Association of GWAS-Based Candidate Genes with HDL-Cholesterol Levels before and after Bariatric Surgery in the Swedish Obese Subjects Study

Context and Objective: The magnitude of weight loss-induced high-density lipoprotein cholesterol (HDL-C) changes may depend on genetic factors. We examined the associations of eight candidate genes, identified by genome-wide association studies, with HDL-C at baseline and 10 yr after bariatric surgery in the Swedish Obese Subjects study. Methods: Single-nucleotide polymorphisms (SNP) (n = 60) in the following gene loci were genotyped: ABCA1, APOA5, CETP, GALNT2, LIPC, LIPG, LPL, and MMAB/MVK. Cross-sectional associations were tested before (n = 1771) and 2 yr (n = 1583) and 10 yr (n = 1196) after surgery. Changes in HDL-C were tested between baseline and yr 2 (n = 1518) and yr 2 and 10 (n = 1149). A multiple testing corrected threshold of P = 0.00125 was used for statistical significance. Results: In adjusted multivariate models, CETP SNP rs3764261 explained from 3.2–4.2% (P < 10−14) of the variation in HDL-C at all three time points, whereas CETP SNP rs9939224 contributed an additional 0.6 and 0.9% at baseline and yr 2, respectively. LIPC SNP rs1077834 showed consistent associations across all time points (R2 = 0.4–1.1%; 3.8 × 10−6 < P < 3 × 10−3), whereas LPL SNP rs6993414 contributed approximately 0.5% (5 × 10−4 < P < 0.0012) at yr 2 and 10. In aggregate, four SNP in three genes explained 4.2, 6.8, and 5.6% of the HDL-C variance at baseline, yr 2, and yr 10, respectively. None of the SNP was significantly associated with weight loss-related changes in HDL-C. Conclusions: SNP in the CETP, LIPC, and LPL loci contribute significantly to plasma HDL-C levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, they are not associated with surgery-induced changes in HDL-C levels.

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Associations of Two Obesity-Related Single-Nucleotide Polymorphisms with Adiponectin in Chinese Children

International Journal of Endocrinology ◽

10.1155/2017/6437542 ◽

2017 ◽

Vol 2017 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Lijun Wu ◽

Liwang Gao ◽

Xiaoyuan Zhao ◽

Meixian Zhang ◽

Jianxin Wu ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Multiple Testing ◽

Association Studies ◽

Statistical Significance ◽

Additive Model ◽

Recessive Model ◽

Chinese Children ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

Purpose. Genome-wide association studies have found two obesity-related single-nucleotide polymorphisms (SNPs), rs17782313 near the melanocortin-4 receptor (MC4R) gene and rs6265 near the brain-derived neurotrophic factor (BDNF) gene, but the associations of both SNPs with other obesity-related traits are not fully described, especially in children. The aim of the present study is to investigate the associations between the SNPs and adiponectin that has a regulatory role in glucose and lipid metabolism. Methods. We examined the associations of the SNPs with adiponectin in Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. A total of 3503 children participated in the study. Results. The SNP rs6265 was significantly associated with adiponectin under an additive model (P=0.02 and 0.024, resp.) after adjustment for age, gender, and BMI or obesity statuses. The SNP rs17782313 was significantly associated with low adiponectin under a recessive model. No statistical significance was found between the two SNPs and low adiponectin after correction for multiple testing. Conclusion. We demonstrate for the first time that the SNP rs17782313 near MC4R and the SNP rs6265 near BDNF are associated with adiponectin in Chinese children. These novel findings provide important evidence that adiponectin possibly mediates MC4R and BDNF involved in obesity.

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Confirmed effects of candidate variants for milk production, udder health, and udder morphology in dairy cattle

Genetics Selection Evolution ◽

10.1186/s12711-020-00575-1 ◽

2020 ◽

Vol 52 (1) ◽

Cited By ~ 1

Author(s):

Thierry Tribout ◽

Pascal Croiseau ◽

Rachel Lefebvre ◽

Anne Barbat ◽

Mekki Boussaha ◽

...

