scholarly journals Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes

2017 ◽  
Vol 29 (1) ◽  
pp. 335-348 ◽  
Author(s):  
Tanguy Corre ◽  
Francisco J. Arjona ◽  
Caroline Hayward ◽  
Sonia Youhanna ◽  
Jeroen H.F. de Baaij ◽  
...  
Keyword(s):  
General Population ◽  
Meta Analysis ◽  
Human Kidney ◽  
Environment Interaction ◽  
Genetic Determinants ◽  
Metabolic Disturbances ◽  
Renal Handling ◽  
Gene Environment ◽  
Genome Wide ◽  
A Genome

Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10−13) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1×10−11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene–environment interaction linking Mg2+ deficiency to insulin resistance and obesity.

scholarly journals Genome-wide stress sensitivity moderates the stress-depression relationship in a nationally representative sample of adults

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Trent Davidson ◽  
David B. Braudt ◽  
Robert Keers ◽  
Elham Assary ◽  
Kathleen Mullan Harris ◽  
...  
Keyword(s):  
Add Health ◽  
Stress Sensitivity ◽  
Environment Interaction ◽  
Genetic Determinants ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Genome Wide ◽  
A Genome ◽  
Nationally Representative ◽  
The Relationship

AbstractWe re-evaluate the findings of one of the most cited and disputed papers in gene-environment interaction (GxE) literature. In 2003, a paper was published in Science in which the authors demonstrated that the relationship between stress and depression is moderated by a polymorphism in the promoter region (5-HTTLPR) of the gene SLC6A4. Replication has been weak and led many to challenge the overall significance of GxE research. Here, we utilize data from Add Health, a large, nationally representative, and well-powered longitudinal study to re-examine the genetic determinants of stress sensitivity. We characterize environmental sensitivity using a genome-wide polygenic indicator rather than relying on one polymorphism in a single candidate gene. Our results provide support for the stress-diathesis perspective and validate the scientific contributions of the original paper.

Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia

2020 ◽  
Vol 105 (12) ◽  
pp. 3854-3864
Author(s):  
Jin-Fang Chai ◽  
Shih-Ling Kao ◽  
Chaolong Wang ◽  
Victor Jun-Yu Lim ◽  
Ing Wei Khor ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Hba1c Level ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Specific Reference ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Abstract Context Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. Objective To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. Design and Participants We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. Results Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. Conclusion We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

scholarly journals Effect of polygenic risk scores on depression in childhood trauma

2014 ◽  
Vol 205 (2) ◽  
pp. 113-119 ◽  
Author(s):  
Wouter J. Peyrot ◽  
Yuri Milaneschi ◽  
Abdel Abdellaoui ◽  
Patrick F. Sullivan ◽  
Jouke J. Hottenga ◽  
...  
Keyword(s):  
Childhood Trauma ◽  
Meta Analysis ◽  
Genetic Effect ◽  
Risk Scores ◽  
Environment Interaction ◽  
Polygenic Risk ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Genome Wide ◽  
Direct Genetic Effect

BackgroundResearch on gene×environment interaction in major depressive disorder (MDD) has thus far primarily focused on candidate genes, although genetic effects are known to be polygenic.AimsTo test whether the effect of polygenic risk scores on MDD is moderated by childhood trauma.MethodThe study sample consisted of 1645 participants with a DSM-IV diagnosis of MDD and 340 screened controls from The Netherlands. Chronic or remitted episodes (severe MDD) were present in 956 participants. The occurrence of childhood trauma was assessed with the Childhood Trauma Interview and the polygenic risk scores were based on genome-wide meta-analysis results from the Psychiatric Genomics Consortium.ResultsThe polygenic risk scores and childhood trauma independently affected MDD risk, and evidence was found for interaction as departure from both multiplicativity and additivity, indicating that the effect of polygenic risk scores on depression is increased in the presence of childhood trauma. The interaction effects were similar in predicting all MDD risk and severe MDD risk, and explained a proportion of variation in MDD risk comparable to the polygenic risk scores themselves.ConclusionsThe interaction effect found between polygenic risk scores and childhood trauma implies that (1) studies on direct genetic effect on MDD gain power by focusing on individuals exposed to childhood trauma, and that (2) individuals with both high polygenic risk scores and exposure to childhood trauma are particularly at risk for developing MDD.

scholarly journals Re-analysis of a Genome-Wide Gene-By-Environment Interaction Study of Case Parent Trios, Adjusted for Population Stratification

2021 ◽  
Vol 11 ◽  
Author(s):  
Pulindu Ratnasekera ◽  
Brad McNeney
Keyword(s):  
East Asian ◽  
Environment Interaction ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Multivitamin Supplementation ◽  
Gene Environment ◽  
Genome Wide ◽  
A Genome ◽  
The Impact ◽  
East Asian Ancestry

