Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits

Aristotle's 'Cosmic Nose' Argument for the Uniqueness of the World

David Furley's work on the cosmologies of classical antiquity is structured around what he calls "two pictures of the world." The first picture, defended by both Plato and Aristotle, portrays the universe, or all that there is (to pan), as identical with our particular ordered world-system. Thus, the adherents of this view claim that the universe is finite and unique. The second system, defended by Leucippus and Democritus, portrays an infinite universe within which our particular kosmos is only one of countless kosmoi. Aristotle's argument in De caelo I.9 that the world is necessarily unique is an important contribution to this debate. This argument holds interest because it shows Aristotle wrestling with an apparent inconsistency in his own philosophy, as deeply-held convictions within his cosmology collide with an equally deeply-held conviction within his metaphysics. The following three principles, each of which Aristotle appears committed to, are inconsistent: -/- The cosmic uniqueness principle. The world is necessarily unique. The cosmic form principle. The world is an ordered, structured unity. As such, the world has a form. The possibility of multiple instantiation principle. For all F, if F is a form, it is possible that there exist multiple Fs. In De caelo I.9, Aristotle argues that we can establish the uniqueness of the universe, reject the multiple instantiation principle, yet still retain the distinction between 'this world' and 'world in general,' if the following is true (as it is): the world takes up all the matter that exists. Aristotle illustrates this argument with one of the stranger analogies in his corpus: imagine an aquiline nose that takes up all the flesh in the universe. If this were so, then there could not exist any other aquiline objects whatsoever. (For this reason, we dub the De caelo I.9 argument the 'Cosmic Nose argument.') This paper is an interpretation of how this argument is supposed to proceed and an assessment of its success. The first section states the problem Aristotle is confronted with, sorts through Aristotle's various statements of the Cosmic Nose argument, which exhibit some sloppiness, and reconstructs charitably a single argument. We also spend some time examining the significance of Aristotle's example of a gigantic aquiline nose. We argue that, even charitably reconstructed, the argument appears to commit a serious modal fallacy. The remainder of the paper explores whether this modal fallacy can be overcome. We conclude that, although not a cogent argument for the uniqueness of the world (as this would require a significant revision of our current astronomy), the Cosmic Nose argument does succeed on its own terms. However, it should not be regarded as a free-standing argument for the uniqueness of the world. Instead, it depends crucially on the earlier argument in De caelo I.8 for the universe's uniqueness; De caelo I.9 should be viewed as an attempt to extend the conclusion of De caelo I.8 and to show how this conclusion can be made consistent with Aristotle's metaphysical principles about the nature of form