Keyword(s):

Dairy Cattle ◽

Candidate Genes ◽

Milk Production ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Production Traits ◽

Milk Production Traits ◽

Udder Health ◽

Gwas Approach

Abstract Background Over the last years, genome-wide association studies (GWAS) based on imputed whole-genome sequences (WGS) have been used to detect quantitative trait loci (QTL) and highlight candidate genes for important traits. However, in general this approach does not allow to validate the effects of candidate mutations or determine if they are truly causative for the trait(s) in question. To address these questions, we applied a two-step, within-breed GWAS approach on 15 traits (5 linked with milk production, 2 with udder health, and 8 with udder morphology) in Montbéliarde (MON), Normande (NOR), and Holstein (HOL) cattle. We detected the most-promising candidate variants (CV) using imputed WGS of 2515 MON, 2203 NOR, and 6321 HOL bulls, and validated their effects in three younger populations of 23,926 MON, 9400 NOR, and 51,977 HOL cows. Results Bull sequence-based GWAS detected 84 QTL: 13, 10, and 30 for milk production traits; 3, 0, and 2 for somatic cell score (SCS); and 8, 2 and 16 for udder morphology traits, in MON, NOR, and HOL respectively. Five genomic regions with effects on milk production traits were shared among the three breeds whereas six (2 for production and 4 for udder morphology and health traits) had effects in two breeds. In 80 of these QTL, 855 CV were highlighted based on the significance of their effects and functional annotation. The subsequent GWAS on MON, NOR, and HOL cows validated 8, 9, and 23 QTL for production traits; 0, 0, and 1 for SCS; and 4, 1, and 8 for udder morphology traits, respectively. In 47 of the 54 confirmed QTL, the CV identified in bulls had more significant effects than single nucleotide polymorphisms (SNPs) from the standard 50K chip. The best CV for each validated QTL was located in a gene that was functionally related to production (36 QTL) or udder (9 QTL) traits. Conclusions Using this two-step GWAS approach, we identified and validated 54 QTL that included CV mostly located within functional candidate genes and explained up to 6.3% (udder traits) and 37% (production traits) of the genetic variance of economically important dairy traits. These CV are now included in the chip used to evaluate French dairy cattle and can be integrated into routine genomic evaluation.

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Puberty Status Modifies the Effects of Genetic Variants, Lifestyle Factors and Their Interactions on Adiponectin: The BCAMS Study

Frontiers in Endocrinology ◽

10.3389/fendo.2021.737459 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yunpeng Wu ◽

Ling Zhong ◽

Ge Li ◽

Lanwen Han ◽

Junling Fu ◽

...

Keyword(s):

Genetic Variants ◽

Association Studies ◽

Pubertal Development ◽

Lifestyle Factors ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Exercise Frequency ◽

