Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.

METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.

RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)).

CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

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.

An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes

Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.

Johnson Creek S108

The South Carolina Department of Natural Resources provides maps to recreational and state shellfish grounds, available to the public for recreational harvesting or to commercial harvest. This map shows the location of Johnson Creek S108 Recreational Shellfish Ground in Beaufort County.

The Edinburgh Critical Edition of the Selected Writings of Andrew Lang: volume 1

This is the first critical edition of the works of Andrew Lang (1844-1912), the Scottish writer whose enormous output spanned the whole range of late nineteenth century intellectual culture. Neglected since his death, partly because of the diversity of his interests and the volume of his writing, his cultural centrality and the interdisciplinary nature of his work make him a vital figure for contemporary scholars. This volume covers his work in anthropology, including that on fairy tale, folklore, the origins of religion, and psychical research.

The Edinburgh Critical Edition of the Selected Writing of Andrew Lang, volume 2

This is the first critical edition of the works of Andrew Lang (1844-1912), the Scottish writer whose enormous output spanned the whole range of late nineteenth-century intellectual culture. Neglected since his death, partly because of the diversity of his interests and the volume of his writing, his cultural centrality and the interdisciplinary nature of his work make him a vital figure for contemporary scholars. This volume covers his work on literary criticism, history and biography.

Lisboa e a Invasão de Junot: população, periódicos e panfletos (1807-1808)

No termo das comemorações dos duzentos anos da Guerra Peninsular (1808-1814), este trabalho propõe-se trazer uma reflexão sobre a ocupação de Lisboa pelo exército francês, comandado pelo general Jean-Andoche Junot, e a luta do povo da cidade contra as forças napoleónicas, durante um período de nove meses, entre 30 de Novembro de 1807 e 30 de Agosto de 1808. A cidade de Lisboa foi personagem principal e testemunha dos acontecimentos que marcaram a ocupação militar francesa, cujos participantes foram, em primeiro lugar a população de Lisboa, com maior relevo para o povo simples, mas também outros estratos da população que, em menor ou maior grau, sofreram igualmente as difíceis condições criadas pela presença militar estrangeira. A importância do papel que Lisboa viria a desempenhar nestas difíceis circunstâncias, justifica o relevo que foi dado ao período da sua ocupação pelo exército francês, através das diversas formas de que se revestia a vida na cidade, nos seus aspectos sociais e culturais, incluindo, além da sua morfologia urbana, a vida social e cultural, os hábitos e tradições, as condições de vida, os entretenimentos e as instituições que identificavam a cidade. Em seguida, estabelecemos as circunstâncias em que a cidade se encontrava nesse último mês de Dezembro de 1807, com a retirada para o Brasil do Príncipe Regente D. João, acompanhado pela família real, a corte e a maioria da primeira nobreza do país, coincidindo com a entrada das tropas francesas em Lisboa. Finalmente, abordámos as consequências destes acontecimentos para a população, cuja manifestação se evidenciou no sentimento de perda e na fraqueza de ânimo por ela sentidos. Por último, sublinha-se o papel desempenhado pela imprensa portuguesa da época que, embora pouco representativa em número, conseguiu um efeito mobilizador junto de largas camadas da população, transformando-se num dos principais veículos da sustentação da luta contra o ocupante francês, através não apenas da imprensa periódica mas, igualmente, dos panfletos anti-napoleónicos que se imprimiram e distribuíram às centenas.

The scramble for the seas : the ballad evidence of Sir Andrew Barton

The presence and importance of the sea as a factor that has helped shape the history of England since at least the Roman invasions of 55-54 BC (less successful, incidentally, than most of Caesar’s other military ventures ...) need no particular urging or demonstration. Nonetheless, a bird’s-eye view would necessarily survey the waves of invasions and settlements that, one after the other, came dashing over the centuries upon England’s shores; not to mention the requested invasion of 1688, Angles and Saxons, Scandinavians, Normans, they all crossed the whale’s path and cast anchor in England’s green and pleasant land. In the course of this retrospective voyage through the oceans of History, one would inevitably stop at the so-called ‘Discoveries’ of the 15th-16th centuries, meet their navigators, sailors and pirates extolled by Richard Hakluyt (1553?-1616), face an anonymous crowd of merchants and witness the huge expansion of trade, largely to the benefit of the ‘discovering’ countries as prescribed by the economic Gospel Adam Smith (1723-90) would later baptize as “mercantilism”.