Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.     

Maligned for mathematics: Sir Thomas Urquhart and his Trissotetras

Thomas Urquhart (1611–1660), celebrated for his English translation of Rabelais’ Gargantua et Pantagruel, has earned some notoriety for his eccentric, putatively incomprehensible early book on trigonometry The Trissotetras (1645). The Trissotetras was too impractical to succeed in its own day as a textbook, since it lacked both trigonometric tables and sample calculations. But its current bad reputation is based on literary authors’ amplifications of the verdict prefaced to its 19th century reprinting by one mathematician, William Wallace, who lacked the background to appreciate the book’s historical context. Considering that context (including seventeenth century ‘copious’ prose, and medieval logic and ‘art of memory’), the bad reputation is undeserved: the book is mathematically clear, clever (e.g. in superimposing 16 problems into one diagram), and complete. The Trissotetras may thus be viewed as simply one more of Urquhart’s polymathic projects and involvements – which included education, rise of the middle class, religious and class conflicts, development of science and mathematics, search for patronage, universal language construction, and development of English prose – which serve to make him a lively and instructive intellectual Everyman for his time.     

The transcendental method from Newton to Kant

Kant’s transcendental method, as applied to natural philosophy, considers the laws of physics as conditions of the possibility of experience. A more modest transcendental project is to show how the laws of motion explicate the concepts of motion, force, and causal interaction, as conditions of the possibility of an objective account of nature. This paper argues that such a project is central to the natural philosophy of Newton, and explains some central aspects of the development of his thinking as he wrote the Principia. One guiding scientific aim was the dynamical analysis of any system of interacting bodies, and in particular our solar system; the transcendental question was, what are the conceptual prerequisites for such an analysis? More specifically, what are the conditions for determining “true motions” within such a system—for posing the question of “the frame of the system of the world” as an empirical question? A study of the development of Newton’s approach to these questions reveals surprising connections with his developing conceptions of force, causality, and the relativity of motion. It also illuminates the comparison between his use of the transcendental method and that of Euler and Kant.     

Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.     

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10??). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.     

Genome-wide association analysis identifies three psoriasis susceptibility loci

We carried out a meta-analysis of two recent psoriasis genome-wide association studies with a combined discovery sample of 1,831 affected individuals (cases) and 2,546 controls. One hundred and two loci selected based on P value rankings were followed up in a three-stage replication study including 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland and Germany. In the combined meta-analysis, we identified three new susceptibility loci, including one at NOS2 (rs4795067, combined P = 4 × 10?11), one at FBXL19 (rs10782001, combined P = 9 × 10?1?) and one near PSMA6-NFKBIA (rs12586317, combined P = 2 × 10??). All three loci were also associated with psoriatic arthritis (rs4795067, combined P = 1 × 10??; rs10782001, combined P = 4 × 10??; and rs12586317, combined P = 6 × 1??) and purely cutaneous psoriasis (rs4795067, combined P = 1 × 10??; rs10782001, combined P = 2 × 10??; and rs12586317, combined P = 1 × 10??). We also replicated a recently identified association signal near RNF114 (rs495337, combined P = 2 × 10??).