Cross Sectional ◽

Individual Snps ◽

Diet Score

BackgroundHypoadiponectinemia has been associated with various cardiometabolic disease states. Previous studies in adults have shown that adiponectin levels were regulated by specific genetic and behavioral or lifestyle factors. However, little is known about the influence of these factors on adiponectin levels in children, particularly as mitigated by pubertal development.MethodsWe performed a cross-sectional analysis of data from 3,402 children aged 6-18 years from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. Pubertal progress was classified as prepubertal, midpuberty, and postpuberty. Six relevant single nucleotide polymorphisms (SNPs) were selected from previous genome-wide association studies of adiponectin in East Asians. Individual SNPs and two weighted genetic predisposition scores, as well as their interactions with 14 lifestyle factors, were analyzed to investigate their influence on adiponectin levels across puberty. The effect of these factors on adiponectin was analyzed using general linear models adjusted for age, sex, and BMI.ResultsAfter adjustment for age, sex, and BMI, the associations between adiponectin levels and diet items, and diet score were significant at prepuberty or postpuberty, while the effect of exercise on adiponectin levels was more prominent at mid- and postpuberty. Walking to school was found to be associated with increased adiponectin levels throughout puberty. Meanwhile, the effect of WDR11-FGFR2-rs3943077 was stronger at midpuberty (P = 0.002), and ADIPOQ-rs6773957 was more effective at postpuberty (P = 0.005), while CDH13-rs4783244 showed the strongest association with adiponectin levels at all pubertal stages (all P < 3.24 × 10-15). We further found that effects of diet score (Pinteraction = 0.022) and exercise (Pinteraction = 0.049) were stronger in children with higher genetic risk of hypoadiponectinemia, while higher diet score and exercise frequency attenuated the differences in adiponectin levels among children with different genetic risks.ConclusionsOur study confirmed puberty modulates the associations between adiponectin, and genetic variants, lifestyle factors, and gene-by-lifestyle interactions. These findings provide new insight into puberty-specific lifestyle suggestions, especially in genetically susceptible individuals.

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Identification of three genetic variants as novel susceptibility loci for body mass index in a Japanese population

Physiological Genomics ◽

10.1152/physiolgenomics.00117.2017 ◽

2018 ◽

Vol 50 (3) ◽

pp. 179-189 ◽

Cited By ~ 4

Author(s):

Yoshiki Yasukochi ◽

Jun Sakuma ◽

Ichiro Takeuchi ◽

Kimihiko Kato ◽

Mitsutoshi Oguri ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Genetic Variants ◽

Japanese Population ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Susceptibility Loci ◽

Cross Sectional ◽

Japanese Subjects

Recent genome-wide association studies have identified various obesity or metabolic syndrome (MetS) susceptibility loci. However, most studies were conducted in a cross-sectional manner. To address this gap, we performed a longitudinal exome-wide association study to identify susceptibility loci for obesity and MetS in a Japanese population. We traced clinical data of 6,022 Japanese subjects who had annual health check-ups for several years (mean follow-up period, 5 yr) and genotyped ~244,000 genetic variants. The association of single nucleotide polymorphisms (SNPs) with body mass index (BMI) or the prevalence of obesity and MetS was examined in a generalized estimating equation model. Our longitudinal exome-wide association studies detected 21 BMI- and five MetS-associated SNPs (false discovery rate, FDR <0.01). Among these SNPs, 16 have not been previously implicated as determinants of BMI or MetS. Cross-sectional data for obesity- and MetS-related phenotypes in 7,285 Japanese subjects were examined in a replication study. Among the 16 SNPs, three ( rs9491140 , rs145848316 , and rs7863248 ) were related to BMI in the replication cohort ( P < 0.05). In conclusion, three SNPs [ rs9491140 of NKAIN2 (FDR = 0.003, P = 1.9 × 10−5), rs145848316 of KMT2C (FDR = 0.007, P = 4.5 × 10−5), and rs7863248 of AGTPBP1 (FDR = 0.006, P = 4.2 × 10−5)] were newly identified as susceptibility loci for BMI.

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Snp Characteristics and Validation Success in Genome Wide Association Studies

10.21203/rs.3.rs-704899/v1 ◽

2021 ◽

Author(s):

Olga Gorlova ◽

Xiangjun Xiao ◽

Spiridon Tsavachidis ◽

Christopher I. Amos ◽

Ivan P. Gorlov

Keyword(s):

Success Rate ◽

Association Studies ◽

Statistical Significance ◽

Positive Association ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Multivariable Logistic Regression Model ◽

