Objective To report the genome-wide significant and/or replicable risk variants for alcohol dependence and explore their potential biological functions. Methods We searched in PubMed for all genome-wide association studies (GWASs) of alcohol dependence. The following three types of the results were extracted: genome-wide significant associations in an individual sample, the combined samples, or the meta-analysis (p < 5 × 10−8); top-ranked associations in an individual sample (p < 10−5) that were nominally replicated in other samples (p < .05); and nominally replicable associations across at least three independent GWAS samples (p < .05). These results were meta-analyzed. cis-eQTLs in human, RNA expression in rat and mouse brains and bioinformatics properties of all of these risk variants were analyzed. Results The variants located within the alcohol dehydrogenase (ADH) cluster were significantly associated with alcohol dependence at the genome-wide level (p < 5 × 10−8) in at least one sample. Some associations with the ADH cluster were replicable across six independent GWAS samples. The variants located within or near SERINC2, KIAA0040, MREG–PECR or PKNOX2 were significantly associated with alcohol dependence at the genome-wide level (p < 5 × 10−8) in meta-analysis or combined samples, and these associations were replicable across at least one sample. The associations with the variants within NRD1, GPD1L–CMTM8 or MAP3K9–PCNX were suggestive (5 × 10−8 < p < 10−5) in some samples, and nominally replicable in other samples. The associations with the variants at HTR7 and OPA3 were nominally replicable across at least three independent GWAS samples (10−5 < p < .05). Some risk variants at the ADH cluster, SERINC2, KIAA0040, NRD1, and HTR7 had potential biological functions. Conclusion The most robust risk locus was the ADH cluster. SERINC2, KIAA0040, NRD1, and HTR7 were also likely to play important roles in alcohol dependence. PKNOX2, MREG, PECR, GPD1L, CMTM8, MAP3K9, PCNX, and OPA3 might play less important roles in risk for alcohol dependence based on the function analysis. This conclusion will significantly contribute to the post-GWAS follow-up studies on alcohol dependence. (Am J Addict 2014;23:526–539)
Abstract Background: Obesity is a leading risk factor for breast cancer in post-menopausal women and is associated with greater risk of recurrence and cancer-specific mortality. There are over 3 million female breast cancer survivors in the United States, and nearly 65% are either overweight or obese. Lifestyle intervention studies have been shown to be effective in achieving clinically meaningful weight loss for breast cancer survivors with a BMI > 25 kg/m2. However, individual variability in body weight response to diet or exercise interventions has been previously reported among carriers of common obesity-genetic variants. Our study examined whether common variants of obesity-associated genes FTO, MC4R, BDNF, and CREB moderated the effects of an exercise and nutrition intervention on weight change among breast cancer survivors. Methods: A total of 151 breast cancer survivors with a body mass index (BMI) ≥ 25 kg/m2 at baseline were randomly assigned to a 6-month weight loss intervention (n=93) or usual care group (n=58). The weight loss intervention included eleven 30-min counseling sessions on improving nutrition and increasing physical activity. Height, weight and body composition (via dual energy X-ray absorptiometry) were measured at baseline and six months. Genotyping of FTO rs9939609, MC4R rs6567160, BDNF rs11030104, CREB1 rs17203016 was performed using Taqman® SNP genotyping assays. Association analyses were performed in SAS version 9.4, separately for each SNP and assuming a dominant genetic model. Linear mixed models were used to analyze the main effects of genotype and the intervention on weight, BMI, and percent body fat changes at 6 months, with adjustment for age. Appropriate cross product terms were included in each regression model to analyze the potential interaction between genotype and treatment arm. All statistical tests were evaluated against a Bonferroni-corrected alpha of 0.0125. Results: The genetic distributions of the FTO SNP rs9939609, MC4R SNP rs6567160, BDNF SNP rs11030104, CREB1 SNP rs17203016 did not differ significantly by treatment arm. Changes in weight, BMI, and percent body fat did not differ significantly between carriers of the FTO SNP rs9939609, MC4R SNP rs6567160, BDNF SNP rs11030104, and CREB1 SNP rs17203016 risk alleles compared to non-carriers (p-interaction > 0.0125 for each SNP and across all outcomes). Women in the intervention group achieved significantly greater weight loss than the usual care group (-4.8 kg vs -0.6 kg, p < 0.001) regardless of genotype. Conclusions: Common variants of known obesity-associated genes (FTO, MC4R, BDNF, and MC4R) did not modify the effect of the nutrition and exercise intervention on changes in body weight and body fat. Women who are genetically predisposed to obesity and recently diagnosed with breast cancer may benefit from lifestyle changes similarly to women who are not genetically predisposed to obesity. Our findings may help guide the incorporation of lifestyle interventions and weight loss counseling into breast cancer survivorship care. Citation Format: ThaiHien Nguyen, Melinda L Irwin, Andrew T Dewan, Maura Harrigan, Brenda Cartmel, Tara Sanft, Lingeng Lu, Fangyong Li, Yasmmyn D Salinas. Assessing effect modification of obesity-associated genes variants in FTO, MC4R, BDNF, and CREB1 on weight loss among breast cancer survivors enrolled in the randomized lifestyle, exercise, and nutrition (LEAN) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-17.
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