Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease

Association studies offer a potentially powerful approach to identify genetic variants that influence susceptibility to common disease, but are plagued by the impression that they are not consistently reproducible. In principle, the inconsistency may be due to false positive studies, false negative studies or true variability in association among different populations. The critical question is whether false positives overwhelmingly explain the inconsistency. We analyzed 301 published studies covering 25 different reported associations. There was a large excess of studies replicating the first positive reports, inconsistent with the hypothesis of no true positive associations (P < 10(-14)). This excess of replications could not be reasonably explained by publication bias and was concentrated among 11 of the 25 associations. For 8 of these 11 associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. Thus, a sizable fraction (but under half) of reported associations have strong evidence of replication; for these, false negative, underpowered studies probably contribute to inconsistent replication. We conclude that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.     

Gut hormone PYY(3-36) physiologically inhibits food intake

Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY(3-36) (PYY(3-36)), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY(3-36) in rats inhibits food intake and reduces weight gain. PYY(3-36) also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY(3-36) increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY(3-36) inhibits food intake. PYY(3-36) also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY(3-36) significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY(3-36) may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.     

In the platypus a meiotic chain of ten sex chromosomes shares genes with the bird Z and mammal X chromosomes

Two centuries after the duck-billed platypus was discovered, monotreme chromosome systems remain deeply puzzling. Karyotypes of males, or of both sexes, were claimed to contain several unpaired chromosomes (including the X chromosome) that form a multi-chromosomal chain at meiosis. Such meiotic chains exist in plants and insects but are rare in vertebrates. How the platypus chromosome system works to determine sex and produce balanced gametes has been controversial for decades. Here we demonstrate that platypus have five male-specific chromosomes (Y chromosomes) and five chromosomes present in one copy in males and two copies in females (X chromosomes). These ten chromosomes form a multivalent chain at male meiosis, adopting an alternating pattern to segregate into XXXXX-bearing and YYYYY-bearing sperm. Which, if any, of these sex chromosomes bears one or more sex-determining genes remains unknown. The largest X chromosome, with homology to the human X chromosome, lies at one end of the chain, and a chromosome with homology to the bird Z chromosome lies near the other end. This suggests an evolutionary link between mammal and bird sex chromosome systems, which were previously thought to have evolved independently.     

Observation of an O8 molecular lattice in the epsilon phase of solid oxygen

Of the simple diatomic molecules, oxygen is the only one to carry a magnetic moment. This makes solid oxygen particularly interesting: it is considered a 'spin-controlled' crystal that displays unusual magnetic order. At very high pressures, solid oxygen changes from an insulating to a metallic state; at very low temperatures, it even transforms to a superconducting state. Structural investigations of solid oxygen began in the 1920s and at present, six distinct crystallographic phases are established unambiguously. Of these, the epsilon phase of solid oxygen is particularly intriguing: it exhibits a dark-red colour, very strong infrared absorption, and a magnetic collapse. It is also stable over a very large pressure domain and has been the subject of numerous X-ray diffraction, spectroscopic and theoretical studies. But although epsilon-oxygen has been shown to have a monoclinic C2/m symmetry and its infrared absorption behaviour attributed to the association of oxygen molecules into larger units, its exact structure remains unknown. Here we use single-crystal X-ray diffraction data collected between 13 and 18 GPa to determine the structure of epsilon-oxygen. We find that epsilon-oxygen is characterized by the association of four O2 molecules into a rhombohedral molecular unit, held together by what are probably weak chemical bonds. This structure is consistent with existing spectroscopic data, and further validated by the observation of a newly predicted Raman stretching mode.     

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.     

List of Montana Scolytidae (Coleoptera) and notes on new records

Listed are 96 species of Scolytidae (Coleoptera) from Montana. Eighteen species reported from Montana for the first time are: Scierus pubescens Swaine, Hylastinus obscurus (Marsham), Hylesinus aculeatus Say, Hylesinus californicus (Swaine), Hylesinus criddlei (Swaine), Pseudohylesinus granulatus (LeConte), Dendroctunus punctatus LeConte, Phloeosinus hoferi Blackman, Phloeosinus pini Swaine, Carphoborus pinicolens Wood, Scolytus subscaber LeConte, Ips grandicollis (Eichhoff), Trypodendron betulae Swaine, Trypodendron retusum (LeConte), Trypophloeus populi Hopkins, Procryphalus mucronatus, (LeConte), Pityophthorus alpinensis G. Hopping, and Gnathotrichus denticulatus Blackman.     

Bionomics of the cone spittlebug, Aphrophora canadensis (Homoptera: Cercopidae) on mugo pine in Idaho

The spittlebug, Aphrophora canadensis Walley (Homoptera: Cercopidae), was discovered at Moscow, Idaho, in 1979 infesting Pinus mugo Turra, an exotic ornamental pine. Masses of spittle, densely populated with nymphs, have continued to be abundant since then. The nymphs congregated and fed mainly on cones and did not cause visible reddening of foliage that is typical of other pine-infesting spittlebugs. Immature stages and behavior are described for the first time and are compared to other nearctic pine-infesting species. Beginning in mid-August, eggs were laid under fascicle sheaths at the bases of needles, where they overwintered. Nymphs appeared in late April and began transforming to adults in mid-July. Mating occurred from early August to late September. Adults lingered in diminishing numbers until mid-October.