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Key Points Obesity is an important disease globally, and has resulted in significant increases in morbidity and mortality in both the developed and developing worlds. There are many proposed explanations for the current obesity epidemic, but it is clear that genetics plays a significant part in whether a person becomes obese by affecting susceptibility to the current obesogenic environment, which is characterized by easy access to high-calorie food and reduced energy expenditure owing to decreased levels of physical activity in daily life. Although the precise physiological basis of obesity remains unclear, skewed energy balance, abnormalities of fat storage and mobilization, and disordered feeding behaviour may all play a part. Both genome-wide linkage scans and candidate gene association studies have had limited success in identifying genes underlying non-syndromic obesity, although genes responsible for monogenic obesity have been identified. Recently, the genome-wide association scan method has been used to successfully identify many novel SNPs associated with non-syndromic obesity. These results have significantly increased the number of obesity-related loci for which there is strong statistical evidence at the genome-wide level. The question remains why analysis of SNPs has not identified any variants of sufficiently large genetic effect to account for the level of heritability observed in obesity. Other forms of genomic variation may account for this, for example, low frequency SNPs, copy number variants and epigenetic modifications. Key strategies for the future of genetic studies in obesity include improving subject selection, phenotype measurement, and genome-wide study design. A systems-based approach to synthesizing genome-wide data sets is likely to be a fruitful approach to identifying obesity genes. Recent genome-wide studies have identified many common variants that are associated with non-syndromic obesity, providing new opportunities to explore its biological basis. Understanding the roles of epigenetics and of rare and copy number variants are important goals for the future. The last few years have seen major advances in common non-syndromic obesity research, much of it the result of genetic studies. This Review outlines the competing hypotheses about the mechanisms underlying the genetic and physiological basis of obesity, and then examines the recent explosion of genetic association studies that have yielded insights into obesity, both at the candidate gene level and the genome-wide level. With obesity genetics now entering the post-genome-wide association scan era, the obvious question is how to improve the results obtained so far using single nucleotide polymorphism markers and how to move successfully into the other areas of genomic variation that may be associated with common obesity.

We evaluated the presence/absence of proteins encoded by 14 077 genes in adipocytes obtained from different tissue samples using immunohistochemistry. By combining this with previously published adipocyte‐specific proteome data, we identified proteins associated with 7340 genes in human adipocytes. This information was used to reconstruct a comprehensive and functional genome‐scale metabolic model of adipocyte metabolism. The resulting metabolic model, iAdipocytes1809 , enables mechanistic insights into adipocyte metabolism on a genome‐wide level, and can serve as a scaffold for integration of omics data to understand the genotype–phenotype relationship in obese subjects. By integrating human transcriptome and fluxome data, we found an increase in the metabolic activity around androsterone, ganglioside GM2 and degradation products of heparan sulfate and keratan sulfate, and a decrease in mitochondrial metabolic activities in obese subjects compared with lean subjects. Our study hereby shows a path to identify new therapeutic targets for treating obesity through combination of high throughput patient data and metabolic modeling. Combining large‐scale immunohistochemical analysis and proteomics data, 7340 gene products are identified in human adipocytes. Based on this data, a genome‐scale metabolic model is reconstructed and used to integrate clinical and transcriptome data from lean and obese subjects. Synopsis Combining large‐scale immunohistochemical analysis and proteomics data, 7340 gene products are identified in human adipocytes. Based on this data, a genome‐scale metabolic model is reconstructed and used to integrate clinical and transcriptome data from lean and obese subjects. We simulated the metabolic differences between the individuals with different body mass indexes (BMIs) using transcriptome and fluxome data. An increase in the metabolic activity around androsterone, ganglioside GM2 and degradation products of heparan sulfate and keratan sulfate, and a decrease in mitochondrial metabolic activities are found in obese subjects compared with lean subjects. We simulated the change in lipid droplet (LD) size and found that lean subjects have large dynamic changes in LD formation compared with obese subjects. Besides enabling patient stratification, our study allows the identification of novel therapeutic targets for obesity.

