scholarly journals Whole-Exome sequencing identifies a Type 2 Diabetes candidate mutation in PTPRF

2020 ◽  
Author(s):  
Erik J.M. Toonen ◽  
Michael Kwint ◽  
Alexander Hoischen ◽  
Cees J. Tack
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Association Studies ◽  
Family Members ◽  
Genome Wide Association Studies ◽  
Whole Exome

Objectives: Identification of genetic factors involved in Type 2 diabetes mellitus (T2DM) has been challenging. While genome-wide association studies (GWAS) have identified over 60 loci associated with T2DM, these variants only explain a small proportion of the total heritability of the disease. Whole-exome sequencing has become a powerful approach to identify genetic variants that are not captured by GWAS. We applied exome sequencing to identify causal genetic variants in a family with a 2-generation history of T2DM characterized by substantial insulin resistance, hypertension and isolated hypertriglyceridemia. Methods: Exome sequencing was performed on genomic DNA of two affected family members. Twenty-four identified variants that were present in both family members were further tested for segregation in all other family members by Sanger sequencing. Results: Three rare missense variants, located in the genes PTPRF, FUCA1 and FBXO30, were present in all affected family members but also in one unaffected family member. Protein-protein interaction analysis showed that PTPRF strongly interacts with several members of the insulin signaling pathway. Conclusions: Our results suggest that the variant in the PTPRF gene might be causal for an unusual T2DM subtype that is characterized by a severe insulin resistance and isolated hypertriglyceridemia.

Whole exome sequencing identifies the novel putative gene variants related with type 2 diabetes in Mizo population, northeast India

Gene ◽  
2021 ◽  
Vol 769 ◽  
pp. 145229
Author(s):  
Freda Lalrohlui ◽  
John Zohmingthanga ◽  
Vanlal hruaii ◽  
Andrew Vanlallawma ◽  
Nachimuthu Senthil Kumar
Keyword(s):  
Type 2 Diabetes ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Northeast India ◽  
Gene Variants ◽  
The Novel ◽  
Putative Gene ◽  
Whole Exome

scholarly journals Whole-Exome Sequencing of 2,000 Danish Individuals and the Role of Rare Coding Variants in Type 2 Diabetes

2014 ◽  
Vol 94 (3) ◽  
pp. 479
Author(s):  
Kirk E. Lohmueller ◽  
Thomas Sparsø ◽  
Qibin Li ◽  
Ehm Andersson ◽  
Thorfinn Korneliussen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome ◽  
Coding Variants

scholarly journals Identification of novel non-synonymous variants associated with type 2 diabetes-related metabolites in Korean population

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Tae-Joon Park ◽  
Heun-Sik Lee ◽  
Young Jin Kim ◽  
Bong-Jo Kim
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Variants ◽  
Multiple Testing ◽  
Association Studies ◽  
Linear Regression Analysis ◽  
Genetic Regulation ◽  
Genome Wide Association Studies ◽  
Functional Variants ◽  
Genome Wide

Abstract Metabolome-genome wide association studies (mGWASs) are useful for understanding the genetic regulation of metabolites in complex diseases, including type 2 diabetes (T2D). Numerous genetic variants associated with T2D-related metabolites have been identified in previous mGWASs; however, these analyses seem to have difficulty in detecting the genetic variants with functional effects. An exome array focussed on potentially functional variants is an alternative platform to obtain insight into the genetics of biochemical conversion processes. In the present study, we performed an mGWAS using 27,140 non-synonymous variants included in the Illumina HumanExome BeadChip and nine T2D-related metabolites identified by a targetted metabolomics approach to evaluate 2,338 Korean individuals from the Korea Association REsource (KARE) cohort. A linear regression analysis controlling for age, sex, BMI, and T2D status as covariates was performed to identify novel non-synonymous variants associated with T2D-related metabolites. We found significant associations between glycine and CPS1 (rs1047883) and PC ae C36:0 and CYP4F2 (rs2108622) variants (P<2.05 × 10−7, after the Bonferroni correction for multiple testing). One of the two significantly associated variants, rs1047883 was newly identified whereas rs2108622 had been previously reported to be associated with T2D-related traits. These findings expand our understanding of the genetic determinants of T2D-related metabolites and provide a basis for further functional validation.

scholarly journals Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes

2021 ◽  
Author(s):  
Jayant Mahadevan ◽  
Ajai Kumar Pathak ◽  
Alekhya Vemula ◽  
Ravi Kumar Nadella ◽  
Biju Viswanath ◽  
...  
Keyword(s):  
Mental Illness ◽  
Severe Mental Illness ◽  
Positive Selection ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Association Studies ◽  
Psychiatric Disease ◽  
Genome Wide Association Studies ◽  
Whole Exome ◽  
Selection Of

Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 75 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimers disease and cognitive abilities in genome wide association studies. We then checked whether any of these 75 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 75 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.

scholarly journals A maternal GOT1 novel variant associated with early-onset severe preeclampsia identified by whole-exome sequencing

