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.     

Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10?1?). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10?3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10?2?, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.     

A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease

Mice that overexpress the human mutant amyloid precursor protein (hAPP) show learning deficits, but the apparent lack of a relationship between these deficits and the progressive beta-amyloid plaque formation that the hAPP mice display is puzzling. In the water maze, hAPP mice are impaired before and after amyloid plaque deposition. Here we show, using a new water-maze training protocol, that PDAPP mice also exhibit a separate age-related deficit in learning a series of spatial locations. This impairment correlates with beta-amyloid plaque burden and is shown in both cross-sectional and longitudinal experimental designs. Cued navigation and object-recognition memory are normal. These findings indicate that A beta overexpression and/or A beta plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimer's-disease-type pathologies.     

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ～ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.     

Perlecan: how does one molecule do so many things?

Perlecan is a large multi-domain extracellular matrix proteoglycan that plays a crucial role in tissue development and organogenesis. In vertebrates, perlecan functions in a diverse range of developmental and biological processes, from the establishment of cartilage to the regulation of wound healing. How can a single molecule modulate such a wide variety of processes? We suggest that perlecan employs the same basic mechanism, based on interactions with growth factors, morphogens and matrix proteins, to regulate each of these processes and that the local extracellular environment determines the function of perlecan and consequently its downstream effects on the structure and function of the organ. We discuss this hypothesis in relation to its role in three major vertebrate developmental processes: angiogenesis, chondrogenesis and endochondral ossification.     

Intensification of amphetamine-induced excitation by methysergide,a serotonergic receptor blocker

Summary Methysergide, a serotonergic receptor blocker, was studied to determine its effects against d-amphetamine-induced excitation as measured by convulsions elicited by handling in mice. Significant intensification (p<0.01) of the action of d-amphetamine was observed in mice. These results indicate that reduction in serotonergic activity in the central nervous system enhances excitation induced by d-amphetamine.This work was supported by the Pharmaceutical Manufacturer Association Starter Grant, No. 5 S01 RR 05654-06 and the Air Force Office of Scientific Research Grant. The authors are grateful to Ben Wiggins, Michael Wallace, Maria Salazar, and Sanford Futterman for their technical assistance. The authors are also grateful to Dr Boris Tabakoff for supplying the formula of the CSF used in this experiment and we are indebted to San Antonio College for the use of their computer facilities. Dr Blum is a Career Teacher in drug addiction sponsored by NIDA, grant No. 1-T01-DA00290-01.