We investigate the impact of confounding on the results of a genome-wide association analysis by Beaty et al., which identified multiple single nucleotide polymorphisms that appeared to modify the effect of maternal smoking, alcohol consumption, or multivitamin supplementation on risk of cleft palate. The study sample of case-parent trios was primarily of European and East Asian ancestry, and the distribution of all three exposures differed by ancestral group. Such differences raise the possibility that confounders, rather than the exposures, are the risk modifiers and hence that the inference of gene-environment (G×E) interaction may be spurious. Our analyses generally confirmed the result of Beaty et al. and suggest the interaction G×E is driven by the European trios, whereas the East Asian trios were less informative.

scholarly journals Genome-wide meta-analysis of cognitive empathy: heritability, and correlates with sex, neuropsychiatric conditions and brain anatomy

2016 ◽  
Author(s):  
Varun Warrier ◽  
Katrina Grasby ◽  
Florina Uzefovsky ◽  
Roberto Toro ◽  
Paula Smith ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Cognitive Empathy ◽  
European Ancestry ◽  
Brain Anatomy ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Cognitive Aptitude ◽  
Genome Wide ◽  
A Genome ◽  
Research Volunteers

We conducted a genome-wide meta-analysis of cognitive empathy using the ‘Reading the Mind in the Eyes’ Test (Eyes Test) in 88,056 research volunteers of European Ancestry (44,574 females and 43,482 males) from 23andMe Inc., and an additional 1,497 research volunteers of European Ancestry (891 females and 606 males) from the Brisbane Longitudinal Twin Study (BLTS). We confirmed a female advantage on the Eyes Test (Cohen’s d = 0.21, P < 2.2x10−16), and identified a locus in 3p26.1 that is associated with scores on the Eyes Test in females (rs7641347, Pmeta = 1.58 x 10−8). Common single nucleotide polymorphisms (SNPs) explained 5.8% (95% CI: 0.45 - 0.72; P = 1.00 x 10−17) of the total trait variance in both sexes, and we identified a twin heritability of 0.28 (95% CI: 0.13-0.42). Finally, we identified significant genetic correlation between the Eyes Test and anorexia nervosa, measures of empathy (the Empathy Quotient), openness (NEO-Five Factor Inventory), and different measures of educational attainment and cognitive aptitude, and show that the genetic determinants of volumes of the dorsal striatum (caudate nucleus and putamen) are positively correlated with the genetic determinants of performance on the Eyes Test.

scholarly journals Genetics of addictive behavior: the example of nicotine dependence

2017 ◽  
Vol 19 (3) ◽  
pp. 237-245 ◽  
Keyword(s):  
Lung Cancer ◽  
Nicotine Dependence ◽  
Genome Wide Association Study ◽  
Environment Interaction ◽  
Addictive Disorders ◽  
Gene Environment ◽  
Genome Wide ◽  
A Genome ◽  
Significant Heritability ◽  
Parent Monitoring

The majority of addictive disorders have a significant heritability—roughly around 50%. Surprisingly, the most convincing association (a nicotinic acetylcholine receptor CHRNA5-A3-B4 gene cluster in nicotine dependence), with a unique attributable risk of 14%, was detected through a genome-wide association study (GWAS) on lung cancer, although lung cancer has a low heritability. We propose some explanations of this finding, potentially helping to understand how a GWAS strategy can be successful. Many endophenotypes were also assessed as potentially modulating the effect of nicotine, indirectly facilitating the development of nicotine dependence. Challenging the involved phenotype led to the demonstration that other potentially overlapping disorders, such as schizophrenia and Parkinson disease, could also be involved, and further modulated by parent monitoring or the existence of a smoking partner. Such a complex mechanism of action is compatible with a gene-environment interaction, most clearly explained by epigenetic factors, especially as such factors were shown to be, at least partly, genetically driven.

scholarly journals Using Genome Wide Estimates of Heritability to Examine the Relevance of Gene-Environment Interplay

2016 ◽  
Author(s):  
BENJAMIN W DOMINGUE ◽  
Jason D. Boardman
Keyword(s):  
Genome Wide Association Study ◽  
Environment Interaction ◽  
Education Group ◽  
Gene Environment ◽  
Genome Wide ◽  
Heart Study ◽  
A Genome ◽  
Genome Wide Data ◽  
Higher Educational Attainment ◽  
Family Based

We use genome-wide data from the third generation respondents of the Framingham Heart Study to estimate heritability in body mass index using different quantities of the measured genotype. Heritability decreases rapidly when SNPs implicated by a genome-wide association study are removed but shows essentially no decline when SNPs implicated by a gene-environment interaction in a second genome-wide analysis are removed. This second result is highlighted by our additional finding that the SNPs which explain heritability amongst a subsample defined by higher educational attainment explain no heritability of the heritability in the lower education group, and vice-versa. Finally, we do find consistent heritability estimates when we compare family-based estimates versus those based on measured genotype.

Genetic determinants of chronic oxaliplatin-induced peripheral neurotoxicity: a genome-wide study replication and meta-analysis

2015 ◽  
Vol 20 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Salvatore Terrazzino ◽  
Andreas A. Argyriou ◽  
Sarah Cargnin ◽  
Anna G. Antonacopoulou ◽  
Chiara Briani ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Genetic Determinants ◽  
Peripheral Neurotoxicity ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Study
Sign in / Sign up

Export Citation Format

Share Document