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1.
Recessive Genome-Wide Meta-analysis Illuminates Genetic Architecture of Type 2 Diabetes.
O'Connor, MJ, Schroeder, P, Huerta-Chagoya, A, Cortés-Sánchez, P, Bonàs-Guarch, S, Guindo-Martínez, M, Cole, JB, Kaur, V, Torrents, D, Veerapen, K, et al
Diabetes. 2022;(3):554-565
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Abstract
Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 case subjects and 279,507 control subjects from 7 European-ancestry cohorts, including the UK Biobank. We identified 51 loci associated with type 2 diabetes, including five variants undetected by prior additive analyses. Two of the five variants had minor allele frequency of <5% and were each associated with more than a doubled risk in homozygous carriers. Using two additional cohorts, FinnGen and a Danish cohort, we replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19; P = 1 × 10-16) and a stronger effect in men than in women (for interaction, P = 7 × 10-7). The signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL cholesterol and a 20% increase in triglycerides; colocalization analysis linked this signal to reduced expression of the nearby PELO gene. These results demonstrate that recessive models, when compared with GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.
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A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.
Whitfield, JB, Schwantes-An, TH, Darlay, R, Aithal, GP, Atkinson, SR, Bataller, R, Botwin, G, Chalasani, NP, Cordell, HJ, Daly, AK, et al
Journal of hepatology. 2022;(2):275-282
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Abstract
BACKGROUND & AIMS Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions. LAY SUMMARY Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.
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FokI polymorphism of the vitamin D receptor (VDR) gene and susceptibility to tuberculosis: Evidence through a meta-analysis.
Yadav, U, Kumar, P, Rai, V
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2021;:104871
Abstract
BACKGROUND Tuberculosis is one of the top ten causes of deaths worldwide. The deficiency of vitamin D was reported to be associated with the increased susceptibility of tuberculosis. Various previous reports were published to check the association of FokI polymorphism of the vitamin D receptor gene with tuberculosis risk. But their results were inconsistent so, we performed a meta-analysis to know the exact relation of the two. METHODS Different databases were screened up to November 2020 with the keywords "Vitamin D receptor", "VDR", and "FokI", along with "Tuberculosis" and "TB" to find the suitable articles. All the statistical analyses were performed by the Open Meta-Analyst program and all p-values were two-tailed with a significance level of 0.05. RESULTS No statistically significant association was observed in the allele contrast model (ORfvs.F = 1.11, 95%CI = 0.99-1.24, p = 0.05, I2 = 73.46%), in the dominant model (ORff+Ffvs.FF = 1.11, 95%CI = 0.96-1.28, p = 0.14, I2 = 71.39%), and in the co-dominant model (ORFfvs.FF = 1.05, 95%CI = 0.92-1.21, p = 0.41, I2 = 65.97%). However, a significant association was found in the homozygote model (ORffvs.FF = 1.32, 95%CI = 1.03-1.69, p = 0.02, I2 = 67.02%) and in the recessive model (ORFF+Ff vs.ff = 1.26, 95%CI = 1.03-1.54, p = 0.02, I2 = 58.01%). Further analysis was performed on the bases of the ethnicity. In Asian population a significant association was found in the homozygote model (ORffvs.FF = 1.57, 95%CI = 1.12-2.21, p = 0.008, I2 = 70.37%) and in the recessive model (ORFF+Ff vs.ff = 1.43, 95%CI = 1.08-1.89, p = 0.01, I2 = 63.13%). CONCLUSION In conclusion, a significant association of FokI with tuberculosis susceptibility was found in the overall analysis and in the Asian population.
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TRIM28 variants and Wilms' tumour predisposition.