Functional Studies ◽

Genome Wide

Abstract Genome wide association studies (GWASs) have identified tens of thousands of single nucleotide polymorphisms (SNPs) associated with human diseases and characteristics. A significant fraction of GWAS findings can be false positives. The gold standard for true positives is an independent validation. The goal of this study was to identify SNP features associated with validation success. Summary statistics from the Catalog of Published GWASs were used in the analysis. Since our goal was an analysis of reproducibility, we focused on the diseases/phenotypes targeted by at least 10 GWASs. GWASs were arranged in discovery-validation pairs based on the time of publication, with the discovery GWAS published before validation. We used four definitions of the validation success that differ by stringency. Associations of SNP features with validation success were consistent across the definitions. The strongest predictor of SNP validation was the level of statistical significance in the discovery GWAS. The magnitude of the effect size was associated with validation success in a non-linear manner. SNPs with risk allele frequencies in the range 30-70% showed a higher validation success rate compared to rarer or more common SNPs. Missense, 5’UTR, stop gained, and SNPs located in transcription factor binding sites had a higher validation success rate compared to intergeneic, intronic, or synonymous SNPs. There was a positive association between validation success and the level of evolutionary conservation of the sites. In addition, validation success was higher when discovery and validation GWASs targeted the same ethnicity. All predictors of validation success remained significant in a multivariable logistic regression model indicating their independent contribution. To conclude, we identified SNP features predicting validation success of GWAS hits. These features can be used to select SNPs for validation and downstream functional studies.

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No correlation between the variants of exostosin 2 gene and type 2 diabetes in Burkina Faso population

Journal of Public Health in Africa ◽

10.4081/jphia.2020.1233 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Serge Yannick Ouedraogo ◽

Daméhan Tchelougou ◽

Jonas Koudougou Kologo ◽

Herman Karim Sombie ◽

Moutanou Modeste Judes Zeye ◽

...

Keyword(s):

Type 2 Diabetes ◽

Burkina Faso ◽

Association Studies ◽

Statistical Significance ◽

Black Population ◽

Allelic Exclusion ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

African Black

Recent genome-wide association studies and replication analyses have reported the association of variants of the exostosin- 2 gene (EXT2) and risk of type 2 diabetes (T2D) in some populations, but not in others. This study aimed to characterize the variants rs1113132, rs3740878 and rs11037909 of EXT2 and to determine the existence of a possible correlation with T2D in Burkina Faso. It is a case-control study undertaken in Burkina Faso in the city of Ouagadougou at the Hospital of Saint Camille of Ouagadougou from December 2014 to June 2015. It relates to 121 type 2 diabetes cases and 134 controls. The genotyping of these polymorphisms was done by real-time PCR using the allelic exclusion method with TaqMan probes. The minor allele frequencies (MAFs) was almost identical in diabetic and control subjects for the all three Single Nucleotide Polymorphisms (SNPs) with no statistical significance, p>0.05: rs1113132 (OR=0.89; p=0.82); rs11037909 (OR=0.89; p=0.74) and rs3740878 (OR=1.52; p=0.42). None of the three polymorphisms studied was associated with the risk of DT2. However, an association between the BMI, age and type 2 diabetes was noted. The variants of EXT2 would not be associated to the risk of T2D in the African black population of Burkina Faso.

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Bayesian network analysis of plasma microRNA sequencing data in patients with venous thrombosis

European Heart Journal Supplements ◽

10.1093/eurheartj/suaa008 ◽

2020 ◽

Vol 22 (Supplement_C) ◽

pp. C34-C45 ◽

Cited By ~ 3

Author(s):

Florian Thibord ◽

Gaëlle Munsch ◽

Claire Perret ◽

Pierre Suchon ◽

Maguelonne Roux ◽

...

