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

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.Molecular Epidemiolog

Does a Comparison View Improve the Reliability of Staging Wrist Osteoarthritis?

Background: Radiological grading of wrist osteoarthritis associated with scaphoid nonunion advanced collapse (SNAC) can be difficult. A comparison radiograph of the contralateral healthy wrist and an educational training in the various SNAC stages may improve reliability. Our purposes were to evaluate the difference in the reliability: (1) between observers who rate SNAC wrists with and without a comparison radiograph; and (2) between observers who receive training prior to ratings and those who do not. Methods: In this cross-sectional survey study, 82 fully trained orthopedic or hand surgeons rated anteroposterior radiographs of 19 patient wrists following a scaphoid nonunion based on SNAC stages 0 to 4. Observers were randomized online in 4 groups: one group rated unilateral views without training, a second group unilateral views with training, a third group bilateral views without training, and a fourth group bilateral views with training. Training included a 1-page clarification of the SNAC stages. Interobserver agreement was calculated using kappa statistics. Results: There was no significant difference between agreement between observers who rated unilateral radiographs (κ = 0.55) and who rated bilateral radiographs (κ = 0.58) (P =.14), nor between agreement between observers who received training (κ = 0.59) and who did not (κ = 0.54) (P =.058). Conclusions: The use of an additional comparison view and/or training does not seem to be clinically relevant in SNAC staging. There is room for improvement in the way we assess patients with SNAC wrists

Prenatal and early life influences on epigenetic age in children: A study of mother-offspring pairs from two cohort studies.

DNA methylation based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. Age acceleration (AA) was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging

Free fibula flap for humerus segmental reconstruction: report on 13 cases

In the period between 1994 and 2004, 13 patients (10 male, 3 female) presenting with post-traumatic defects to the humerus were treated with vascularised fibula graft. Age ranged from 21 to 62 (mean 37) years. Length of the bony defect ranged from 6 to 16 cm. Graft fixation was performed with plates in 12 cases, and in one case only screws were used. All patients were clinically reviewed between 120 days and 14 months after surgery. In one patient the flap was lost and a second free fibula flap was performed to achieve the reconstructive goal. Mean time for segmental bony union was 6 months (range from 3 to 13 months). Vascularised fibula graft allows for a successful humerus reconstruction when traditional techniques provide unsatisfactory results