A Common Genetic Variant Is Associated with Adult and Childhood Obesity (original) (raw)
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BMC Medical Genetics, 2009
Background In a genome-wide association study performed in the Framingham Offspring Cohort, individuals homozygous for the rs7566605 C allele located upstream of insulin-induced gene 2 (INSIG2) were reported to incur an increased risk of obesity. This finding was later replicated in four out of five populations examined. The goal of the study reported here was to assess the role of the INSIG2 single nucleotide polymorphism (SNP) in susceptibility to obesity in the prospective longitudinal Atherosclerosis Risk in Communities (ARIC) study (n = 14,566) and in three other cohorts: the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 3,888), the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 4,766), and extremely obese and lean individuals ascertained at the University of Ottawa (n = 1,502). The combined study sample is comprised of 24,722 white, African-American, and Mexican-American participants. Methods Differences in mean body mass index (BMI) and...
Obesity is becoming an escalating global epidemic in many parts of the world and results in a huge rise of sanity costs due to its associate comorbidities. In this sense, body weight regulation depends on a combination of interactions between genetic and environmental factors. Among inheritance factors, body weight is normally a polygenic condition determined by the presence of genes of high prevalence but with a low relevant effect. In the last years, Candidate Genes Analyses and Genome Wide Association Studies (GWAS) have become very useful strategies to detect new polymorphisms and copy number variants (CNVs) associated with obesity and its related comorbidities. From these studies, more than a hundred genetic variants involved in metabolic pathways including adipogenesis, energy intake, lipolysis or energy expenditure have been found. These findings along with epigenetics and nutrigenetics are the basis to the development of new tools that would allow predicting individual obesi...
BMC medical genetics, 2006
Obesity is a major public health problem. Body mass index (BMI) is a highly heritable phenotype but robust associations of genetic polymorphisms to BMI or other obesity-related phenotypes have been difficult to establish. Recently a large genetic association study showed evidence for association of the single nucleotide polymorphism (SNP) rs7566605, which lies 10 Kb 5' to the first exon of the insulin-induced gene 2 (INSIG-2), with obesity in several cohorts. We tested this polymorphism for association with body mass related phenotypes in a large family study whose mean BMI was consistent with moderate overweight. We studied 1428 members of 248 British Caucasian families who had been ascertained through a proband with hypertension. We measured BMI, waist and hip circumference, and plasma levels of leptin. We genotyped the rs7566605 SNP using a restriction fragment length polymorphism assay, and carried out a family-based association test for quantitative traits related to obesit...
Comment on "A Common Genetic Variant Is Associated with Adult and Childhood Obesity
Science, 2007
Herbert et al. (Reports, 14 April 2006, p. 279) reported an association between the INSIG2 gene variant rs7566605 and obesity in four sample populations, under a recessive model. We attempted to replicate this result in 10,265 Caucasian individuals, combining family-based, case-control, and general population studies, but found no support for a major role of this variant in obesity.
Common body mass index-associated variants confer risk of extreme obesity
Human Molecular Genetics, 2010
To investigate the genetic architecture of severe obesity, we performed a genome-wide association study of 775 cases and 3197 unascertained controls at 550 000 markers across the autosomal genome. We found convincing association to the previously described locus including the FTO gene. We also found evidence of association at a further six of 12 other loci previously reported to influence body mass index (BMI) in the general population and one of three associations to severe childhood and adult obesity and that cases have a higher proportion of riskconferring alleles than controls. We found no evidence of homozygosity at any locus due to identity-by-descent associating with phenotype which would be indicative of rare, penetrant alleles, nor was there excess genomewide homozygosity in cases relative to controls. Our results suggest that variants influencing BMI also contribute to severe obesity, a condition at the extreme of the phenotypic spectrum rather than a distinct condition.
Genetics of obesity: an overview of current approaches and advancement
Elucidation of obesity susceptibility genes through genome wide approaches as well as candidate gene approaches provides great promise in ultimately determining the genetic underpinnings of obesity. The complex nature of human obesity stems from the multiple interaction of several genes that control the physiology of food intake, energy expenditure, development of the body, and behavioural patterns towards food intake, and the environment. According to twin, adoptees and family studies, genetic factors account for 40-70% of the variability observed in human adiposity. Twin studies supported that the heritability of adiposity is higher than other quantitative traits. The heritability of obesity traits has been further evidenced by identification of quantitative trait loci (QTL) and genes through methods such as genome-wide scans (studies conducted on unrelated obese individuals), linkage analyses (conducted in families), and association studies (investigating the correlation between obesity and polymorphisms). The number of contributing genes, however, is still unknown. Although research on the genetic basis of obesity has advanced, the mechanisms underlying the condition are still complex due to its heterogeneity even within families.
A Genome-Wide Association Study on Obesity and Obesity-Related Traits
PLoS ONE, 2011
Large-scale genome-wide association studies (GWAS) have identified many loci associated with body mass index (BMI), but few studies focused on obesity as a binary trait. Here we report the results of a GWAS and candidate SNP genotyping study of obesity, including extremely obese cases and never overweight controls as well as families segregating extreme obesity and thinness. We first performed a GWAS on 520 cases (BMI.35 kg/m 2 ) and 540 control subjects (BMI,25 kg/m 2 ), on measures of obesity and obesity-related traits. We subsequently followed up obesity-associated signals by genotyping the top ,500 SNPs from GWAS in the combined sample of cases, controls and family members totaling 2,256 individuals. For the binary trait of obesity, we found 16 genome-wide significant signals within the FTO gene (strongest signal at rs17817449, P = 2.5610 212 ). We next examined obesity-related quantitative traits (such as total body weight, waist circumference and waist to hip ratio), and detected genome-wide significant signals between waist to hip ratio and NRXN3 (rs11624704, P = 2.67610 29 ), previously associated with body weight and fat distribution. Our study demonstrated how a relatively small sample ascertained through extreme phenotypes can detect genuine associations in a GWAS.
The fat tail of obesity as told by the genome
Current Opinion in Clinical Nutrition and Metabolic Care, 2008
Purpose of review-Many genes affect pathways that predispose to and protect against obesity. We ask how many different variants affect human obesity and how common are they? Recent findings-The current generation of genome-wide association scans is moderately powered to detect and replicate associations between single nucleotide polymorphisms, or common copy number variations and common diseases. They are not designed either to find rare germline variants or those somatic changes, unique to an individual, that arise with high frequency in adult stem cells. They do not directly assay the epigenetic reprogramming of outcomes related to maternal or environmental exposures. Summary-There are more gene variants, more gene-gene and gene-environmental interactions leading to obesity than current GWAS studies can validate. Those genetic associations that can be verified provide valuable insight into the pathways contributing to human obesity.