Keyword(s):

Venous Thrombosis ◽

Association Studies ◽

Statistical Significance ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Sequencing Data ◽

New Associations ◽

Significance Threshold ◽

The Impact ◽

Plasma Mirna

Abstract MicroRNAs (miRNAs) are small regulatory RNAs participating to several biological processes and known to be involved in various pathologies. Measurable in body fluids, miRNAs have been proposed to serve as efficient biomarkers for diseases and/or associated traits. Here, we performed a next-generation-sequencing based profiling of plasma miRNAs in 344 patients with venous thrombosis (VT) and assessed the association of plasma miRNA levels with several haemostatic traits and the risk of VT recurrence. Among the most significant findings, we detected an association between hsa-miR-199b-3p and haematocrit levels (P = 0.0016), these two markers having both been independently reported to associate with VT risk. We also observed suggestive evidence for association of hsa-miR-370-3p (P = 0.019), hsa-miR-27b-3p (P = 0.016) and hsa-miR-222-3p (P = 0.049) with VT recurrence, the observations at the latter two miRNAs confirming the recent findings of Wang et al. Besides, by conducting Genome-Wide Association Studies on miRNA levels and meta-analyzing our results with some publicly available, we identified 21 new associations of single nucleotide polymorphisms with plasma miRNA levels at the statistical significance threshold of P < 5 × 10−8, some of these associations pertaining to thrombosis associated mechanisms. In conclusion, this study provides novel data about the impact of miRNAs’ variability in haemostasis and new arguments supporting the association of few miRNAs with the risk of recurrence in patients with venous thrombosis.

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Commonly Studied Single-Nucleotide Polymorphisms and Breast Cancer: Results From the Breast Cancer Association Consortium

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djj374 ◽

2006 ◽

Vol 98 (19) ◽

pp. 1382-1396 ◽

Cited By ~ 186

Author(s):

Keyword(s):

Breast Cancer ◽

Single Nucleotide Polymorphisms ◽

Association Studies ◽

Statistical Tests ◽

Statistical Significance ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Odds Ratios ◽

Single Nucleotide ◽

Breast Cancer Association Consortium

Abstract Background: The Breast Cancer Association Consortium (BCAC) is an international collaboration that was established to provide large sample sizes for examining genetic associations. We conducted combined analyses on all single-nucleotide polymorphisms (SNPs) whose associations with breast cancer have been investigated by at least three participating groups. Methods: Data from up to 12 studies were pooled for each SNP ( ADH1C I350V, AURKA F31I, BRCA2 N372H, CASP8 D302H, ERCC2 D312N, IGFBP3 −202 c > a , LIG4 D501D, PGR V660L, SOD2 V16A, TGFB1 L10P, TP53 R72P, XRCC1 R399Q, XRCC2 R188H, XRCC3 T241M, XRCC3 5′ UTR, and XRCC3 IVS7-14). Genotype frequencies in case and control subjects were compared, and genotype-specific odds ratios for the risk of breast cancer in heterozygotes and homozygotes for the rare allele compared with homozygotes for the common allele were estimated with logistic regression. Statistical tests were two-sided. Results: The total number of subjects for analysis of each SNP ranged from 12 013 to 31 595. For five SNPs— CASP8 D302H, IGFBP3 −202 c > a , PGR V660L, SOD2 V16A, and TGFB1 L10P—the associations with breast cancer were of borderline statistical significance ( P = .016, .060, .047, .056, and .0088 respectively). The remaining 11 SNPs were not associated with breast cancer risk; genotype-specific odds ratios were close to unity. There was some evidence for between-study heterogeneity ( P <.05) for four of the 11 SNPs ( ADH1C I350V, ERCC2 D312N, XRCC1 R399Q, and XRCC3 IVS5-14). Conclusion: Pooling data within a large consortium has helped to clarify associations of SNPs with breast cancer. In the future, consortia such as the BCAC will be important in the analysis of rare polymorphisms and gene × gene or gene × environment interactions, for which individual studies have low power to identify associations, and in the validation of associations identified from genome-wide association studies.

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MTCH2 in Human White Adipose Tissue and Obesity

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-3050 ◽

2011 ◽

Vol 96 (10) ◽

pp. E1661-E1665 ◽

Cited By ~ 13

Author(s):

Agné Kulyté ◽

Mikael Rydén ◽

Niklas Mejhert ◽

Elisabeth Dungner ◽

Eva Sjölin ◽

...

