NEGR1 Research Articles

Impact of NEGR1 genetic variability on psychological traits of patients with eating disorders.

Genetics variants in the NEGR1 gene, strongly expressed in the brain, have been reported to affect the neuronal control of food intake therefore inducing obesity. With the same rationale, we hypothesized that this genetic variability may be associated with psychological traits commonly displayed by eating disorder (ED) patients and/or with the risk for the disorder. We analyzed 21 tag-single-nucleotide polymorphisms (SNPs) in the coding sequence and adjacent regions of the NEGR1 gene. A total of 169 ED patients (106 with anorexia nervosa (AN) and 63 with bulimia nervosa (BN)) and 312 healthy subjects were genotyped. Personality traits and general psychopathological symptoms were assessed by the Eating Disorders Inventory Test-2 (EDI-2) and Symptom Checklist 90 Revised inventories. None of the SNPs or haplotypes analyzed were associated with a greater risk of ED or correlated with anthropometric parameters. However, in patients with BN, four SNPs (rs12740031, rs10789322, rs6659202 and rs591540) correlated with the scores in Drive for Thinness (DT), Ineffectiveness (I) and Interoceptive Awareness (IA) (Bonferroni-P<0.05 in all instances). The first two SNPs along with rs954299 and rs2422021 formed a haplotype block, which showed a consistent association with the EDI-2 score in BN patients (Bonferroni-P=0.01). A subsequent three-SNP sliding-window approach identified a central area, encompassing both the haplotype block and the individually relevant SNPs that strongly correlated with the scores of BN patients in DT, I, IA and Bulimia. No associations were identified in the AN group. These preliminary results indicate that NEGR1 could be an important locus influencing certain personality dimensions in BN patients.

Common variants in BDNF, FAIM2, FTO, MC4R, NEGR1, and SH2B1 show association with obesity-related variables in Spanish Roma population.

The objective of this study is to investigate the association between previously GWAS identified genetic variants predisposing to obesity in Europeans and obesity-related phenotypes in Roma population. A total of 24 representative single nucleotide polymorphisms (SNPs) were genotyped in 372 individuals belonging to 50 extended families of Roma population. SNPs were tested for association with seven quantitative obesity-related phenotypes in the PLINK program. Risk variants in NEGR1, FAIM2, FTO, and SH2B1 genes were associated with increased adiposity accumulation in Roma population with effect sizes between 0.21 and 0.34 Z-scores for each copy of the BMI increasing allele. Additionally, variants in BDNF and MC4R were significantly associated with adiposity distribution but not with overall fatness. No significant association was detected between obesity-related phenotypes and variants in the first intron of the FTO gene (e.g., rs9939609). The results of this study suggest that SNPs in or near six genes (BDNF, FAIM2, FTO, MC4R, NEGR1, and SH2B1) are significantly associated with body fat accumulation and distribution in Roma people. However, the association observed among variants in the first intron of FTO and obesity in European derived populations is not evident in the analyzed Roma sample.

Contribution of 32 GWAS-identified common variants to severe obesity in European adults referred for bariatric surgery.

The prevalence of severe obesity, defined as body mass index (BMI) ≥35.0 kg/m2, is rising rapidly. Given the disproportionately high health burden and healthcare costs associated with this condition, understanding the underlying aetiology, including predisposing genetic factors, is a biomedical research priority. Previous studies have suggested that severe obesity represents an extreme tail of the population BMI variation, reflecting shared genetic factors operating across the spectrum. Here, we sought to determine whether a panel of 32 known common obesity-susceptibility variants contribute to severe obesity in patients (n = 1,003, mean BMI 48.4±8.1 kg/m2) attending bariatric surgery clinics in two European centres. We examined the effects of these 32 common variants on obesity risk and BMI, both as individual markers and in combination as a genetic risk score, in a comparison with normal-weight controls (n = 1,809, BMI 18.0–24.9 kg/m2); an approach which, to our knowledge, has not been previously undertaken in the setting of a bariatric clinic. We found strong associations with severe obesity for SNP rs9939609 within the FTO gene (P = 9.3×10−8) and SNP rs2815752 near the NEGR1 gene (P = 3.6×10−4), and directionally consistent nominal associations (P<0.05) for 12 other SNPs. The genetic risk score associated with severe obesity (P = 8.3×10−11) but, within the bariatric cohort, this score did not associate with BMI itself (P = 0.264). Our results show significant effects of individual BMI-associated common variants within a relatively small sample size of bariatric patients. Furthermore, the burden of such low-penetrant risk alleles contributes to severe obesity in this population. Our findings support that severe obesity observed in bariatric patients represents an extreme tail of the population BMI variation. Moreover, future genetic studies focused on bariatric patients may provide valuable insights into the pathogenesis of obesity at a population level.

Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations

Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993-2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987-1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991-1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10(-5)) and inversely associated with percentage of calories derived from carbohydrate (βmeta = -0.2796 (standard error, 0.0709); P = 8 × 10(-5)). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)(2)) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m(2), 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake.

Obesity-related genetic variants, human pigmentation, and risk of melanoma

Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5, NEGR1, FLJ35779, ETV5, CADM2, and NUDT3 genes were nominally significantly associated with hair color among 5,876 individuals of European ancestry. The genetic score combining 35 independent obesity-risk loci was significantly associated with darker hair color (beta-coefficient per ten alleles = 0.12, P value = 4 × 10(-5)). However, single SNPs or genetic scores showed non-significant association with tanning ability. We further examined the SNPs at the FTO locus for their associations with pigmentation and risk of melanoma. Among the 783 SNPs in the FTO gene with imputation R (2) quality metric >0.8 using the 1,000 genome data set, ten and three independent SNPs were significantly associated with hair color and tanning ability respectively. Moreover, five independent FTO SNPs showed nominally significant association with risk of melanoma in 1,804 cases and 1,026 controls. But none of them was associated with obesity or in linkage disequilibrium with obesity-related variants. FTO locus may confer variation in human pigmentation and risk of melanoma, which may be independent of its effect on obesity.

Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4Rgenes to obesity in Mexican children

BackgroundRecent genome wide association studies (GWAS) and previous positional linkage studies have identified more than 50 single nucleotide polymorphisms (SNPs) associated with obesity, mostly in Europeans. We aimed to assess the contribution of some of these SNPs to obesity risk and to the variation of related metabolic traits, in Mexican children.MethodsThe association of six European obesity-related SNPs in or near FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes with risk of obesity was tested in 1,463 school-aged Mexican children (Ncases = 514; Ncontrols = 949). We also assessed effects of these SNPs on the variation of body mass index (BMI), fasting serum insulin levels, fasting plasma glucose levels, total cholesterol and triglyceride levels, in a subset of 1,171 nonobese Mexican children.ResultsWe found a significant effect of GNPDA2 rs10938397 on risk of obesity (odds ratio [OR] = 1.30; P = 1.34 × 10-3). Furthermore, we found nominal associations between obesity risk or BMI variation and the following SNPs: ENPP1 rs7754561, MC4R rs17782313 and NEGR1 rs2815752. Importantly, the at-risk alleles of both MC4R rs17782313 and NPC1 rs1805081 showed significant effect on increased fasting glucose levels (β = 0.36 mmol/L; P = 1.47 × 10-3) and decreased fasting serum insulin levels (β = −0.10 μU/mL; P = 1.21 × 10-3), respectively.ConclusionOur present results suggest that some obesity-associated SNPs previously reported in Europeans also associate with risk of obesity, or metabolic quantitative traits, in Mexican children. Importantly, we found new associations between MC4R and fasting glucose levels, and between NPC1 and fasting insulin levels.

Study of eight GWAS-identified common variants for association with obesity-related indices in Chinese children at puberty

