Pathway-Based Genome-wide Association Studies Reveal That the Rac1 Pathway Is Associated with Plasma Adiponectin Levels.
ABSTRACT: Pathway-based analysis as an alternative and effective approach to identify disease-related genes or loci has been verified. To decipher the genetic background of plasma adiponectin levels, we performed genome wide pathway-based association studies in extremely obese individuals and normal-weight controls. The modified Gene Set Enrichment Algorithm (GSEA) was used to perform the pathway-based analyses (the GenGen Program) in 746 European American females, which were collected from our previous GWAS in extremely obese (BMI?>?35?kg/m(2)) and never-overweight (BMI<25?kg/m(2)) controls. Rac1 cell motility signaling pathway was associated with plasma adiponectin after false-discovery rate (FDR) correction (empirical P?
Project description:Pathway-based analysis as an alternative approach can provide complementary information to single-marker genome-wide association studies (GWASs), which always ignore the epistasis and does not have sufficient power to find rare variants. In this study, using genotypes from a genome-wide association study (GWAS), pathway-based association studies were carried out by a modified Gene Set Enrichment Algorithm (GSEA) method (GenGen) for triglyceride in 1028 unrelated European-American extremely obese females (BMI?35kg/m2) and normal-weight controls (BMI<25kg/m2), and another pathway association analysis (ICSNPathway) was also used to verify the GenGen result in the same data. The GO0009110 pathway (vitamin anabolism) was among the strongest associations with triglyceride (empirical P<0.001); the result remained significant after FDR correction (P = 0.022). MMAB, an obesity-related locus, included in this pathway. The ABCG1 and BCL6 gene was found in several triglyceride-related pathways (empirical P<0.05), which were also replicated by ICSNPathway (empirical P<0.05, FDR<0.05). We also performed single-marked GWAS using PLINK for TG levels (log-transformed). Significant associations were found between ASTN2 gene SNPs and plasma triglyceride levels (rs7035794, P = 2.24×10-10). Our study suggested that vitamin anabolism pathway, BCL6 gene pathways and ASTN2 gene may contribute to the genetic variation of plasma triglyceride concentrations.
Project description:Objective: We investigated gene interactions (epistasis) for body mass index (BMI) in a European-American adult female cohort via genome-wide interaction analyses (GWIA) and pathway association analyses. Methods: Genome-wide pairwise interaction analyses were carried out for BMI in 493 extremely obese cases (BMI > 35 kg/m2) and 537 never-overweight controls (BMI < 25 kg/m2). To further validate the results, specific SNPs were selected based on the GWIA results for haplotype-based association studies. Pathway-based association analyses were performed using a modified Gene Set Enrichment Algorithm (GSEA) (GenGen program) to further explore BMI-related pathways using our genome wide association study (GWAS) data set, GIANT, ENGAGE, and DIAGRAM Consortia. Results: The EXOC4-1q23.1 interaction was associated with BMI, with the most significant epistasis between rs7800006 and rs10797020 (P = 2.63 × 10-11). In the pathway-based association analysis, Tob1 pathway showed the most significant association with BMI (empirical P < 0.001, FDR = 0.044, FWER = 0.040). These findings were further validated in different populations. Conclusion: Genome-wide pairwise SNP-SNP interaction and pathway analyses suggest that EXOC4 and TOB1-related pathways may contribute to the development of obesity.
