Balancing the Local and the Universal in Maintaining Ethical Access to a Genomics Biobank

Background: In policy and governance discussions of genetic and genomic data sharing, the rights of research subjects are often balanced against the scientific benefits of allowing open access to biomedical data. However, this dichotomous focus can obscure other matters that are relevant to the ethical running of the biobank. These include the will and the ability to sustain the resource. We will consider Generation Scotland (GS) as one context in which a global policy agenda favouring open access meets local issues of governance and sustainability. We seek to address gaps in discussion in scientific, law and policy arenas about the means to ensure that open access functions well but often neglects the contextual aspects of Biobanking. In order to explore these aspects we use the case of access to Generation Scotland. Participant recruitment and collection of data from the 24,000 plus participants in this genomics research biobank began in 2006 and a GS infrastructure continues to exist and manage access to a repository more than a decade later. We explore the balancing of data accessibility with ethical considerations and governance for GS in the evolving policy landscape of the past ten years. A time when data sharing and open data access have become increasingly important topics within the biomedical research community. Methods: We carried out a review of policy documents and academic articles drawn from science and bioethics literatures. We focussed on literature covering open access, the protection of data subjects and questions pertaining to sustainability, for example in relation to funding or attribution of credit to repository staff. A further aspect of the methodology is based upon participant-observation within the Generation Scotland Access Committee, of which both authors are members. Results: Using our engagement with GS we foreground the local elements of biorepository governance. Whilst decisions around data access are influenced by global policy objectives, local arrangements for governance and practices such as linkage to health records are also central. At the local level, we argue, moreover, that governance decisions regarding access to the biobank are intertwined with considerations about maintenance and viability. We show that in addition to the focus upon ever more universal and standardised practices, the local expertise and commitment built up when creating and maintaining repositories such as GS must be taken into account. Conclusions: A commitment to open access in genomics research has found broad backing in science and health policy circles. This has led to a focus in science policy literature on facilitating access, at the risk of overlooking the contextual aspects of biobanking. Yet repositories of data and samples from human subjects may have to operate under managed access, to ensure both that the terms of consent are met and that the resource can be managed in a sustainable way. The importance of nurturing what is particular about the biobank in its local context, therefore, ought not to be ignored. A video of this presentation can be viewed at https://media.ed.ac.uk/media/0_bw9i5gm

Impact of preeclampsia on cardiovascular events: an analysis of the Generation Scotland: Scottish Family Health Study

Preeclampsia is a recognised cause of an increased risk of major adverse cardiovascular events when compared to the background risk in women who did not have hypertensive disorders during pregnancy. The Generation Scotland: Scottish Family Health Study (GS:SFHS) is a population cohort of more than 20,000 members of the Scottish population. Using the Scottish Morbidity Records, we linked the women in the GS:SFHS cohort to validated maternity and inpatient admission data. This allowed us to robustly identify cardiovascular outcomes in the form of inpatient admission for cardiovascular events, We also aimed to explore the risk of pregnancy on future cardiovascular events, using data from nulliparous and parous women.In total, 9732 women were selected. 3693 women were nulliparous, and after study exclusion, 5253 women with 9583 pregnancies remained. Pregnancies from 1980 until the end of the study period of 1st of July 2013 were included. Cardiovascular events occurred in 9.0% of nulliparous women, 4.2% of women with pregnancies and in 7.6% of women with a history of preeclampsia. A total of 218 parous women experienced cardiovascular events, 25 in the preeclampsia group and 193 in the normotensive group.Survival analysis was undertaken, with index pregnancy taken as first pregnancy in normotensive controls and first preeclampsia pregnancy in cases. Endpoint of interest was admission to hospital with first cardiovascular event. After further exclusions a total of 169 cardiovascular events occurred in the normotensive pregnancy group and 20 in the preeclampsia group. Women with a history of preeclampsia were more likely to have cardiovascular events later in life than women with normotensive deliveries., This was statistically significantly different on Kaplan Meier survival analysis, (log rank Mantel-Cox p-value < 0.001). The women in our study were middle-aged, within 33 years of pregnancy, with a mean age of 53 years in the preeclampsia cardiovascular events group.Our study supports the urgent need for uniform guidelines and implementation to improve the health in women with this medical history. Increased awareness among the public of the cardiovascular risk associated with PE is vital to aid uptake of cardiovascular prevention programmes

VIKING II, a Worldwide Observational Cohort of Volunteers with Northern Isles Ancestry