Hol, JA, Diets, IJ, de Krijger, RR, van den Heuvel-Eibrink, MM, Jongmans, MC, Kuiper, RP
The Journal of pathology. 2021;(4):494-504
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Abstract
TRIM28 was recently identified as a Wilms' tumour (WT) predisposition gene, with germline pathogenic variants identified in around 1% of isolated and 8% of familial WT cases. TRIM28 variants are associated with epithelial WT, but the presence of other tumour components or anaplasia does not exclude the presence of a germline or somatic TRIM28 variant. In children with WT, TRIM28 acts as a classical tumour suppressor gene, with both alleles generally disrupted in the tumour. Therefore, loss of TRIM28 (KAP1/TIF1beta) protein expression in tumour tissue by immunohistochemistry is an effective strategy to identify patients carrying pathogenic TRIM28 variants. TRIM28 is a ubiquitously expressed corepressor that binds transcription factors in a context-, species-, and cell-type-specific manner to control the expression of genes and transposable elements during embryogenesis and cellular differentiation. In this review, we describe the inheritance patterns, histopathological and clinical features of TRIM28-associated WT, as well as potential underlying mechanisms of tumourigenesis during embryonic kidney development. Recognizing germline TRIM28 variants in patients with WT can enable counselling, genetic testing, and potential early detection of WT in other children in the family. A further exploration of TRIM28-associated WT will help to unravel the diverse and complex mechanisms underlying WT development. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Insight into susceptibility genes associated with bipolar disorder: a systematic review.
Kalcev, G, Preti, A, Scano, A, Orrù, G, Carta, MG
European review for medical and pharmacological sciences. 2021;(18):5701-5724
Abstract
OBJECTIVE Bipolar disorder (BD) is a severe disorder, and it is associated with an increased risk of mortality. About 25% of patients with BD have attempted and 11% have died by suicide. All these characteristics suggest that the disorders within the bipolar spectrum are a crucial public health problem. With the development of molecular genetics in recent decades, it was possible to more easily detect risk genes associated with this disorder. This study aimed at summarizing the findings of systematic reviews and meta-analyses on the topic and assessing the quality of the available evidence. MATERIALS AND METHODS PubMed/Medline and Web of Science were searched to identify systematic reviews and meta-analyses published during 2013-2019. Standard methodology was applied to synthesize and assess the retrieved literature. RESULTS This systematic review identifies a number of potential risk genes associated with bipolar disorder whose mechanism of action has yet to be confirmed. They are divided into several groups: 1) a list of the most significant susceptibility genetic factors associated with BD; 2) the implication of the ZNF804A gene in BD; 3) the role of genes involved in calcium signaling in BD; 4) DNA methylation in BD; 5) BD and risk suicide genes; 6) susceptibility genes for early-onset BD; 7) candidate genes common to both BD and schizophrenia; 8) genes involved in cognitive status in BD cases; 9) genes involved in structural alteration in BD brain tissue; 10) genes involved in lithium response in BD. CONCLUSIONS Future research should concentrate on molecular mechanisms by which genetic variants play a major role in BD. Supplemental research is needed to replicate the applicable results.
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ATP2B1 gene polymorphisms rs2681472 and rs17249754 are associated with susceptibility to hypertension and blood pressure levels: A systematic review and meta-analysis.
Xie, M, Yuan, S, Zeng, Y, Zheng, C, Yang, Y, Dong, Y, He, Q
Medicine. 2021;(15):e25530
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Abstract
OBJECTIVE The present study aimed to conduct a systematic review and meta-analysis to evaluate the relationships between ATP2B1 gene polymorphisms with blood pressure (BP) level and susceptibility to hypertension. METHODS PubMed, Web of Science, Embase and China National Knowledge Infrastructure (CNKI) Databases were systematically searched by 2 independent researchers to screen studies on ATP2B1 gene polymorphisms and BP related phenotypes. The records retrieval period was limited from the formation of the database to March 4, 2021. Pooled odds rations (ORs) or β and their 95% confidence intervals (95%CI) were calculated to assess the association between ATP2B1 gene polymorphisms and the risk of hypertension or BP levels. Publication bias and sensitivity analysis were conducted to find potential bias. All the statistical analysis were conducted with Stata version 11.0 software. RESULTS A total of 15 articles were ultimately included in the present study, including 15 polymorphisms of ATP2B1 gene. Nine articles (N = 65,362) reported the polymorphism rs17249754, and 7 articles(N = 91,997) reported rs2681472 (both loci were reported in 1 article). Meta-analysis showed that rs17249754 (G/A) and rs2681472 (A/G) were associated with the susceptibility to hypertension (rs17249754: OR = 1.19, 95%CI: 1.10-1.28; rs2681472: OR = 1.15, 95%CI: 1.12-1.17), and were positively associated with systolic BP (SBP) and diastolic blood pressure (DBP) (rs17249754: SBP, β=1.01, 95%CI: 0.86-1.16, DBP, β=0.48, 95%CI: 0.30-0.66; rs2681472: SBP, β=0.92, 95%CI: 0.77-1.07, DBP, β=0.50, 95%CI: 0.42-0.58) in the additive genetic model. Subgroup analysis stratified by race, population, sample size, and BP measurement method revealed that the association between A allele in rs2681472 polymorphism and risk of hypertension was slightly stronger in European (EUR) populations (OR = 1.16, 95%CI: 1.13-1.20) than in East Asians (OR = 1.14, 95%CI: 1.10-1.17). While in East Asians, relation between rs17249754 with risk of hypertension (OR = 1.19, 95%CI: 1.10-1.28) is stronger than rs2681472 (OR = 1.14, 95%CI: 1.10-1.17). CONCLUSIONS Our study demonstrated that ATP2B1 gene polymorphism rs2681472 and rs17249754 were associated with BP levels and the susceptibility to hypertension.