Project description:The substantial reduction in adiponectin concentration among obese individuals seems to depend on fat distribution and is a marker of metabolic and adipose tissue dysfunction. We aimed to: (i) address whether abdominal fat from different compartments (visceral, deep subcutaneous abdominal and superficial subcutaneous abdominal) and gluteofemoral fat are independently associated with blood adiponectin concentration; and (ii) investigate whether abdominal (proxied by waist circumference) and gluteofemoral fat (proxied by hip circumference) accumulation causally determine blood adiponectin concentration.To investigate the independent association of abdominal and gluteofemoral fat with adiponectin concentration, we used multivariable regression and data from 30-year-old adults from the 1982 Pelotas Birth Cohort (n = 2,743). To assess the causal role of abdominal and gluteofemoral fat accumulation on adiponectin concentration, we used Mendelian randomization and data from two consortia of genome-wide association studies-the GIANT (n > 210 000) and ADIPOGen consortia (n = 29 347).In the multivariable regression analysis, all abdominal fat depots were negatively associated with adiponectin concentration, specially visceral abdominal fat [men: ? = -0.24 standard unit of log adiponectin per standard unit increase in abdominal fat; 95% confidence interval (CI) = -0.31, -0.18; P = 8*10-13; women: ? = -0.31; 95% CI = -0.36, -0.25; P = 7*10-27), whereas gluteofemoral fat was positively associated with adiponectin concentration (men: ? = 0.13 standard unit of log adiponectin per standard unit increase in gluteofemoral fat; 95% CI = 0.03, 0.22; P = 0.008; women: ? = 0.24; 95% CI = 0.17, 0.31; P = 7*10-11). In the Mendelian randomization analysis, genetically-predicted waist circumference was inversely related to blood adiponectin concentration (? = -0.27 standard unit of log adiponectin per standard unit increase in waist circumference; 95% CI = -0.36, -0.19; P = 2*10-11), whereas genetically-predicted hip circumference was positively associated with blood adiponectin concentration (? = 0.17 standard unit of log adiponectin per standard unit increase in hip circumference; 95% CI = 0.11, 0.24; P = 1*10-7).These results support the hypotheses that there is a complex interplay between body fat distribution and circulating adiponectin concentration, and that whereas obesity-induced hypoadiponectinaemia seems to be primarily attributed to abdominal fat accumulation, gluteofemoral fat accumulation is likely to exert a protective effect.
Project description:OBJECTIVE:A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. METHODS:Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium (n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium (n = 85,274). RESULTS:In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing (P < 4.4 × 10(-4)). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD (P = 5.4 × 10(-7)). CONCLUSION:These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal.
Project description:RATIONALE:Hypoadiponectinemia correlates with several coronary heart disease (CHD) risk factors. However, it is unknown whether adiponectin is causally implicated in CHD pathogenesis. OBJECTIVE:We aimed to investigate the causal effect of adiponectin on CHD risk. METHODS AND RESULTS:We undertook a Mendelian randomization study using data from genome-wide association studies consortia. We used the ADIPOGen consortium to identify genetic variants that could be used as instrumental variables for the effect of adiponectin. Data on the association of these genetic variants with CHD risk were obtained from CARDIoGRAM (22?233 CHD cases and 64?762 controls of European ancestry) and from CARDIoGRAMplusC4D Metabochip (63?746 cases and 130?681 controls; ? 91% of European ancestry) consortia. Data on the association of genetic variants with adiponectin levels and with CHD were combined to estimate the influence of blood adiponectin on CHD risk. In the conservative approach (restricted to using variants within the adiponectin gene as instrumental variables), each 1 U increase in log blood adiponectin concentration was associated with an odds ratio for CHD of 0.83 (95% confidence interval, 0.68-1.01) in CARDIoGRAM and 0.97 (95% confidence interval, 0.84-1.12) in CARDIoGRAMplusC4D Metabochip. Findings from the liberal approach (including variants in any locus across the genome) indicated a protective effect of adiponectin that was attenuated to the null after adjustment for known CHD predictors. CONCLUSIONS:Overall, our findings do not support a causal role of adiponectin levels in CHD pathogenesis.
Project description:This study investigated genetic determinants of adiponectin during pregnancy to reveal novel biology of adipocyte regulation.A genome-wide association study was conducted in 1,322 pregnant women from the Hyperglycemia and Adverse Pregnancy Outcome Study with adiponectin measured at ?28 weeks of gestation. Variants reaching P?<?5×10-5 for de novo genotyping in two replication cohorts (Genetics of Glycemic regulation in Gestation and Growth N?=?522; ECOGENE-21 N?=?174) were selected.In the combined meta-analysis, the maternal T allele of rs900400 located on chr3q25 (near LEKR1/CCNL1) was associated with lower maternal adiponectin (??±?standard error [SE]?=?-0.18?±?0.03 standard deviation [SD] of adiponectin per risk allele; P?=?1.5 ×10-8 ; N?=?2,004; multivariable adjusted models). In contrast, rs900400 showed only nominal association with adiponectin in a large sample of nonpregnant women (??±?SE?=?-0.012?±?0.006; P?=?0.05; N?=?16,678 women from the ADIPOgen consortium). The offspring rs900400 T risk allele was associated with greater neonatal skinfold thickness (? ±SE?=?0.19?±?0.04 SD per risk allele; P?=?4.1×10-8 ; N?=?1,489) and higher cord blood leptin (??±?SE?=?0.28?±?0.05 log-leptin per risk allele; P?=?8.2 ×10-9 ; N?=?502), but not with cord blood adiponectin (P?=?0.23; N?=?495). The T allele of rs900400 was associated with higher expression of TIPARP in adipocytes.These investigations of adipokines during pregnancy and early life suggest that rs900400 has a role in adipocyte function.
