Andrew D. Morris

Estimated Life Expectancy in a Scottish Cohort With Type 1 Diabetes, 2008-2010

IMPORTANCEnType 1 diabetes has historically been associated with a significant reduction in life expectancy. Major advances in treatment of type 1 diabetes have occurred in the past 3 decades. Contemporary estimates of the effect of type 1 diabetes on life expectancy are needed.nnnOBJECTIVEnTo examine current life expectancy in people with and without type 1 diabetes in Scotland. We also examined whether any loss of life expectancy in patients with type 1 diabetes is confined to those who develop kidney disease.nnnDESIGN, SETTING, AND PARTICIPANTSnProspective cohort of all individuals alive in Scotland with type 1 diabetes who were aged 20 years or older from 2008 through 2010 and were in a nationwide register (n=24,691 contributing 67,712 person-years and 1043 deaths).nnnMAIN OUTCOMES AND MEASURESnDifferences in life expectancy between those with and those without type 1 diabetes and the percentage of the difference due to various causes.nnnRESULTSnLife expectancy at an attained age of 20 years was an additional 46.2 years among men with type 1 diabetes and 57.3 years among men without it, an estimated loss in life expectancy with diabetes of 11.1 years (95% CI, 10.1-12.1). Life expectancy from age 20 years was an additional 48.1 years among women with type 1 diabetes and 61.0 years among women without it, an estimated loss with diabetes of 12.9 years (95% CI, 11.7-14.1). Even among those with type 1 diabetes with an estimated glomerular filtration rate of 90 mL/min/1.73 m2 or higher, life expectancy was reduced (49.0 years in men, 53.1 years in women) giving an estimated loss from age 20 years of 8.3 years (95% CI, 6.5-10.1) for men and 7.9 years (95% CI, 5.5-10.3) for women. Overall, the largest percentage of the estimated loss in life expectancy was related to ischemic heart disease (36% in men, 31% in women) but death from diabetic coma or ketoacidosis was associated with the largest percentage of the estimated loss occurring before age 50 years (29.4% in men, 21.7% in women).nnnCONCLUSIONS AND RELEVANCEnEstimated life expectancy for patients with type 1 diabetes in Scotland based on data from 2008 through 2010 indicated an estimated loss of life expectancy at age 20 years of approximately 11 years for men and 13 years for women compared with the general population without type 1 diabetes.

Cohort Profile: Generation Scotland: Scottish Family Health Study (GS:SFHS). The study, its participants and their potential for genetic research on health and illness

GS:SFHS is a family-based genetic epidemiology study with DNA and socio-demographic and clinical data from about 24 000 volunteers across Scotland aged 18-98 years, from February 2006 to March 2011. Biological samples and anonymized data form a resource for research on the genetics of health, disease and quantitative traits of current and projected public health importance. Specific and important features of GS:SFHS include the family-based recruitment, with the intent of obtaining family groups; the breadth and depth of phenotype information, including detailed data on cognitive function, personality traits and mental health; consent and mechanisms for linkage of all data to comprehensive routine health-care records; and broad consent from participants to use their data and samples for a wide range of medical research, including commercial research, and for re-contact for the potential collection of other data or samples, or for participation in related studies and the design and review of the protocol in parallel with in-depth sociological research on (potential) participants and users of the research outcomes. These features were designed to maximize the power of the resource to identify, replicate or control for genetic factors associated with a wide spectrum of illnesses and risk factors, both now and in the future.

Epidemiology and Heritability of Major Depressive Disorder, Stratified by Age of Onset, Sex, and Illness Course in Generation Scotland: Scottish Family Health Study (GS:SFHS)

The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.

Mosaic structural variation in children with developmental disorders

Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2–1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case–control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e − 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e − 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic–phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.

Unleashing the power of administrative health data: the Scottish model

Data and information generated through the provision and administration of health and social care provide potentially valuable untapped resources that can contribute to the development of effective and efficient services. We describe the Scottish system, which seeks to unleash, at scale, the power of administrative and health service data as part of the UK-wide Farr Institute of Health Informatics Research program. The Scottish model balances current public attitudes and views around the use of administrative and health data for research purposes with researchers data requirements, and does so within Scotlands legal framework. The past 3 years has seen the completion of more than 150 projects by researchers from industry (17%), academia (53%) and health service providers (30%). In the future, the aim will be to ensure that research findings are disseminated widely and used to both improve health service provision and further develop public trust.

A common missense variant of LILRB5 is associated with statin intolerance and myalgia

Abstract Aims A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: Tu2009>u2009C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study. Methods and results In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34–2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07–1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05–2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10–1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16–1.54). Conclusion This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

Cohort Profile: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS)

Cohort Profile: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) Harry L Hébert, Bridget Shepherd, Keith Milburn, Abirami Veluchamy, Weihua Meng, Fiona Carr, Louise A Donnelly, Roger Tavendale, Graham Leese, Helen M Colhoun, Ellie Dow, Andrew D Morris, Alexander S Doney, Chim C Lang, Ewan R Pearson, Blair H Smith and Colin NA Palmer* Division of Population Health Sciences, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Health Informatics Centre Services, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK, Institute of Genetics & Molecular Medicine and Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

Lp-PLA2 activity is associated with increased risk of diabetic retinopathy: a longitudinal disease progression study

Aims/hypothesisThe aim of the study was to examine the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) activity levels and incident diabetic retinopathy and change in retinopathy grade.MethodsThis was a cohort study of diabetic participants with serum collected at baseline and routinely collected diabetic retinal screening data. Participants with type 2 diabetes from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort were used. This cohort is composed of individuals of white Scottish ancestry from the Tayside region of Scotland. Survival analysis accounting for informative censoring by modelling death as a competing risk was performed for the development of incident diabetic retinopathy from a disease-free state in a 3xa0year follow-up period (nu2009=u20091364) by stratified Lp-PLA2 activity levels (in quartiles). The same analysis was performed for transitions to more severe grades.ResultsThe hazard of developing incident diabetic retinopathy was 2.08 times higher (95% CI 1.64, 2.63) for the highest quartile of Lp-PLA2 activity compared with the lowest. Higher Lp-PLA2 activity levels were associated with a significantly increased risk for transitions to all grades. The hazards of developing observable (or more severe) and referable (or more severe) retinopathy were 2.82 (95% CI 1.71, 4.65) and 1.87 (95% CI 1.26, 2.77) times higher for the highest quartile of Lp-PLA2 activity compared with the lowest, respectively.Conclusions/interpretationHigher Lp-PLA2 levels are associated with increased risk of death and the development of incident diabetic retinopathy, as well as transitions to more severe grades of diabetic retinopathy. These associations are independent of calculated LDL-cholesterol and other traditional risk factors. Further, this biomarker study shows that the association is temporally sensitive to the proximity of the event to measurement of Lp-PLA2.

A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes

Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy.