scholarly journals Pervasive Modulation of Obesity Risk by the Environment and Genomic Background

Genes ◽  
2018 ◽  
Vol 9 (8) ◽  
pp. 411 ◽  
Author(s):  
Sini Nagpal ◽  
Greg Gibson ◽  
Urko Marigorta
Keyword(s):  
Association Studies ◽  
Disease Incidence ◽  
Genome Wide Association Studies ◽  
Sudden Increase ◽  
Obesity Risk ◽  
Disease Etiology ◽  
Genome Wide ◽  
Two Generations ◽  
The Uk

The prevalence of the so-called diseases of affluence, such as type 2 diabetes or hypertension, has increased dramatically in the last two generations. Although genome-wide association studies (GWAS) have discovered hundreds of genes involved in disease etiology, the sudden increase in disease incidence suggests a major role for environmental risk factors. Obesity constitutes a case example of a modern trait shaped by contemporary environment, although with considerable debates about the extent to which gene-by-environment (G×E) interactions accentuate obesity risk in individuals following obesogenic lifestyles. Although interaction effects have been robustly confirmed at the FTO locus, accumulating evidence at the genome-wide level implicates a role for polygenic risk-by-environment interactions. Through a variety of analyses using the UK Biobank, we confirm that the genomic background plays a major role in shaping the expressivity of alleles that increase body mass index (BMI).

Genome-Wide Association Studies Identify Two Novel Loci Conferring Susceptibility to Diabetic Retinopathy in Japanese Patients with Type 2 Diabetes

2021 ◽  
Author(s):  
Minako Imamura ◽  
Atsushi Takahashi ◽  
Masatoshi Matsunami ◽  
Momoko Horikoshi ◽  
Minoru Iwata ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Association Studies ◽  
Meta Analysis ◽  
Japanese Patients ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Stage 1

Abstract Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases, and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (p < 1.0 × 10−4) in an independent case–control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stage-1 and -2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, p = 1.62 × 10−9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11–1.23, and rs140508424 within PALM2 on chromosome 9, p = 4.19 × 10−8, OR = 1.61, 95% CI 1.36–1.91. However, the association of these two loci were not replicated in Korean, European, or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (p = 2.17 × 10−6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.

scholarly journals Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Minako Imamura ◽  
Atsushi Takahashi ◽  
Toshimasa Yamauchi ◽  
Kazuo Hara ◽  
Kazuki Yasuda ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Japanese Population ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide

scholarly journals Reproducibility in the UK Biobank of Genome-Wide Significant Signals Discovered in Earlier Genome-wide Association Studies

2020 ◽  
Author(s):  
Jack W. O’Sullivan ◽  
John P. A. Ioannidis
Keyword(s):  
Effect Size ◽  
Association Studies ◽  
Genome Wide Association ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Single Nucleotide ◽  
Genome Wide ◽  
The Uk ◽  
Open Question

AbstractWith the establishment of large biobanks, discovery of single nucleotide polymorphism (SNPs) that are associated with various phenotypes has been accelerated. An open question is whether SNPs identified with genome-wide significance in earlier genome-wide association studies (GWAS) are replicated also in later GWAS conducted in biobanks. To address this question, the authors examined a publicly available GWAS database and identified two, independent GWAS on the same phenotype (an earlier, “discovery” GWAS and a later, replication GWAS done in the UK biobank). The analysis evaluated 136,318,924 SNPs (of which 6,289 had reached p<5e-8 in the discovery GWAS) from 4,397,962 participants across nine phenotypes. The overall replication rate was 85.0% and it was lower for binary than for quantitative phenotypes (58.1% versus 94.8% respectively). There was a18.0% decrease in SNP effect size for binary phenotypes, but a 12.0% increase for quantitative phenotypes. Using the discovery SNP effect size, phenotype trait (binary or quantitative), and discovery p-value, we built and validated a model that predicted SNP replication with area under the Receiver Operator Curve = 0.90. While non-replication may often reflect lack of power rather than genuine false-positive findings, these results provide insights about which discovered associations are likely to be seen again across subsequent GWAS.

scholarly journals CONVERGENT AGING LOCI: PATHWAYS THAT TRANSCEND INDIVIDUAL DISEASES

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S221-S221
Author(s):  
Luke C Pilling ◽  
Luigi Ferrucci ◽  
David Melzer
Keyword(s):  
Disease Risk ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Telomere Shortening ◽  
Chronic Disease Risk ◽  
Trade Offs ◽  
Age Related ◽  
Genome Wide ◽  
Artery Disease

Abstract Thousands of loci across the genome have been identified for specific diseases in genome-wide association studies (GWAS), yet very few are associated with lifespan itself. We hypothesized that specific biological pathways transcend individual diseases and affect health and lifespan more broadly. Using the published results for the most recent GWAS for 10 key age-related diseases (including coronary artery disease, type-2 diabetes, and several cancers) we identified 22 loci with a strong genetic association with at least three of the diseases. These multi-trait aging loci include known genes affecting multiple diverse health end points, such as CDKN2A/B (9p21.3) and APOE. There are also novel multi-trait genes including SH2B3 and CASC8, likely involved in hallmark pathways of aging biology, including telomere shortening and inflammation. Several of these loci involve trade-offs between chronic disease risk and cancer.

Identification of two genes as novel susceptibility loci for type 2 diabetes mellitus in Japanese

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Oguri ◽  
K Kato ◽  
H Horibe ◽  
T Fujimaki ◽  
J Sakuma ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Association Studies ◽  
East Asian ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Asian Populations ◽  
Genome Wide ◽  
Minor Alleles

Abstract Background The heritability of Type 2 diabetes mellitus (T2DM) has been estimated to be 50% to 60%. Although genome-wide association studies identified &gt;120 loci that confer susceptibility to T2DM, these studies were commonly conducted in a cross-sectional manner. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to T2DM in Japanese. We have now performed longitudinal exome-wide association studies (EWASs) to identify novel loci for T2DM by examining temporal changes in fasting plasma glucose (FPG) level, blood hemoglobin A1c (HbA1c) content, and the prevalence of T2DM. Methods Longitudinal EWASs (mean follow-up period, 5 years) were performed with Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip arrays and with 6,022 Japanese (755 subjects with T2DM, 5267 controls). The relation of genotypes of 24,579 SNPs that passed quality control to FPG level, blood HbA1c content, or the prevalence of T2DM was examined with the generalized estimating equation (GEE). To compensate for multiple comparisons of genotypes with each of the three parameters, we applied Bonferroni's correction for statistical significance of association. Results Longitudinal EWASs (GEE with adjustment for age, sex, body mass index, and smoking) revealed that rs6414624 of EVC (P&lt;2.0×10–16 for T2DM, P=9.1×10–11 for FPG), rs78338345 of GGA3 (P&lt;2.0×10–16 for T2DM, P=4.3×10–9 for FPG), rs10490775 of PTPRG (P&lt;2.0×10–16 for T2DM, P=3.3×10–7 for FPG), and rs61739510 of GLT6D1 (P&lt;2.0×10–16 for T2DM, P=5.8×10–7 for FPG) were significantly associated with the prevalence of T2DM and FPG levels; and rs11558471 in SLC30A8 with FPG level (P=1.8×10–8) and blood HbA1c content (P=1.2×10–7). After examination of the relation of identified SNPs to FPG level and blood HbA1c content, linkage disequilibrium of the SNPs, and results of the previous genome-wide association studies, we identified rs6414624 of EVC and rs78338345 of GGA3 as novel susceptibility loci for T2DM. In the identified SNPs (rs6414624 and rs7833834), FPG level, blood HbA1c content, and the prevalence of T2DM were significantly lower in homozygotes with the minor alleles than in homozygotes with the major alleles or heterozygotes. These results suggest that the minor alleles of rs6414624 and rs78338345 are protective against T2DM in Japanese. According to allele frequency data from the 1000 Genomes Project database, the minor G allele of rs78338345 of GGA3 is specifically distributed in East Asia. This suggests that the minor allele frequency may have increased in East Asian populations after the split of East Asian and non-East Asian populations. Conclusion We have newly identified EVC and GGA3 as susceptibility loci for T2DM in Japanese. Determination of genotypes for these SNPs at these loci may prove informative for assessment of the genetic risk for T2DM in Japanese. Funding Acknowledgement Type of funding source: None

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