Genetic variation and effects on human eating behavior.

Feeding is a physiological process, influenced by genetic factors and the environment. In recent years, many studies have been performed to unravel the involvement of genetics in both eating behavior and its pathological forms: eating disorders and obesity. In this review, we provide a condensed introduction on the neurological aspects of eating and we describe the current status of research into the genetics of eating behavior, primarily focused on specific traits such as taste, satiation, and hunger. This is followed by an overview on the genetic studies done to unravel the heritable background of obesity and eating disorders. We examine the discussion currently taking place in the field of genetics of complex disorders and phenotypes on how to perform good and powerful studies, with the use of large-scale whole-genome association studies as one of the possible solutions. In the final part of this review, we give our view on the latest developments, including endophenotype approaches and animal studies. Studies of endophenotypes of eating behavior may help to identify core traits that are genetically influenced. Such studies would yield important knowledge on the underlying biological scaffold on which diagnostic criteria for eating disorders could be based and would provide information to influence eating behavior toward healthier living.

Common genetic variations in CCK, leptin, and leptin receptor genes are associated with specific human eating patterns.

Obesity has a heritable component; however, the heterogeneity of obesity complicates dissection of its genetic background. In this study, we therefore focused on eating patterns as specific traits within obesity. These traits have a heritable component; genes associated with a specific eating pattern have not yet been reported at the population level. In this study, we determined whether genetic variations in cholecystokinin (CCK) and leptin genes underlie specific eating patterns. We selected obese individuals showing extreme snacking behavior or use of excessive portion sizes from a large population-based sample (n = 17,357) from the Prospect-EPIC (European Prospective Study into Cancer and Nutrition) study. Using allele-specific PCRs, we tested several single nucleotide polymorphisms in the candidate genes and performed haplotype analysis. Obese carriers of common allelic variations in leptin or the leptin receptor gene had an increased risk to display extreme snacking behavior. In contrast, obese carriers of common allelic variations in CCK had an increased risk to eating increased meal sizes. In conclusion, we identified common allelic variants specifically associated with distinctly different eating patterns, namely extreme snacking behavior or excessive portion size.

Multimeric alpha-MSH has increased efficacy to activate the melanocortin MC4 receptor.

alpha-Melanocyte stimulating hormone (alpha-MSH) has a relatively low affinity for the melanocortin MC4 receptor. Constructs of multimeric alpha-MSH varying from one to eight subunits were synthesized to test whether they displayed an improved ability to bind to and activate the human melanocortin MC4 receptor. alpha-MSH subunits were coupled by a flexible linker and placed in front of an IRES-eGFP sequence. Efficacy for activation of the melanocortin MC4 receptor increased with every extra subunit, resulting in a 100 fold lower EC50 value of alpha-MSH8 when compared with alpha-MSH1. Furthermore, supernatant of cells transfected with alpha-MSH8 proved to have an increased affinity to the melanocortin MC4 receptor when compared to cells transfected with the other multimers. Together, these data show that multimeric alpha-MSH has improved ability to activate the human melanocortin MC4 receptor in vitro.

An embryonic-specific repressor element located 3' to the Agamma-globin gene influences transcription of the human beta-globin locus in transgenic mice.

OBJECTIVE: Persistent expression of the human fetal gamma-globin genes in the adult stage is often associated with naturally occurring deletions in the human beta-globin locus. The mapping of the 5' breakpoints of these deletions within the Agamma- to delta-globin intergenic region has suggested that regulatory elements involved in the silencing of the gamma-globin genes in the adult may be present. We previously identified two elements in this region, termed Enh and F, located 3' to the Agamma-globin gene acting as silencers in transient transfection assays. Here, we tested directly the in vivo significance of these elements in the developmental regulation of the human beta-like globin genes. MATERIALS AND METHODS. We selectively deleted both Enh and F elements in the context of a 185-kb human beta-globin locus PAC (P1 phage artificial chromosome) and tested the effects of this deletion on the expression of the human P-like globin genes in transgenic mice. RESULTS: The Enh/F deletion resulted in an increase in epsilon- and gamma-globin mRNA levels in the embryonic yolk sac stage of erythropoiesis, which appears to be due to an increase in the rate of transcription rather than to an increase in the number of cells transcribing the human globin locus. However, the human developmental switching from fetal gamma-globin to adult beta-globin gene expression in transgenic mice was not affected by this deletion. CONCLUSION: These results identify Enh and F as locus-wide regulatory elements capable of down-regulating transcription of the human beta-globin locus in an embryonic-specific manner.

Brief report: the dopamine-3-receptor gene (DRD3) is associated with specific repetitive behavior in autism spectrum disorder (ASD).

