Genome-wide Association Study Implicates HLA-C*01:02 as a Risk Factor at the Major Histocompatibility Complex Locus in Schizophrenia

BACKGROUND: We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia. METHODS: The discovery scan included 1606 patients and 1794 controls from Ireland, using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis. RESULTS: One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 × 10(-9) and in combined samples (rs2523722 p combined = 2.88 × 10(-16)) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study. CONCLUSIONS: This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4, VRK2, and ZNF804A loci.

When did Britain industrialise? The sectoral distribution of the labour force and labour productivity in Britain, 1381-1851

Britain's labour force industrialised early. The industrial and service sectors already accounted for 40% of the labour force in 1381, and a substantial further shift of labour out of agriculture occurred between 1522 and 1700. From the early seventeenth century rising agricultural labour productivity underpinned steadily increasing employment in industry and services, so that by 1759 agriculture's share of the labour force had shrunk to 37% and industry's grown to 34%. Thereafter, industry's output acceleration during the Industrial Revolution owed more to gains in labour productivity consequent upon mechanisation than the expansion of employment.

Proteolytic cleavage of elafin by 20S proteasome may contribute to inflammation in acute lung injury

RATIONALE:
We hypothesise that elafin levels in acute lung injury (ALI) decrease over time due, in part, to proteolytic degradation as observed in other lung diseases.
OBJECTIVES:
The aim of this study was to characterise temporal changes in elafin concentration in patients with ALI and to evaluate whether a decrease in elafin levels is due to elevated protease activity.
METHODS:
Bronchoalveolar lavage fluid (BALF) was obtained from patients with ALI within 48 h of onset of ALI (day 0), at day 3 and at day 7. Elafin levels were quantified by ELISA. Elafin susceptibility to proteolytic cleavage by ALI BALF was assessed by Western blot and by high-performance liquid chromatography-mass spectrometry.
MEASUREMENTS AND MAIN RESULTS:
Elafin levels were found to be significantly increased at the onset of ALI compared with healthy volunteers and fell significantly by day 7 compared with day 0. In contrast, levels of secretory leukocyte protease inhibitor did not decrease over time. This decrease in elafin was due to cleavage by the 20S proteasome which was significantly increased in ALI BALF. Incubation of ALI BALF with the proteasome inhibitor epoxomicin confirmed that 20S proteasome protease activity was responsible for proteolytic cleavage of elafin, resulting in diminished anti-elastase activity. In addition, free neutrophil elastase activity significantly increased in ALI BALF from day 0 to day 7.
CONCLUSIONS:
Elafin concentrations fall within the pulmonary compartment over the course of ALI as a result of proteolytic degradation. This loss of elafin may predispose people, in part, to excessive inflammation in ALI.

No evidence that runs of homozygosity are associated with schizophrenia in an Irish genome-wide association dataset

Runs of homozygosity (ROH), regions of the genome containing many consecutive homozygous SNPs, may represent two copies of a haplotype inherited from a common ancestor. A rare variant on this haplotype could thus be present in a homozygous and potentially recessive state. To detect rare risk variants for schizophrenia, we performed an ROH analysis in a homogeneous Irish genome wide association study (GWAS) dataset consisting of 1606 cases and 1794 controls. There was no genome-wide excess of ROH in cases compared to controls (p=0.7986). No consensus ROH at individual loci showed association with schizophrenia after genome-wide correction.

Citizenship and (Un)Sustainability: A Green Republican Perspective

This chapter explores some of the connections (causal and other) between the decline in active citizenship, the displacement of citizenship by consumer identities and interests, and the shift to a transactional mode of democratic politics and how and in what ways these are connected with “actually existing unsustainability.” It proposes an account of “green republican citizenship” as an appropriate theory and practice of establishing a link between the practices of democracy and the processes of democratization in the transition from unsustainability. The chapter begins from the (not uncontroversial) position that debt-based consumer capitalism (and especially its more recent neoliberal incarnation) is incompatible with a version of democratic politics and associated norms and practices of green citizenship required for a transition from unsustainable development. It outlines an explicitly “green republican” conception of citizenship as an appropriate way to integrate democratic citizenship and creation of a more sustainable political and socio-ecological order.

From Francis Hutcheson to James McCosh: Irish Presbyterians and Defining the Scottish Philosophy in the Nineteenth Century

This article examines the disputes amongst Irish Presbyterians about the teaching of moral philosophy by Professor John Ferrie in the college department of the Royal Belfast Academical Institution in the early nineteenth century and the substantive philosophical and theological issues that were raised. These issues have largely been ignored by Irish historians, but a discussion of them is of general relevance to historians of ideas as they illuminate a series of broader questions about the definition and development of Scottish philosophy. These are represented in the move from two philosophers who had strong connections with Irish Presbyterianism—Francis Hutcheson, the early eighteenth-century moral sense philosopher and theological moderate from County Down, and James McCosh, nineteenth-century exponent of modified Common Sense philosophy at Queen's College Belfast and a committed evangelical. In particular, this article addresses three important themes—the definition and character of ‘the Scottish philosophy’, the relationship between evangelicalism and Common Sense philosophy, and the process of development and adaptation that occurred in eighteenth-century Scottish thought during the first half of the nineteenth century.