web-based text was examined, and key topics were identified, tabulated and counted. To analyse the text further, we used thematic analysis. MAIN RESULTS: Forty websites were identified. Whilst a number of sites provided balanced, accurate information, in the majority supporting evidence was not provided to underpin the information and there was inadequate information on the need for an invasive test to definitely diagnose aneuploidy. CONCLUSIONS: The information provided on many websites does not comply with professional recommendations. Guidelines are needed to ensure that companies offering prenatal testing via the Internet provide accurate and comprehensible information.

Guidance for patients considering direct-to-consumer genetic testing and health professionals involved in their care: development of a practical decision tool.

BACKGROUND: Direct-to-consumer (DTC) genetic tests are available online, but there is little practical guidance for health professionals and consumers concerning their use. Work to produce such guidance was initially informed by three systematic reviews assessing the evidence on views and experiences of users and health professionals and policies of professional and bioethics organizations. The evidence suggested that consumers' motivations include general curiosity, improving their general health, ascertaining the risk of a particular condition or planning for future children. However, health professionals and bioethics organizations expressed concerns about potential harms resulting from these tests. Using this evidence, we constructed a list of topics to be included in proposed guidelines. METHODS: Using an expert group technique, we aimed to develop guidance for (i) potential consumers and (ii) health professionals approached by patients considering or having undertaken such tests. We considered it important to involve a wide range of participants with relevant experience. Accordingly, researchers and clinicians based in four countries were invited to a 2-day workshop in August 2012. Following an iterative process, we decided to produce clinically relevant and pragmatic guidance in the form of a decision support tool for use in primary care. RESULTS: By utilizing both the relevant literature and the experience of the expert group, we identified seven key underlying reasons that might prompt individuals to consider DTC testing. We considered primary care physicians as the most likely health professionals from whom individuals would seek advice. CONCLUSIONS: Based on the outcomes of the workshop, we developed a decision support tool encompassing varied clinical scenarios. Health professionals and patients are guided through a pathway that includes relevant actions and information on the appropriateness of the test. This tool will be freely accessible to health professionals and patients online.

Can I get a retweet please? Health research recruitment and the Twittersphere.

AIM: To evaluate the social networking site Twitter™ as a vehicle for recruitment in online health research and to examine how the Twitter community would share information: the focus of our study was the antenatal experience of mothers of advanced maternal age. BACKGROUND: One result of growth in worldwide Internet and mobile phone usage is the increased ability to source health information online and to use social media sites including Facebook and Twitter. Although social media have been used in previous health research, there is a lack of literature on the use of Twitter in health research. DESIGN: A cross-sectional survey. METHOD: We report a novel recruitment method via a social networking site between May and August 2012. Through a Twitter account, we tweeted and requested other Twitter users to retweet our invitation to be involved in the study. Tweets contained a unique URL directing participants to an online survey hosted on the Survey Monkey™ website. FINDINGS: Over 11 weeks, 749 original tweets were posted by the researcher. A total of 529 mothers accessed the survey as a result of 359 researcher tweets and subsequent retweets that were seen by Twitter users. The survey was fully completed by 299 (56·5%) participants. CONCLUSION: Twitter is a cost-effective means of recruitment, enabling engagement with potentially difficult-to-reach populations, providing participants with transparency, anonymity and a more accessible method by which to participate in health research.

Pharmacogenomic Determinants of Adverse Drug Effects: A Systematic Review and Meta-analysis.

BACKGROUND/AIM: Genomic variants can predispose individuals to adverse drug effects (ADEs), implying the potential for personalised therapy based on genetic data to prevent them. However, existing pharmacogenomic databases lack a comprehensive list of such variants due to irregular updates and incomplete literature coverage. To facilitate the assessment of the feasibility of using pharmacogenetic testing on a larger scale and identify existing gaps in the literature, this study sought to compile a comprehensive list of genomic variants associated with ADEs, with a focus on serious ADEs. PATIENTS AND METHODS: To identify relevant pharmacogenetic studies within randomised controlled trials (RCTs), post-hoc studies of RCTs and meta-analyses, two literature searches were performed across multiple databases. The compiled list of variants associated with ADEs was refined to create a set of variant-drug pairs significantly associated with serious ADEs. RESULTS: We identified 254 RCTs/post-hoc studies and 207 meta-analyses investigating variants associated with ADEs. Among the 254 RCTs/post-hoc studies identified, 24 meta-analyses were conducted. Among these, only G6PD A- showed a significant association with severe anaemia in patients receiving artemisinin-based treatment for malaria. CONCLUSION: This systematic review provides a comprehensive list of variants associated with ADEs and a set of variant-drug pairs significantly associated with serious ADEs. These resources serve as valuable references for regulatory agencies, researchers, and healthcare professionals. This study, however, underscores the need for improved indexing and standardised definitions of ADE seriousness in the literature.

Pharmacogenetics of Toxicities Related to Endocrine Treatment in Breast Cancer: A Systematic Review and Meta-analysis.

BACKGROUND/AIM: Endocrine therapy is the standard treatment for hormone receptor-positive (HR+) breast cancer (BC). Yet, it is accompanied by treatment-related toxicities, leading to poor treatment adherence, high relapse, and low rates of survival. While pharmacogenomic variants have the potential to guide personalized treatment, their predictive value is inconsistent across published studies. MATERIALS AND METHODS: To systematically assess the literature's current landscape of pharmacogenomics of endocrine therapy-related adverse drug effects, systematic searches in MEDLINE, Embase, Cochrane CENTRAL, Google Scholar and PharmGKB databases were conducted. RESULTS: We identified 87 articles. Substantial heterogeneity and variability in pharmacogenomic effects were evident across studies, with many using data from the same cohorts and predominantly focusing on the Caucasian population and postmenopausal women. Meta-analyses revealed Factor V Leiden mutation as a predictor of thromboembolic events in tamoxifen-treated women (p<0.0001). Meta-analyses also found that rs7984870 and rs2234693 were associated with musculoskeletal toxicities in postmenopausal women receiving aromatase inhibitors (p<0.0001 and p<0.0001, respectively). CONCLUSION: Overall, the current body of evidence regarding the potential role of pharmacogenomics in endocrine therapy-related toxicity in BC remains largely inconclusive. Key concerns include the heterogeneity in toxicity definitions, lack of consideration for genotype-treatment interactions, and the failure to account for multiple testing. The review underscores the necessity for larger and well-designed studies, particularly with the inclusion of premenopausal women and non-Caucasian populations.

Guidance for estimating penetrance of monogenic disease-causing variants in population cohorts.

Penetrance is the probability that an individual with a pathogenic genetic variant develops a specific disease. Knowing the penetrance of variants for monogenic disorders is important for counseling of individuals. Until recently, estimates of penetrance have largely relied on affected individuals and their at-risk family members being clinically referred for genetic testing, a 'phenotype-first' approach. This approach substantially overestimates the penetrance of variants because of ascertainment bias. The recent availability of whole-genome sequencing data in individuals from very-large-scale population-based cohorts now allows 'genotype-first' estimates of penetrance for many conditions. Although this type of population-based study can underestimate penetrance owing to recruitment biases, it provides more accurate estimates of penetrance for secondary or incidental findings. Here, we provide guidance for the conduct of penetrance studies to ensure that robust genotypes and phenotypes are used to accurately estimate penetrance of variants and groups of similarly annotated variants from population-based studies.

Colorectal cancer risk stratification using a polygenic risk score in symptomatic primary care patients-a UK Biobank retrospective cohort study.

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Accurate cancer risk assessment approaches could increase rates of early CRC diagnosis, improve health outcomes for patients and reduce pressure on diagnostic services. The faecal immunochemical test (FIT) for blood in stool is widely used in primary care to identify symptomatic patients with likely CRC. However, there is a 6-16% noncompliance rate with FIT in clinic and ~90% of patients over the symptomatic 10 µg/g test threshold do not have CRC. A polygenic risk score (PRS) quantifies an individual's genetic risk of a condition based on many common variants. Existing PRS for CRC have so far been used to stratify asymptomatic populations. We conducted a retrospective cohort study of 50,387 UK Biobank participants with a CRC symptom in their primary care record at age 40+. A PRS based on 201 variants, 5 genetic principal components and 22 other risk factors and markers for CRC were assessed for association with CRC diagnosis within 2 years of first symptom presentation using logistic regression. Associated variables were included in an integrated risk model and trained in 80% of the cohort to predict CRC diagnosis within 2 years. An integrated risk model combining PRS, age, sex, and patient-reported symptoms was predictive of CRC development in a testing cohort (receiver operating characteristic area under the curve, ROCAUC: 0.76, 95% confidence interval: 0.71-0.81). This model has the potential to improve early diagnosis of CRC, particularly in cases of patient noncompliance with FIT.

A role for two-pore potassium (K2P) channels in endometrial epithelial function.

The human endometrial epithelium is pivotal to menstrual cycle progression, implantation and early pregnancy. Endometrial function is directly regulated by local factors that include pH, oxygen tension and ion concentrations to generate an environment conducive to fertilization. A superfamily of potassium channels characterized by two-pore domains (K2P) and encoded by KCNK genes is implicated in the control of the cell resting membrane potential through the generation of leak currents and modulation by various physicochemical stimuli. The aims of the study were to determine the expression and function of K2P channel subtypes in proliferative and secretory phase endometrium obtained from normo-ovulatory women and in an endometrial cancer cell line. Using immunochemical methods, real-time qRT-PCR proliferation assays and electrophysiology. Our results demonstrate mRNA for several K2P channel subtypes in human endometrium with molecular expression of TREK-1 shown to be higher in proliferative than secretory phase endometrium (P < 0.001). The K2P channel blockers methanandamide, lidocaine, zinc and curcumin had antiproliferative effects (P < 0.01) in an endometrial epithelial cancer cell line indicating a role for TASK and TREK-1 channels in proliferation. Tetraethylammonium- and 4-aminopyridine-insensitive outwards currents were inhibited at all voltages by reducing extracellular pH from 7.4 to 6.6. Higher expression of TREK-1 expression in proliferative phase endometrium may, in part, underlie linked to increased cell division. The effects of pH and a lack of effect of non-specific channel blockers of voltage-gated potassium channels imply a role for K2P channels in the regulation of human endometrial function.

Informed consent for blood tests in people with a learning disability.

AIM: This article is a report of a study of informed consent in people with a learning disability. The aims of the study were to explore the information needs of people with mild-to-moderate learning disabilities with respect to consent for blood tests and to identify ways of facilitating informed consent. BACKGROUND: The recent political agenda for social change in the UK has emphasized the right of people with a learning disability to have more autonomy and make their own decisions. As in other countries, there has also been a shift towards shared decision-making in healthcare practice. DESIGN: Qualitative study using an ethnographic approach. METHODS: An ethnographic approach was used for this qualitative study. Phase 1 involved observation of six participants with a learning disability having a routine blood test in general practice, followed by semi-structured interviews with 14 participants with a learning disability in Phase 2. Data were collected between February 2009-February 2010. FINDINGS: The data showed that consent procedures were often inadequate and provision of information to patients prior to a blood test was variable. People with a learning disability expressed clearly their information requirements when having a routine blood test; this included not wanting any information in some cases. CONCLUSIONS: Healthcare practitioners and people with a learning disability need to be familiar with current consent law in their own country to facilitate valid consent in the healthcare context. This study demonstrated the value of qualitative research in exploring the knowledge and attitudes of people with learning disability.

Utility and limitations of genetic/genomic information and testing.

This is the sixth article in a series exploring genetics and genomics health care. The focus of this article is how to apply knowledge and understanding of the utility and limitations of genetic and genomic information and testing to underpin care and support for individuals and families before, during and after decision making. This is essential to ensure that nurses can confidently provide genetics and genomics health care.

Influence of family history on penetrance of hereditary cancers in a population setting.

Background: We sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort. Methods: We analysed 454,712 UK Biobank participants with exome sequence and clinical data (data collected between March 2006 and June 2021). We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for sex, death, recruitment centre, screening and prophylactic surgery). Findings: Women with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was higher in those with a first-degree family history (relative hazard 10.3 and 7.8, respectively) than those without (7.2 and 4.7). Penetrance to age 60 was also higher in those with a family history (44.7%, CI 32.2-59.3 and 24.1%, CI 17.5-32.6) versus those without (22.8%, CI 15.9-32.0 and 17.9%, CI 13.8-23.0). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of colorectal cancer that was significantly higher in those with a family history (relative hazard 35.6, 48.0 and 9.9) than those without (13.0, 15.4 and 7.2). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (30.9%, CI 18.1-49.3 and 38.3%, CI 21.5-61.8) versus those without (20.5% CI 9.6-40.5 and 8.3% CI 2.1-30.4), but not for MSH6 (6.5% CI 2.7-15.1 with family history versus 8.3%, CI 5.1-13.2). Relative risk increases were also observed both within and across conditions. Interpretation: Individuals with pathogenic cancer syndrome variants may be at a less elevated risk of cancer in the absence of a first-degree family history, so in the context of results return, family history should be considered when counselling patients on the risks and benefits of potential follow-up care. Funding: The current work is supported by the MRC (grant no MR/T00200X/1). The MRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Incidental findings in genetic research and clinical diagnostic tests: a systematic review.

Incidental findings arise when clinically relevant genetic information about a research participant or patient is identified outside the scope of the original research objective or diagnostic test being performed. These findings can relate to carrier status for a heritable condition, misattributed paternity or increased susceptibility to a medical condition. The decision whether to disclose these findings to the research subject or patient is underpinned by many ethical, moral, and potentially legal considerations. There is an urgent need for definitive guidelines for researchers and healthcare professionals. We performed a systematic review of the relevant literature concerning the disclosure of incidental findings, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations, using the prescribed flowchart and checklist. At initial screening, 473 articles were retrieved. The inclusion and exclusion criteria aimed at obtaining data that were relevant and of sufficient quality were applied and a total of four relevant studies were identified, comprising 2,680 individual participants and 1,023 guidance documents. Major themes emerging from the included articles include patient autonomy, patient welfare, harmful secrets, and genetic literacy. The lack of relevant studies emphasizes the urgent need for empirical investigations into the disclosure or non-disclosure of genetic incidental findings, and the provision of guidelines to assist healthcare professionals and researchers.