Introduction The purpose of VIKING II is to create an observational cohort of volunteers with ancestry from the Northern Isles of Scotland, primarily for identifying genetic variants influencing disease. The new online protocol is separate to, but follows on from, earlier genetic epidemiological clinic-based studies in the isolated populations of Orkney and Shetland. These populations are favourable for the study of rarer genetic variants due to genetic drift, the large number of relatives, and availability of pedigree information. They are known to be genetically distinct from mainland British populations. Methods and Analysis Online methods are being used to recruit ~4,000 people who have Northern Isles ancestry, living anywhere in the world. The option for participants to have actionable genetic results returned is offered. Consent will be taken electronically. Data will be collected at baseline through an online questionnaire and longitudinally through linkage to NHS data in the electronic health record. The questionnaire collects a variety of phenotypes including personal and family health. DNA will be extracted from saliva samples then genome-wide genotyped and exome sequenced. VIKING II aims to capitalise on the special features of the Northern Isles populations to create a research cohort that will facilitate the analysis of genetic variants associated with a broad range of traits and disease endpoints, including otherwise rare variants that have drifted to high frequency in these populations. Ethics and Dissemination The South East Scotland Research Ethics Committee gave the study a favourable opinion. VIKING II is sponsored by the University of Edinburgh and NHS Lothian. Summary research findings will be disseminated to participants and funding bodies, presented at conferences and reported in peer-reviewed publications. Article Summary Strengths and limitations of this study • Detailed data and biological sample collection of research volunteers with unique ancestry. • Consent for access to routinely collected clinical EHR data and for future re-contact, providing a longitudinal component. • Optional consent for return of actionable genetic results. • ~4,000 participants is a relatively small number for certain types of genetic analyses, so the cohort is underpowered on its own, in some study designs. • Resources to maintain the cohort, and to store data and DNA samples, are significant, with sustainability dependent on infrastructure support and funding

Common Genetic Variants Explain the Majority of the Correlation Between Height and Intelligence : The Generation Scotland Study

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Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP.

We aimed to develop an efficient, flexible and scalable approach to diagnostic genome-wide sequence analysis of genetically heterogeneous clinical presentations. Here we present G2P ( www.ebi.ac.uk/gene2phenotype ) as an online system to establish, curate and distribute datasets for diagnostic variant filtering via association of allelic requirement and mutational consequence at a defined locus with phenotypic terms, confidence level and evidence links. An extension to Ensembl Variant Effect Predictor (VEP), VEP-G2P was used to filter both disease-associated and control whole exome sequence (WES) with Developmental Disorders G2P (G2PDD; 2044 entries). VEP-G2PDD shows a sensitivity/precision of 97.3%/33% for de novo and 81.6%/22.7% for inherited pathogenic genotypes respectively. Many of the missing genotypes are likely false-positive pathogenic assignments. The expected number and discriminative features of background genotypes are defined using control WES. Using only human genetic data VEP-G2P performs well compared to other freely-available diagnostic systems and future phenotypic matching capabilities should further enhance performance

Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions

Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing:a population-based study

Background<p></p> Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.<p></p> Methods<p></p> We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.<p></p> Results<p></p> Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.<p></p> Conclusions<p></p> We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis

Generation Scotland: Donor DNA Databank; A control DNA resource

<p>Abstract</p> <p>Background</p> <p>Many medical disorders of public health importance are complex diseases caused by multiple genetic, environmental and lifestyle factors. Recent technological advances have made it possible to analyse the genetic variants that predispose to complex diseases. Reliable detection of these variants requires genome-wide association studies in sufficiently large numbers of cases and controls. This approach is often hampered by difficulties in collecting appropriate control samples. The Generation Scotland: Donor DNA Databank (GS:3D) aims to help solve this problem by providing a resource of control DNA and plasma samples accessible for research.</p> <p>Methods</p> <p>GS:3D participants were recruited from volunteer blood donors attending Scottish National Blood Transfusion Service (SNBTS) clinics across Scotland. All participants gave full written consent for GS:3D to take spare blood from their normal donation. Participants also supplied demographic data by completing a short questionnaire.</p> <p>Results</p> <p>Over five thousand complete sets of samples, data and consent forms were collected. DNA and plasma were extracted and stored. The data and samples were unlinked from their original SNBTS identifier number. The plasma, DNA and demographic data are available for research. New data obtained from analysis of the resource will be fed back to GS:3D and will be made available to other researchers as appropriate.</p> <p>Conclusions</p> <p>Recruitment of blood donors is an efficient and cost-effective way of collecting thousands of control samples. Because the collection is large, subsets of controls can be selected, based on age range, gender, and ethnic or geographic origin. The GS:3D resource should reduce time and expense for investigators who would otherwise have had to recruit their own controls.</p

Molecular genetic contributions to socioeconomic status and intelligence

Education, socioeconomic status, and intelligence are commonly used as predictors of health outcomes, social environment, and mortality. Education and socioeconomic status are typically viewed as environmental variables although both correlate with intelligence, which has a substantial genetic basis. Using data from 6815 unrelated subjects from the Generation Scotland study, we examined the genetic contributions to these variables and their genetic correlations. Subjects underwent genome-wide testing for common single nucleotide polymorphisms (SNPs). DNA-derived heritability estimates and genetic correlations were calculated using the ‘Genome-wide Complex Trait Analyses’ (GCTA) procedures. 21% of the variation in education, 18% of the variation in socioeconomic status, and 29% of the variation in general cognitive ability was explained by variation in common SNPs (SEs ~ 5%). The SNP-based genetic correlations of education and socioeconomic status with general intelligence were 0.95 (SE 0.13) and 0.26 (0.16), respectively. There are genetic contributions to intelligence and education with near-complete overlap between common additive SNP effects on these traits (genetic correlation ~ 1). Genetic influences on socioeconomic status are also associated with the genetic foundations of intelligence. The results are also compatible with substantial environmental contributions to socioeconomic status