Homozygosity, inbreeding and health in European populations

Inbreeding results in increased levels of homozygosity for deleterious recessive alleles, leading to increased incidence of monogenic disease in inbred families. It has also been suggested that inbreeding increases the risk of diseases such as cancer and heart disease, implying a role for the combined effects of many recessive alleles distributed across the genome. A better understanding of the links between inbreeding, homozygosity and disease is therefore of interest to those concerned with understanding the genetic architecture of complex disease. A homozygous genotype is defined as autozygous if both alleles originate from the same ancestor. Quantifying inbreeding involves quantifying autozygosity. A new, observational method of quantifying autozygosity using genomic data is developed here. Based on runs of homozygosity (ROH), this approach has a sound theoretical basis in the biological processes involved in inbreeding. It is also backed by strong empirical evidence, correlating strongly with pedigree-derived estimates of inbreeding and discriminating well between populations with different demographic histories. ROH are a signature of autozygosity, but not necessarily autozygosity of recent origin. Short ROH are shown to be abundant in demonstrably outbred individuals and it is suggested that this is a source of individual genetic variation which merits investigation as a disease risk factor, although denser genotype scans than those used in the present study are required for the reliable detection of very short ROH. In the absence of such dense scans, it is suggested that ROH longer than 1 or 1.5 Mb be used to estimate the effects of inbreeding on disease or quantitative physiological traits (QT), and that a simple measure of homozygosity be used to investigate overall recessive effects. Evidence for recessive effects on 13 QT important in cardiovascular and metabolic disease was investigated in 5 European isolate populations, characterised by heightened levels of inbreeding. A significant decrease in height was associated both with increased homozygosity and (to a lesser extent) with increased ROH longer than 5 Mb (i.e. inbreeding) estimated using a 300,000 SNP panel. No evidence was found for recessive effects on any of the other QTs. Evidence for recessive effects on colorectal cancer risk were investigated in two outbred case control samples typed with a 500,000 SNP panel. Cases were significantly more homozygous and had more of their genome in short ROH than did controls. Cases were significantly more homozygous than controls even when inbred individuals were removed from the sample. There was also some evidence of an inbreeding effect, with inbred subjects having slightly significantly higher odds of colorectal cancer than outbred subjects. This study provides evidence of recessive effects on a common, complex disease in outbred populations and on height in both inbred and outbred populations and shows that such effects are not solely attributable to increased levels of homozygosity resulting from recent inbreeding. Individual variation among outbred individuals in the proportion of the genome that is homozygous may be important in disease risk. The development of denser genotype scans will facilitate better enumeration of short ROH in outbred individuals so that these can be properly enumerated and investigated as a disease risk factor

Facilitating a positive transition:A case study exploring the factors that support social, emotional and mental wellbeing from primary to secondary school

The transition from primary school to secondary school can be a difficult time for young people, yet little is known about what schools do to support the social, emotional and mental wellbeing (SEMWB) of their pupils during this period. The purpose of this research is to explore the ways in which an urban Scottish secondary school and two of its local feeder primary schools attempt to support their pupils’ SEMWB as they make this transition. A case study design was adopted to create a rich and situated account of teachers’ experiences and perceptions about transition approaches through semi structured interviews. Participants were teachers in the secondary school, a large primary school serving a relatively affluent area and a smaller primary school in a more diverse, less affluent area. Thematic analysis of the data, led to the identification of three inter-connected themes underpinning the ability of schools to support their pupils’ transition effectively: positive relationships, positive communities and positive environments. This suggests that teachers adopt a broadly socio-ecological perspective, viewing transition as a multi-faceted process, in which not only individual pupil characteristics but also social, cultural and relational factors are important. However, within this broad framework, teachers’ precise understanding of SEMWB varied within and across contexts, suggesting the importance of leadership and of a shared understanding, both within each school and across a cluster of schools. Teachers should also be supported to evaluate their initiatives and the impact these have on transition.</p

A Systematic Review and Meta-Analysis to assess the association between Urogenital Schistosomiasis and HIV/AIDS Infection

