Prioritizing genes for follow-up from genome wide association studies using information on gene expression in tissues relevant for type 2 diabetes mellitus

The method of Genome-Wide Association Studies (GWAS) steadily becomes the basis for searching for candidate genes of monogenic and multifactorial diseases, including type 1 and 2 diabetes mellitus, coronary heart disease, obesity, vascular diseases, and others. To date, approximately 40 loci associated with type 2 diabetes mellitus (T2DM) have been identified and genetic predisposition factors for cardiovascular diseases have been determined. In some cases, the GWAS results not only enable understanding of the pathophysiologic basis for diseases, but also may give rise to new drugs. However, the question naturally arises about the possibility of implementing the accumulated knowledge to predict the development of diseases, including T2DM and its vascular complications. This review summarises the literature data on the possibilities to use the GWAS results to calculate the risk of developing diabetes and cardiovascular diseases. Determination of the individual genetic risk will allow for the primary prevention of diseases and will apparently be the basis of personalised predictive medicine in the near future.

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Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

Diabetologia ◽

10.1007/s00125-008-1196-4 ◽

2008 ◽

Vol 52 (2) ◽

pp. 253-261 ◽

Cited By ~ 147

Author(s):

Y. M. Cho ◽

T. H. Kim ◽

S. Lim ◽

S. H. Choi ◽

H. D. Shin ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Genetic Variants ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

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Genetic Susceptibility to Type 2 Diabetes and Obesity: Follow-Up of Findings from Genome-Wide Association Studies

International Journal of Endocrinology ◽

10.1155/2014/769671 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 44

Author(s):

Kevin J. Basile ◽

Matthew E. Johnson ◽

Qianghua Xia ◽

Struan F. A. Grant

Keyword(s):

Type 2 Diabetes ◽

Association Studies ◽

Genetic Research ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Clinical Genetic ◽

Genome Wide ◽

Diabetes And Obesity

Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies ofTCF7L2andFTOhave typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context.

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Genetics and Epigenetics: New Insight on Gestational Diabetes Mellitus

Frontiers in Endocrinology ◽

10.3389/fendo.2020.602477 ◽

2020 ◽

Vol 11 ◽

Author(s):

Maria Grazia Dalfrà ◽

Silvia Burlina ◽

Gloria Giovanna Del Vescovo ◽

Annunziata Lapolla

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Gestational Diabetes ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Maternal Metabolism

Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy, with a prevalence that has increased significantly in the last decade, coming to affect 12–18% of all pregnancies. GDM is believed to be the result of a combination of genetic, epigenetic and environmental factors. Following the identification of susceptibility genes for type 2 diabetes by means of genome-wide association studies, an association has also been demonstrated between some type 2 diabetes susceptibility genes and GDM, suggesting a partial similarity of the genetic architecture behind the two forms of diabetes. More recent genome-wide association studies, focusing on maternal metabolism during pregnancy, have demonstrated an overlap in the genes associated with metabolic traits in gravid and non-gravid populations, as well as in genes apparently unique to pregnancy. Epigenetic changes—such as DNA methylation, histone modifications and microRNA gene silencing—have also been identified in GDM patients. Metabolomics has been used to profile the metabolic state of women during pregnancy, based on the measurement of numerous low-molecular-weight metabolites. Measuring amino acids and conventional metabolites has revealed changes in pregnant women with a higher insulin resistance and high blood glucose levels that resemble the changes seen in non-gravid, insulin-resistant populations. This would suggest similarities in the metabolic profiles typical of insulin resistance and hyperglycemia whether individuals are pregnant or not. Future studies combining data obtained using multiple technologies will enable an integrated systems biology approach to maternal metabolism during a pregnancy complicated by GDM. This review highlights the recent knowledge on the impact of genetics and epigenetics in the pathophysiology of GDM and the maternal and fetal complications associated with this pathology condition.

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

Human Molecular Genetics ◽

10.1093/hmg/ddab044 ◽

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.

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