Preterm birth places infants in an adverse environment that leads to abnormal brain development and cerebral injury through a poorly understood mechanism known to involve neuroinflammation. In this study, we integrate human and mouse molecular and neuroimaging data to investigate the role of microglia in preterm white matter damage. Using a mouse model where encephalopathy of prematurity is induced by systemic interleukin-1β administration, we undertake gene network analysis of the microglial transcriptomic response to injury, extend this by analysis of protein-protein interactions, transcription factors and human brain gene expression, and translate findings to living infants using imaging genomics. We show that DLG4 (PSD95) protein is synthesised by microglia in immature mouse and human, developmentally regulated, and modulated by inflammation; DLG4 is a hub protein in the microglial inflammatory response; and genetic variation in DLG4 is associated with structural differences in the preterm infant brain. DLG4 is thus apparently involved in brain development and impacts inter-individual susceptibility to injury after preterm birth. Inflammation mediated by microglia plays a key role in brain injury associated with preterm birth, but little is known about the microglial response in preterm infants. Here, the authors integrate molecular and imaging data from animal models and preterm infants, and find that microglial expression of DLG4 plays a role.

Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76_98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans.

Atopic dermatitis (AD) and asthma are characterized by IgE-mediated atopic (allergic) responses to common proteins (allergens), many of which are proteinases. Loci influencing atopy have been localized to a number of chromosomal regions 1 , including the chromosome 5q31 cytokine cluster 2 , 3 , 4 . Netherton disease is a rare recessive skin disorder in which atopy is a universal accompaniment 5 . The gene underlying Netherton disease ( SPINK5 ) 6 encodes a 15-domain serine proteinase inhibitor (LEKTI) which is expressed in epithelial and mucosal surfaces and in the thymus 6 , 7 . We have identified six coding polymorphisms in SPINK5 ( Table 1 ) and found that a Glu420→Lys variant shows significant association with atopy and AD in two independent panels of families. Our results implicate a previously unrecognized pathway for the development of common allergic illnesses. Table 1 Single-nucleotide polymorphisms in SPINK5

We have carried out a genome screen for atopic dermatitis (AD) and have identified linkage to AD on chromosomes 1q21, 17q25 and 20p. These regions correspond closely with known psoriasis loci, as does a previously identified AD locus on chromosome 3q21. The results indicate that AD is influenced by genes with general effects on dermal inflammation and immunity.

Background The consequences of preterm birth are a major public health concern with high rates of ensuing multisystem morbidity, and uncertain biological mechanisms. Common genetic variation may mediate vulnerability to the insult of prematurity and provide opportunities to predict and modify risk. Objective To gain novel biological and therapeutic insights from the integrated analysis of magnetic resonance imaging and genetic data, informed by prior knowledge. Methods We apply our previously validated pathway‐based statistical method and a novel network‐based method to discover sources of common genetic variation associated with imaging features indicative of structural brain damage. Results Lipid pathways were highly ranked by Pathways Sparse Reduced Rank Regression in a model examining the effect of prematurity, and PPAR (peroxisome proliferator‐activated receptor) signaling was the highest ranked pathway once degree of prematurity was accounted for. Within the PPAR pathway, five genes were found by Graph Guided Group Lasso to be highly associated with the phenotype: aquaporin 7 (AQP7), malic enzyme 1, NADP(+)‐dependent, cytosolic (ME1), perilipin 1 (PLIN1), solute carrier family 27 (fatty acid transporter), member 1 (SLC27A1), and acetyl‐CoA acyltransferase 1 (ACAA1). Expression of four of these (ACAA1, AQP7, ME1, and SLC27A1) is controlled by a common transcription factor, early growth response 4 (EGR‐4). Conclusions This suggests an important role for lipid pathways in influencing development of white matter in preterm infants, and in particular a significant role for interindividual genetic variation in PPAR signaling. We apply our previously validated pathway‐ and network‐based statistical methods to discover possible sources of common genetic variation associated with imaging features indicative of structural brain damage. Lipid pathways were highly ranked by Pathways Sparse Reduced Rank Regression in a model examining the effect of prematurity, and PPAR (peroxisome proliferator‐activated receptor) signaling was the highest ranked pathway once degree of prematurity was accounted for. This suggests an important role for lipid pathways in brain injury of prematurity, and in particular a significant role for interindividual genetic variation in PPAR signaling.