Genome-wide association studies (GWAS) have identified some common variants associated with obesity risk in European descents. However, their influences on obesity-related indices for the Chinese children at puberty are not widely clear yet. To address this question, we conducted a study that aims to examine effects of eight previously reported GWAS single-nucleotide polymorphisms (SNPs) on four obesity-related indices in a sample of Chinese children aged 10-12 years. Anthropometric indices were measured in 1688 children (10.8±0.4 years, boys=877, girls=811) from Shanghai Children's Sleep Project. Eight SNPs within the NEGR1, TMEM18, GNPDA2, MTCH2, SH2B1, FTO, MC4R and KCTD15 genes were genotyped using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Linear regression and genetic additive model were used to test for the association betweens SNPs and obesity-related indices (weight, body mass index (BMI), waist-to-height ratio and body fat). Only two SNPs, rs6548238 (TMEM18) and rs9939609 (FTO), were associated with all obesity-related indices with P<0.05. After adjusting for multiple tests, rs9939609 is the only one significantly associated with the indices. SNPs, rs6548238 and rs9939609 explained 0.28% (P=0.03) and 0.54% (P=0.002) variance of BMI, respectively, that are almost two-fold of the previously GWAS-reported effects. In addition, rs6548238 was associated with four indices in boys, but not in girls. In contrast, rs9939609 showed a strong association only in girls. Six other SNPs, rs2815752 (NEGR1), rs10938397 (GNPDA2), rs10838738 (MTCH2), rs7498665 (SH2B1), rs17782313 (MC4R) and rs11084753 (KCTD15), were not associated with obesity (P>0.05). Variants of TMEM18 and FTO are associated with obesity indices during puberty in Chinese children, but candidate SNPs of NEGR1, GNPDA2, MTCH2, SH2B1, MC4R and KCTD15 have no significant effects on obesity indices. The findings also suggest that obesity susceptibility genes may exert more obvious effects during children's puberty. In addition, gender differences may exist in various obesity-related genes.

P1-34 Can associations between prenatal nutrition and body mass index be explained by common genetic variants? Findings from the Dutch hunger winter families study

Genome wide association (GWAS) studies have identified single nucleotide polymorphisms (SNPs) related to body mass index (BMI: kg/m2). Associations have also been reported between fetal malnutrition and BMI. We use...

Implication of European-derived adiposity loci in African Americans

Recent genome-wide association studies (GWAS) have identified multiple novel loci associated with adiposity in European-derived study populations. Limited study of these loci has been reported in African Americans. Here we examined the effects of these previously identified adiposity loci in African Americans. A total of 46 representative single-nucleotide polymorphisms (SNPs) in 19 loci that were previously reported in GWAS in Europeans (including FTO and MC4R) were genotyped in 4992 subjects from six African-American cohorts. These SNPs were tested for association with body mass index (BMI) after adjustment for age, gender, disease status and population structure in each cohort. Meta-analysis was conducted to combine the results. Meta-analysis of 4992 subjects revealed seven SNPs near four loci, including NEGR1, TMEM18, SH2B1 /ATP2A1 and MC4R, showing significant association at 0.005<P<0.05, and had effect sizes between 0.04 and 0.06 s.d. units (or 0.30 to 0.44 g m(-2)) of BMI for each copy of the BMI-increasing allele. The most significantly associated SNPs (rs9424977, rs3101336 and rs2568958) are located in the NEGR1 gene (P=0.005, 0.020 and 0.019, respectively). We replicated the association of variants at four loci in six African-American cohorts that demonstrated a consistent direction of association with previous studies of adiposity in Europeans. These loci are all highly expressed in the brain, consistent with an important role for central nervous system processes in weight regulation. However, further comprehensive examination of these regions may be necessary to fine map and elucidate for possible genetic differences between these two populations.

Obesity-susceptibility loci have a limited influence on birth weight: a meta-analysis of up to 28,219 individuals

High birth weight is associated with adult body mass index (BMI). We hypothesized that birth weight and BMI may partly share a common genetic background. The objective was to examine the associations of 12 established BMI variants in or near the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, BCDIN3D, SH2B1, FTO, MC4R, and KCTD15 genes and their additive score with birth weight. A meta-analysis was conducted with the use of 1) the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, Hertfordshire, Fenland, and European Youth Heart Study cohorts (n(max) = 14,060); 2) data extracted from the Early Growth Genetics Consortium meta-analysis of 6 genome-wide association studies for birth weight (n(max) = 10,623); and 3) all published data (n(max) = 14,837). Only the MTCH2 and FTO loci showed a nominally significant association with birth weight. The BMI-increasing allele of the MTCH2 variant (rs10838738) was associated with a lower birth weight (β ± SE: -13 ± 5 g/allele; P = 0.012; n = 23,680), and the BMI-increasing allele of the FTO variant (rs1121980) was associated with a higher birth weight (β ± SE: 11 ± 4 g/allele; P = 0.013; n = 28,219). These results were not significant after correction for multiple testing. Obesity-susceptibility loci have a small or no effect on weight at birth. Some evidence of an association was found for the MTCH2 and FTO loci, ie, lower and higher birth weight, respectively. These findings may provide new insights into the underlying mechanisms by which these loci confer an increased risk of obesity.