A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.     

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.     

Identification of ten loci associated with height highlights new biological pathways in human growth

Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in >10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for approximately 2% of the population variation in height. Individuals with < or =8 height-increasing alleles and > or =16 height-increasing alleles differ in height by approximately 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait.     

Evaluating organizations: A systems and contingency approach

It has become increasingly difficult to keep pace with the amount of information being generated about how to evaluate organizations. If it were not enough that the situation is made difficult by the sheer mass of material on evaluation, clarity is further hindered by many of the publications on the subject failing to make explicit the principles and assumptions upon which they are based. This was the situation confronting the authors when they began a national project with the National Association of Councils for Voluntary Service on the evaluation of the performance of Councils for Voluntary Service. In an attempt to bring some order to the field, this paper adopts a systems and contingency approach to elucidate the nature and practical usefulness of the different methods of evaluation. It first seeks, using some tools of Checkland's soft systems methodology, to present a systematic analysis of the subject of evaluation. Then, in the light of the analysis, an attempt is made to formulate a simple classification of approaches to evaluation which serves to match the different forms of evaluation to the contexts in which they are most appropriate for use.     

Total systems intervention: A research program

The development of TSI represents a real advance in management science in our view. Further developments are necessary however. This Research Note has outlined what we currently consider to be key issues in this development. We welcome other criticisms and suggestions. We invite you to join with us in this project.     

Ethylene, the natural regulator of leaf abscission

Natural leaf fall is triggered by increased ethylene production in senescing cells close to abscission zones.     

Epithelial cell swelling during incubation of rat small intestine in vitro

Résumé L'augmentation du fluide du tissu de l'intestin grèle incubé in vitro s'accompagne d'un accroissement du volume des cellules épithéliales.     

Influence of the pineal gland on the reproductive system of the male house mouse

Summary Procedures designed to express pineal-mediated antigonadotropic activity were performed upon male house mice. Neither blinding nor blinding plus olfactory bulbectomy of house mice resulted in testicular involution within 12 weeks. The pineal gland appears to be of little significance to reproduction in the house mouse.Supported by NICHHD grant No. HDO 7119-092.Supported by NICHHD grant No. 5P5 OHDO 8338.Supported by NSF grant No. SPI 7922 372.