Differences in the pattern and regulation of mineral deposition in human cell lines of osteogenic and non-osteogenic origin.

Bone marrow-derived mesenchymal stem cells (MSCs) are widely used as a cellular model of bone formation, and can mineralize in vitro in response to osteogenic medium (OM). It is unclear, however, whether this property is specific to cells of mesenchymal origin. We analysed the OM response in 3 non-osteogenic lines, HEK293, HeLa and NTera, compared to MSCs. Whereas HEK293 cells failed to respond to OM conditions, the 2 carcinoma-derived lines NTera and HeLa deposited a calcium phosphate mineral comparable to that present in MSC cultures. However, unlike MSCs, HeLa and NTera cultures did so in the absence of dexamethasone. This discrepancy was confirmed, as bone morphogenetic protein inhibition obliterated the OM response in MSCs but not in HeLa or NTera, indicating that these 2 models can deposit mineral through a mechanism independent of established dexamethasone or bone morphogenetic protein signalling.

A Comparative Safety Analysis of Medicines Based on the UK Pharmacovigilance and General Practice Prescribing Data in England.

BACKGROUND/AIM: Adverse drug reactions (ADRs) represent a major concern leading to significant increases in both morbidity and mortality globally. Providing healthcare professionals (HCPs) and patients with real-world data on drug safety is imperative to facilitate informed decision-making. The study aimed to determine the feasibility of creating comparative safety charts for medicines by mapping ADR reporting onto prescribing data. MATERIALS AND METHODS: Data on serious and fatal ADR reports from the Yellow Card database was mapped onto general practice prescription data in England. The rate of serious and fatal ADR reports per million items prescribed was calculated for commonly-prescribed medicines. RESULTS: Quantitative comparative analyses for 137 medicines belonging to 26 therapeutic classes were conducted. Significant differences were observed within most therapeutic classes for the rate of serious and fatal ADR reports per prescribing unit. CONCLUSION: Despite the limitations of ADR reporting and prescribing databases, the study provides a proof-of-concept for the feasibility of mapping ADR reporting onto prescribing data to create comparative safety charts that could support evidence-based decision-making around formulary choices.

Genetic counselling as a route to enhanced autonomy: using a sequential mixed methods research approach to develop a theory regarding presymptomatic genetic testing for young adults at risk of inherited cancer syndromes.

Undertaking presymptomatic or predictive genetic testing should involve a considered choice. Decisions regarding genetic testing for young adults have to be considered within the context of their key life stage, which may involve developing a career, forming partnerships and/or becoming parents. The aim of this study was to develop a theoretical model regarding the factors involved when young adults (18-30 years) undergo presymptomatic genetic testing for inherited cancer syndromes. The model evolved from synthesis of results of a sequential mixed methods study involving a systematic review, a qualitative study and a quantitative study. The resulting model shows that young adults at risk of inherited cancer syndromes are influenced by others to have testing and come to counselling with their decision already made. However, genetic counselling enhances their feelings of autonomy and integration of their genetic status into their lives. Our theoretical model could be a valid support during the genetic counselling process for young adults and their parents, as it may sensitise professionals to the specific needs of this population, including education and support to autonomous decision-making. Counselling approaches should be modified in this population: an inclusive, multi-step counselling process is needed, with timing and setting set according to the specific features of this sensitive population.

Development of a Secure Website to Facilitate Information Sharing in Families at High Risk of Bowel Cancer-The Familyweb Study.

Individuals with pathogenic variants in genes predisposing to bowel cancer are encouraged to share this information within their families. Close relatives at 50% risk can have access to bowel cancer surveillance. However, many relatives remain unaware of their vulnerability or have insufficient information. We investigated the feasibility and acceptability of using a secure website to support information sharing within families at high risk of bowel cancer. Patients (n = 286) answered an anonymous cross-sectional survey, with 14 participating in telephone interviews. They reported that the diagnosis had a profound effect on them and their family relationships, and consequently desired more support from health professionals. Website content was created in response to the preferences of survey and interview participants. Reactions to the website from 12 volunteers were captured through remote usability testing to guide further refinement of the website. Participants welcomed the opportunity to store and share personal information via the website and wanted more information and help informing their relatives about the diagnosis. Important website topics were: healthy lifestyle; genetic testing; and how to talk to children about the diagnosis. A website providing online access to confidential documents was both feasible and acceptable and could translate into increased uptake of cancer surveillance, resulting in lower morbidity and mortality in these families.