Recently the DRD3 gene has been associated with ASD in two independent samples. Follow up analysis of the risk allele of the SNP rs167771 in 91 subjects revealed a significant association with a specific type of repetitive behavior: the factor "insistence on sameness" (IS) derived from the Autism Diagnostic Interview. This risk allele was associated with a decreased risk for IS, but not with any other symptomatology. Further study and replication of this finding is necessary, bearing in mind that these results would not be statistically significant if corrected for multiple testing.

A common variant in DRD3 receptor is associated with autism spectrum disorder.

BACKGROUND: The presence of specific and common genetic etiologies for autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) was investigated for 132 candidate genes in a two-stage design-association study. METHODS: 1,536 single nucleotide polymorphisms (SNPs) covering these candidate genes were tested in ASD (n = 144) and ADHD (n = 110) patients and control subjects (n = 404) from The Netherlands. A second stage was performed with those SNPs from Stage I reaching a significance threshold for association of p < .01 in an independent sample of ASD patients (n = 128) and controls (n = 124) from the United Kingdom and a Dutch ADHD (n = 150) and control (n = 149) sample. RESULTS: No shared association was found between ASD and ADHD. However, in the first and second ASD samples and in a joint statistical analysis, a significant association between SNP rs167771 located in the DRD3 gene was found (joint analysis uncorrected: p = 3.11 x 10(-6); corrected for multiple testing and potential stratification: p = .00162). CONCLUSIONS: The DRD3 gene is related to stereotyped behavior, liability to side effects of antipsychotic medication, and movement disorders and may therefore have important clinical implications for ASD.

Variations in the uncoupling protein-3 gene are associated with specific obesity phenotypes.

OBJECTIVE: Uncoupling protein 3 (UCP-3) uncouples oxidative metabolism from ATP synthesis, resulting in the production of heat instead of energy storage. Single nucleotide polymorphisms (SNPs) in UCP-3 might result in a reduced function or expression of UCP-3 and therefore lead to an increased capacity to store energy as fat. DESIGN: We conducted a population-based, cross-sectional single-center study among 400 Dutch men between 40 and 80 years. METHODS: Seven SNPs in the UCP-3 gene were genotyped by means of an allele-specific real-time TaqMan PCR. Linear regression analyses were performed to examine the independent effects of these SNPs on obesity phenotypes. RESULTS: We found a significant association between homozygosity for the minor allele of rs647126, rs1685356, and rs2075577 and an increase in body mass index (BMI; P=0.033, P=0.016, and P=0.019 respectively). Heterozygosity for rs1685354 was associated with a significant decrease in visceral fat mass (P=0.030). CONCLUSIONS: Our results suggest that genetic variations in the UCP-3 gene are associated with an increase in BMI. A plausible mechanism by which these SNPs lead to an increase in BMI is that due to these SNPs, the UCP-3 activity might be decreased. As a result, uncoupling activity may also decrease, which will lead to an increase in body weight and BMI.

Stochastic patterns in globin gene expression are established prior to transcriptional activation and are clonally inherited.

We have undertaken a detailed characterization of mouse globin gene expression patterns in the nucleus and cytoplasm of single erythroid cells. We demonstrate an imbalance of alpha- versus beta-globin expression in a significant proportion of cells both in nuclear transcription patterns and cytoplasmic mRNA levels. Clonal cell analysis showed these expression patterns to be clonally inherited, while analysis of a multicopy transgenic locus showed an all-or-none effect in the activation of all the genes in one locus. These data provide strong evidence for a stochastic basis of globin gene activation resulting in heritable all-or-none expression patterns.

Multiple interactions between regulatory regions are required to stabilize an active chromatin hub.

The human beta-globin locus control region (LCR) is required for the maintenance of an open chromatin configuration of the locus. It interacts with the genes and the hypersensitive regions flanking the locus to form an active chromatin hub (ACH) transcribing the genes. Proper developmental control of globin genes is largely determined by gene proximal regulatory sequences. Here, we provide the first functional evidence of the role of the most active sites of the LCR and the promoter of the beta-globin gene in the maintenance of the ACH. When the human beta-globin gene promoter is deleted in the context of a full LCR, the ACH is maintained with the beta-globin gene remaining in proximity. Additional deletion of hypersensitive site HS3 or HS2 of the LCR shows that HS3, but not HS2, in combination with the beta-globin promoter is crucial for the maintenance of the ACH at the definitive stage. We conclude that multiple interactions between the LCR and the beta-globin gene are required to maintain the appropriate spatial configuration in vivo.