BackgroundUrogenital schistosomiasis and HIV/AIDS infections are widespread in sub-Saharan Africa (SSA) leading to substantial morbidity and mortality. The co-occurrence of both diseases has led to the possible hypothesis that urogenital schistosomiasis leads to increased risk of acquiring HIV infection. However, the available evidence concerning this association is inconsistent. The aim of this study was to systematically review and quantitatively synthesize studies that investigated the association between urogenital schistosomiasis and HIV/AIDS infection.MethodsA systematic review basing on PRISMA guidelines was conducted. It is registered with PROSPERO, number CRD42018116648. We searched four databases, MEDLINE, EMBASE, Global Health and Global Index Medicus for studies investigating the association between urogenital schistosomiasis and HIV infection. Only studies published in English were considered. Results of the association were summarised by gender. A meta-analysis was performed for studies on females using random-effects model and a pooled OR with 95% confidence interval was reported.ResultsOf the 993 studies screened, only eight observational studies met the inclusion criteria. Across all studies, the reported unadjusted OR ranged from 0.78 to 3.76. The pooled estimate of unadjusted OR among females was 1.31 (95% CI: 0.87-1.99). Only four of the eight studies reported an adjusted OR. A separate meta-analysis done in the three studies among females that reported an adjusted OR showed that the pooled estimate was 1.85 (95% CI: 1.17-2.92). There were insufficient data to pool results for association between urogenital schistosomiasis and HIV infection in the males.ConclusionOur investigation supports the hypothesis of an association between urogenital schistosomiasis with HIV/AIDS infection in females. Due to insufficient evidence, no conclusion could be drawn in males with urogenital schistosomiasis. Large-scale prospective studies are needed in future

Genome-wide homozygosity and multiple sclerosis in Orkney and Shetland Islanders

There is strong evidence for both genetic and environmental risk factors comprising the aetiology of multiple sclerosis (MS). While much progress has been made in recent years in identifying common genetic variants using genome-wide association studies, alternative approaches have remained relatively neglected. The prevalence of MS in Orkney and Shetland is among the highest in the world. Previous studies have suggested that a higher degree of parental relatedness in these isolated communities may contribute to the high rates of MS, indicating that recessive effects have an important role in MS aetiology. The Northern Isles Multiple Sclerosis (NIMS) study investigated the potential role of genome-wide homozygosity in MS risk by genotyping 88 MS patients, 89 controls matched by age, sex and ancestry, and a further 89 controls matched for sex and ancestry, but passed the majority of lifetime risk of developing MS (>70 years of age). Three participants were removed on the basis of pedigree-genomic anomalies (n=263). Three measures of genome-wide homozygosity were generated for each individual, and association with MS was assessed using logistic regression models. No effect of genome-wide homozygosity was detected, indicating that inbreeding and consanguinity are not risk factors for MS in this population

The benefits, challenges, and best practice for patient and public involvement in evidence synthesis:A systematic review and thematic synthesis

Abstract Introduction Despite the growing evidence on patient and public involvement (PPI) in health research, little emphasis has been placed on understanding its quality and appropriateness to evidence synthesis (ES) and systematic reviews (SR). This study aimed to synthesise qualitative evidence on the benefits, challenges, and best practices for PPI in ES/SR projects from the perspectives of patients/public and researchers. Methods We searched Ovid MEDLINE, Ovid EMBASE, Cochrane Library and CINAHL Plus. We also searched relevant grey literature and conducted hand‐searching to identify qualitative studies which report the benefits and challenges of PPI in individual ES/SR projects. Studies were independently screened by two reviewers for inclusion and appraised using the Joanna Briggs Institute's Qualitative Tool. Included studies were synthesised narratively using thematic synthesis. Results The literature search retrieved 9923 articles, of which eight studies were included in this review. Five themes on benefits emerged: two from patients'/public's perspective—gaining knowledge, and empowerment; and three from researchers' perspective—enhancing relevance, improving quality, and enhancing dissemination of findings. Six themes on challenges were identified: three from patients'/public's perspective—poor communication, time and low self‐esteem; and three from researchers' perspective—balancing inputs and managing relations, time, and resources and training. Concerning recommendations for best practice, four themes emerged: provision of sufficient time and resources, developing a clear recruitment plan, provision of sufficient training and support, and the need to foster positive working relationships. Conclusion Highlighting the benefits and challenges of PPI in ES/SR projects from different stakeholder perspectives is essential to understand the process and contextual factors and facilitate meaningful PPI in ES/SR projects. Future research should focus on the utilisation of existing frameworks (e.g., Authors and Consumers Together Impacting on eVidencE [ACTIVE] framework) by researchers to help describe and/or report the best approaches and methods for involving patients/public in ES/SRs projects. Patient and Public Contribution This review received great contributions from a recognised PPI partner, the Chair of the Cochrane Consumer Network Executive, to inform the final stage of the review (i.e., interpretation, publication and dissemination of findings). The PPI partner has been included as an author of this review