Project description:Purpose:The associations of adiponectin with type 2 diabetes mellitus (T2DM), glucose homeostasis (including ?-cell function index (HOMA-?), insulin resistance (HOMA-IR), fasting insulin (FI) and fasting glucose (FG)) have reported in epidemiological studies. However, the previous observational studies are prone to biases, such as reverse causation and residual confounding factors. Herein, a Mendelian Randomization (MR) study was conducted to determine whether causal effects exist among them. Materials and and Methods:Two-sample MR analyses and multiple sensitivity analyses were performed using the summary data from the ADIPOGen consortium, MAGIC Consortium, and a meta-analysis of GWAS with a considerable sample of T2DM (62,892 cases and 596,424 controls of European ancestry). We got eight valid genetic variants to predict the causal effect among adiponectin and T2DM and glucose homeostasis after excluding the probable invalid or pleiotropic variants. Results:Adiponectin was not associated with T2DM (odds ratio (OR) = 1.004; 95% confidence interval (CI): 0.740, 1.363) when using MR Egger after removing the invalid SNPs, and the results were consistent when using the other four methods. Similar results existed among adiponectin and HOMA-?, HOMA-IR, FI, FG. Conclusion:Our MR study revealed that adiponectin had no causal effect on T2DM and glucose homeostasis and that the associations among them in observational studies may be due to confounding factors.
Project description:Genome-wide association study (GWAS) is widely utilized to identify genes involved in human complex disease or some other trait. One key challenge for GWAS data interpretation is to identify causal SNPs and provide profound evidence on how they affect the trait. Currently, researches are focusing on identification of candidate causal variants from the most significant SNPs of GWAS, while there is lack of support on biological mechanisms as represented by pathways. Although pathway-based analysis (PBA) has been designed to identify disease-related pathways by analyzing the full list of SNPs from GWAS, it does not emphasize on interpreting causal SNPs. To our knowledge, so far there is no web server available to solve the challenge for GWAS data interpretation within one analytical framework. ICSNPathway is developed to identify candidate causal SNPs and their corresponding candidate causal pathways from GWAS by integrating linkage disequilibrium (LD) analysis, functional SNP annotation and PBA. ICSNPathway provides a feasible solution to bridge the gap between GWAS and disease mechanism study by generating hypothesis of SNP ? gene ? pathway(s). The ICSNPathway server is freely available at http://icsnpathway.psych.ac.cn/.
Project description:This study aimed to discover candidate single nucleotide polymorphisms (SNPs) for hypothesizing significant biological pathways of gastric cancer (GC). We performed an Identify Candidate Causal SNPs and Pathways (ICSNPathway) analysis using a GC genome-wide association study (GWAS) dataset, including 472,342 SNPs in 2,240 GC cases and 3,302 controls of Asian ethnicity. By integrating linkage disequilibrium analysis, functional SNP annotation, and pathway-based analysis, seven candidate SNPs, four genes and 12 pathways were selected. The ICSNPathway analysis produced 4 hypothetical mechanisms of GC: (1) rs4745 and rs12904 → EFNA1 → ephrin receptor binding; (2) rs1801019 → UMPS → drug and pyrimidine metabolism; (3) rs364897 → GBA → cyanoamino acid metabolism; and (4) rs11187870, rs2274223, and rs3765524 → PLCE1 → lipid biosynthetic process, regulation of cell growth, and cation homeostasis. This pathway analysis using GWAS dataset suggests that the 4 hypothetical biological mechanisms might contribute to GC susceptibility.
Project description:Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.