2020 ◽  
Author(s):  
Lin Zhang ◽  
Zheng Cao ◽  
Fan Feng ◽  
Ya-Nan Xu ◽  
LIN LI ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Early Onset ◽  
Molecular Mechanisms ◽  
Bioinformatics Analysis ◽  
Perinatal Death ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Mutation Site ◽  
Whole Exome

Abstract Background This study wants to know the genetic cause of preeclampsia (PE) which is a leading cause of maternal and perinatal death, but the underlying molecular mechanisms that cause PE remain poorly understood. Many single nucleotide polymorphisms have been identified by genome-wide association studies and were found to be associated with PE; however, few studies have used whole-exome sequencing (WES) to identify PE mutations. Methods Five patients with severe early-onset preeclampsia (EOPE) were recruited, and WES was performed on each patient. Sanger sequencing was used to confirm the potential causative genetic mutation. Results After a stringent bioinformatics analysis, a rare mutation in the GOT1 gene, c.44C>G:p.P15R, was found in one patient. Bioinformatics analysis showed that the mutation site is highly conserved across several species and was predicted to be a pathogenic mutation according to several online mutational function prediction software packages. Further structural biology homology modeling suggested that P15R would change the electric environment of enzymatic center, and might affect the binding affinity of substrate or product. Conclusion We demonstrated for the first time that the mutation in GOT1 may be associated with EOPE, the results of this study provide researchers and clinicians with a better understanding of the molecular mechanisms that underlie maternal severe EOPE.

scholarly journals A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes

2015 ◽  
Vol 47 (6) ◽  
pp. 215-224 ◽  
Author(s):  
L. Maria Belalcazar ◽  
George D. Papandonatos ◽  
Jeanne M. McCaffery ◽  
Inga Peter ◽  
Nicholas M. Pajewski ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Lifestyle Intervention ◽  
Genetic Variants ◽  
Association Studies ◽  
Lifestyle Changes ◽  
Genome Wide Association Studies ◽  
Look Ahead ◽  
Genome Wide

Overweight/obese individuals with Type 2 diabetes have low adiponectin levels, which may improve with lifestyle changes. We investigated whether genetic variants associated with adiponectin levels in genome-wide association studies (GWAS) would also be related with adiponectin changes in response to an intensive lifestyle intervention (ILI), potentially through mechanisms altering the adipose microenvironment via weight loss and/or improved cardiorespiratory fitness. Look AHEAD was a randomized trial comparing the cardiovascular benefits of ILI-induced weight loss and physical activity compared with diabetes support and education among overweight/obese individuals with Type 2 diabetes. In a subsample of Look AHEAD with adiponectin data and genetic consent ( n = 1,351), we evaluated the effects of 24 genetic variants, demonstrated by GWAS to be cross-sectionally associated with adiponectin, on adiponectin change 1-yr postintervention. We explored via mediational analyses whether any differential effects by treatment arm were occurring through weight loss and/or improved fitness. A variant, rs222857, in the CLDN7 locus, potentially associated with epithelial barrier integrity and tight junction physiology, and a putative cis expression quantitative trail locus for elongator acetyltransferase complex subunit 5 ( ELP5), predicted adiponectin increases within ILI (log-adiponectin in overall sample per copy: β ± SE = 0.05 ± 0.02, P = 0.008; in non-Hispanic whites: 0.06 ± 0.02, P = 0.009). The favorable effects of rs222857 (minor allele frequency 45.5%) appeared to be mediated by mechanisms associated with improved fitness, and not weight loss. This is the first study to identify a genetic variant that modifies adiponectin response to lifestyle intervention in overweight/obese diabetic individuals.

scholarly journals A maternal GOT1 novel mutation associated with early-onset severe preeclampsia identified by whole-exome sequencing

2019 ◽  
Author(s):  
Lin Zhang ◽  
Zheng Cao ◽  
Fan Feng ◽  
Ya-Nan Xu ◽  
LIN LI ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Early Onset ◽  
Molecular Mechanisms ◽  
Bioinformatics Analysis ◽  
Perinatal Death ◽  
Novel Mutation ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Whole Exome

Abstract Purpose: This study wants to know the genetic cause of preeclampsia (PE) which is a leading cause of maternal and perinatal death, but the underlying molecular mechanisms that cause PE remain poorly understood. Many single nucleotide polymorphisms have been identified by genome-wide association studies and were found to be associated with PE; however, few studies have used whole-exome sequencing (WES) to identify PE mutations.Methods: Five patients with severe early-onset preeclampsia (EOPE) were recruited, and WES was performed on each patient. Sanger sequencing was used to confirm the potential causative genetic mutation. Results: After a stringent bioinformatics analysis, a rare mutation in the GOT1 gene, c.44C>G:p.P15R, was found in one patient. Bioinformatics analysis showed that the mutation site is highly conserved across several species and was predicted to be a pathogenic mutation according to several online mutational function prediction software packages. Further structural biology homology modeling suggested that P15R would change the electric environment of enzymatic center, and might affect the binding affinity of substrate or product. Conclusion: We demonstrated for the first time that the mutation in GOT1 may be associated with EOPE, the results of this study provide researchers and clinicians with a better understanding of the molecular mechanisms that underlie maternal severe EOPE.

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