Key Points Obesity is a serious health issue in the developed world and is becoming increasingly important on a global scale. The development of an obesogenic environment, due to ease of access to highly calorific food and reduced energy expenditure in work and leisure activities, has increased the proportion of overweight individuals in society. Over and above the increase in overweight individuals, there has been a dramatic rise in those who can be defined as morbidly obese. As suggested by the 'thrifty gene' hypothesis, these individuals might possess 'obesity-promoting' genetic variants that were previously advantageous, but that now lead them to become morbidly obese in the current environment. The physiology of energy balance is complex, with the arcuate nucleus of the hypothalamus having a central role in this mechanism. Mouse models have been useful in initially highlighting many of the genes and proteins that are involved. Rare, monogenic forms of human obesity — such as mutations in genes that encode leptin, its receptor, pro-opiomelanocortin, and the melanocortin 4 receptor — have provided insights into the pathogenesis of obesity. There are also syndromes where obesity is a component of the phenotype; however, their aetiology is more complex. Heritability studies have demonstrated that genetics also has a significant role in common obesity, which is thought to be caused by a combination of multiple genetic and environmental factors. Using both candidate-gene and whole-genome linkage strategies, novel genes and regions have been found to be linked and/or associated with obesity phenotypes. Studies to define the roles of these genes and their products in the pathophysiological mechanisms that lead to obesity are currently in progress. New strategies, such as whole-genome association studies and the use of microarrays, could allow the identification of large numbers of genes that are involved in obesity in the near future. Obesity is an important cause of morbidity and mortality in developed countries, and is also becoming increasingly prevalent in the developing world. Although environmental factors are important, there is considerable evidence that genes also have a significant role in its pathogenesis. The identification of genes that are involved in monogenic, syndromic and polygenic obesity has greatly increased our knowledge of the mechanisms that underlie this condition. In the future, dissection of the complex genetic architecture of obesity will provide new avenues for treatment and prevention, and will increase our understanding of the regulation of energy balance in humans.

Philippe Froguel and colleagues report an association of variants near the gene encoding melatonin receptor 2 with fasting glucose levels and risk of type 2 diabetes. The association suggests a possible link between circadian rhythm and glucose homeostasis. In genome-wide association (GWA) data from 2,151 nondiabetic French subjects, we identified rs1387153, near MTNR1B (which encodes the melatonin receptor 2 (MT2)), as a modulator of fasting plasma glucose (FPG; P = 1.3 × 10 −7 ). In European populations, the rs1387153 T allele is associated with increased FPG (β = 0.06 mmol/l, P = 7.6 × 10 −29 , N = 16,094), type 2 diabetes (T2D) risk (odds ratio (OR) = 1.15, 95% CI = 1.08–1.22, P = 6.3 × 10 −5 , cases N = 6,332) and risk of developing hyperglycemia or diabetes over a 9-year period (hazard ratio (HR) = 1.20, 95% CI = 1.06–1.36, P = 0.005, incident cases N = 515). RT-PCR analyses confirm the presence of MT2 transcripts in neural tissues and show MT2 expression in human pancreatic islets and beta cells. Our data suggest a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway.

Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens 1 , 2 , 3 . The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4 – 6 ). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases ( N = 6,106; overall P = 9.6 × 10 −8 ). We found that the Mal S180L variant attenuated TLR2 signal transduction.