Keyword(s):

Weight Loss ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Association Studies ◽

Genome Wide Association Studies ◽

Mrna Levels ◽

Nucleotide Polymorphisms ◽

Obese Women ◽

Single Nucleotide ◽

Paired Samples

Abstract Context: Genome-wide association studies have identified single-nucleotide polymorphisms in approximately 40 loci associated with obesity-related traits. How these loci regulate obesity is largely unknown. One obesity-associated single-nucleotide polymorphism is close to the MTCH2 gene (mitochondrial carrier homolog 2). Objective: The objective of the study was to assess the expression of genes in obesity-associated loci in abdominal sc white adipose tissue (scWAT) in relation to obesity. A more comprehensive expression study was performed on MTCH2. Design: mRNA levels of 66 genes from 40 loci were determined by microarray in scWAT from lean and obese women (n = 30). MTCH2 mRNA was measured by quantitative RT-PCR in lean and obese before and after weight loss in intact adipose pieces and isolated adipocytes, paired samples of scWAT and omental WAT, and primary adipocyte cultures (n = 191 subjects in total). MTCH2 genotypes were compared with mRNA expression in 96 women. MTCH2 protein was examined in scWAT of 38 individuals. Results: Adipose expression of eight genes was significantly associated with obesity; of these, MTCH2 displayed the highest absolute signal. MTCH2 mRNA and protein expression was significantly increased in obese women but was not affected by weight loss. MTCH2 was enriched in isolated fat cells and increased during adipocyte differentiation. There was no cis influence of MTCH2 genotypes on mRNA levels. Conclusion: MTCH2 is highly expressed in human WAT and adipocytes with increased levels in obese women. These results suggest that MTCH2 may play a role in cellular processes underlying obesity.

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Multivariate Analysis of Potential Pleiotropic Genes For Breast, Ovarian And Cervical Cancers Using Gene-Based Association Analysis

10.21203/rs.3.rs-695526/v1 ◽

2021 ◽

Author(s):

XiaoCan Jia ◽

Nian Shi ◽

Yu Feng ◽

Huili Zhu ◽

Yuping Wang ◽

...

Keyword(s):

Network Analysis ◽

Association Studies ◽

Statistical Significance ◽

Enrichment Analysis ◽

Biological Pathways ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Ppi Network ◽

Cervical Cancers ◽

Protein Protein Interaction

Abstract Although genome-wide association studies (GWAS) have a dramatic impact on susceptibility locus discovery in gynecological malignancies, the single nucleotide polymorphisms (SNPs) identified by this prevailing univariate approach only explain a small percentage of heredity. The extensive previous studies have repeatedly shown breast, ovarian and cervical cancers have common genetic mechanisms and the overlapping pathophysiological pathways. Novel multivariate analytical methods are necessary to identify shared pleiotropic genes. In this study, a total of 40,859 SNPs mapped in 11,597 gene regions were performed to identify potential common variants by using metaCCA and VEGAS2 analysis. Gene enrichment and protein-protein interaction (PPI) network analysis were used to explore potential biological pathways and connectivity. After metaCCA analysis, 4,203 SNPs (P<1.22×10−6) and 1,886 pleotropic gene (P<4.31×10−6) were identified. By screening the results of gene-based P-values, the existence of 3 confirmed pleiotropic genes and 16 novel genes that achieved statistical significance in the metaCCA analysis and were also associated with at least one cancer in the VEGAS2 analysis were identified. The enrichment analysis showed the biological pathways of these genes were mainly enriched in 4 signaling pathways and 11 differentially expressed genes were found to encode interacting proteins in PPI network analysis. Altogether, we identified novel genetic variants of breast, ovarian and cervical cancers and provided evidence of biological functions which developed new insights for the diagnosis and treatment of these cancers.

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