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A Systematic Review of Genetic Polymorphisms Associated with Binge Eating Disorder.
Manfredi, L, Accoto, A, Couyoumdjian, A, Conversi, D
Nutrients. 2021;(3)
Abstract
The genetic polymorphisms involved in the physiopathology of binge eating disorder (BED) are currently unclear. This systematic review aims to highlight and summarize the research on polymorphisms that is conducted in the BED. We looked for observational studies where there was a genetic comparison between adults with BED, in some cases also with obesity or overweight, and healthy controls or obesity/overweight without BED. Our protocol was written using PRISMA. It is registered at PROSPERO (identification: CRD42020198645). To identify potentially relevant documents, the following bibliographic databases were searched without a time limit, but until September 2020: PubMed, PsycINFO, Scopus, and Web of Science. In total, 21 articles were included in the qualitative analysis of the systematic review, as they met the eligibility criteria. Within the selected studies, 41 polymorphisms of 17 genes were assessed. Overall, this systematic review provides a list of potentially useful genetic polymorphisms involved in BED: 5-HTTLPR (5-HTT), Taq1A (ANKK1/DRD2), A118G (OPRM1), C957T (DRD2), rs2283265 (DRD2), Val158Met (COMT), rs6198 (GR), Val103Ile (MC4R), Ile251Leu (MC4R), rs6265 (BNDF), and Leu72Met (GHRL). It is important to emphasize that Taq1A is the polymorphism that showed, in two different research groups, the most significant association with BED. The remaining polymorphisms need further evidence to be confirmed.
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Diet and physical activity in Greenland: genetic interactions and associations with obesity and diabetes.
Senftleber, NK, Overvad, M, Dahl-Petersen, IK, Bjerregaard, P, Jørgensen, ME
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2021;(8):849-855
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Abstract
The Inuit in Greenland have gone through dramatic lifestyle changes during the last half century. More time is spent being sedentary and imported foods replaces traditional foods like seal and whale. The population has also experienced a rapid growth in obesity and metabolic disturbances and diabetes is today common despite being almost unknown few decades ago. In this paper, we describe and discuss the role of lifestyle changes and genetics for Inuit metabolic health. Novelty: Cardiometabolic disease risk has increased in Greenland. Lifestyle changes and possibly gene-lifestyle interactions play a role.
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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.
, , Dorling, L, Carvalho, S, Allen, J, González-Neira, A, Luccarini, C, Wahlström, C, Pooley, KA, Parsons, MT, Fortuno, C, et al
The New England journal of medicine. 2021;(5):428-439
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Abstract
BACKGROUND Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).
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Causal Association between Periodontitis and Parkinson's Disease: A Bidirectional Mendelian Randomization Study.
Botelho, J, Machado, V, Mendes, JJ, Mascarenhas, P
Genes. 2021;(5)
Abstract
The latest evidence revealed a possible association between periodontitis and Parkinson's disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = -0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = -0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = -0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.