Insulin resistance:Genetic associations with depression and cognition in population based cohorts

We are grateful to the families who took part in GS:SFHS, general practitioners and the Scottish School of Primary Care for their help in recruitment, and the whole GS:SFHS team that includes academic researchers, clinic staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers. The research reported here, and the genotyping of GS:SFHS samples was funded by the Wellcome Trust, (Wellcome Trust Strategic Award ‘STratifying Resilience and Depression Longitudinally’ (STRADL) Reference 104036/Z/14/Z) and by the Medical Research Council. SF acknowledges support from the National Institute of Mental Health, USA (R01MH113619; R01MH116147) and the consortium for Psychopathology and Allostatic load across the Life Span (PALS; https://www.pals-network.org) AMM acknowledges the financial support received from the Dr. Mortimer and Theresa Sackler Foundation. IJD and AMM are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council is gratefully acknowledged.Peer reviewedPublisher PD

Do Administrative Traditions Matter for Climate Change Adaptation Policy? A Comparative Analysis of 32 High-Income Countries

Although governments are developing and implementing policies to adapt to the impacts of climate change, it remains unclear which factors shape how states are developing these policies. This paper aims to assess whether or not administrative traditions matter for the formation of national climate change adaptation policy in 32 high-income countries. We operationalize administrative traditions based on five structural criteria: vertical dispersion of authority, horizontal coordination, interest mediation between state-society, role of public administrator, and how ideas enter bureaucracy. We construct a unique adaptation policy dataset that includes 32 high-income countries to test seven hypotheses. Our results indicate that countries’ adaptation policies align to some extent with their administrative structure, particularly dispersion of authority and horizontal coordination. However, we find limited evidence that other public bureaucracy factors are related to national adaptation policy. We conclude that administrative traditions matter, but that their influence should not be overestimated

A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome

Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges