GWAS of Post-Orthodontic Aggressive External Apical Root Resorption Identified Multiple Putative Loci at X-Y Chromosomes

Personalized dental medicine requires from precise and customized genomic diagnostic. To conduct an association analysis over multiple putative loci and genes located at chromosomes 2, 4, 8, 12, 18, X, and Y, potentially implicated in an extreme type of external apical root resorption secondary to orthodontic forces (aEARR). A genome-wide association study of aEARR was conducted with 480 patients [ratio~1:3 case/control]. Genomic DNA was extracted and analyzed using the high-throughput Axiom platform with the GeneTitan® MC Instrument. Up to 14,377 single nucleotide polymorphisms (SNPs) were selected at candidate regions and clinical/diagnostic data were recorded. A descriptive analysis of the data along with a backward conditional binary logistic regression was used to calculate odds ratios, with 95% confidence intervals [p < 0.05]. To select the best SNP candidates, a logistic regression model was fitted assuming a log-additive genetic model using R software [p < 0.0001]. In this sample the top lead genetic variants associated with aEARR were two novel putative genes located in the X chromosome, specifically, STAG 2 gene, rs151184635 and RP1-30E17.2 gene, rs55839915. These variants were found to be associated with an increased risk of aEARR, particularly restricted to men [OR: 6.09; 95%CI: 2.6–14.23 and OR: 6.86; 95%CI: 2.65–17.81, respectively]. Marginal associations were found at previously studied variants such as SSP1: rs11730582 [OR: 0.54; 95%CI: 0.34–0.86; p = 0.008], P2RX7: rs1718119 [OR: 0.6; 95%CI: 0.36–1.01; p = 0.047], and TNFRSF11A: rs8086340 [OR: 0.6; 95%CI: 0.38–0.95; p = 0.024]), found solely in females. Multiple putative genetic variants located at chromosomes X and Y are potentially implicated in an extreme phenotype of aEARR. A gender-linked association was noted.

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EXPRESS: Effect of genetic liability to visceral adiposity on stroke and its subtypes: a Mendelian randomization study

International Journal of Stroke ◽

10.1177/17474930211006285 ◽

2021 ◽

pp. 174749302110062

Author(s):

Bin Yan ◽

Jian Yang ◽

Li Qian ◽

Fengjie Gao ◽

Ling Bai ◽

...

Keyword(s):

Sensitivity Analysis ◽

Ischemic Stroke ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Visceral Adiposity ◽

Large Artery ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

A Genome ◽

Increased Risk

Background: Observational studies have found an association between visceral adiposity and stroke. Aims: The purpose of this study was to investigate the role and genetic effect of visceral adipose tissue (VAT) accumulation on stroke and its subtypes. Methods: In this two-sample Mendelian randomization (MR) study, genetic variants (221 single nucleotide polymorphisms; P<5Ã10-8) using as instrumental variables for MR analysis was obtained from a genome-wide association study (GWAS) of VAT. The outcome datasets for stroke and its subtypes were obtained from the MEGASTROKE consortium (up to 67,162 cases and 453,702 controls). MR standard analysis (inverse variance weighted method) was conducted to investigate the effect of genetic liability to visceral adiposity on stroke and its subtypes. Sensitivity analysis (MR-Egger, weighted median, MR-PRESSO) were also utilized to assess horizontal pleiotropy and remove outliers. Multi-variable MR analysis was employed to adjust potential confounders. Results: In the standard MR analysis, genetically determined visceral adiposity (per 1 SD) was significantly associated with a higher risk of stroke (odds ratio [OR] 1.30; 95% confidence interval [CI] 1.21-1.41, P=1.48Ã10-11), ischemic stroke (OR 1.30; 95% CI 1.20-1.41, P=4.01Ã10-10), and large artery stroke (OR 1.49; 95% CI 1.22-1.83, P=1.16Ã10-4). The significant association was also found in sensitivity analysis and multi-variable MR analysis. Conclusions: Genetic liability to visceral adiposity was significantly associated with an increased risk of stroke, ischemic stroke, and large artery stroke. The effect of genetic susceptibility to visceral adiposity on the stroke warrants further investigation.

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An artificial neural network approach integrating plasma proteomics and genetic data identifies PLXNA4 as a new susceptibility locus for pulmonary embolism

Scientific Reports ◽

10.1038/s41598-021-93390-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Misbah Razzaq ◽

Maria Jesus Iglesias ◽

Manal Ibrahim-Kosta ◽

Louisa Goumidi ◽

Omar Soukarieh ◽

...

Keyword(s):

Pulmonary Embolism ◽

Genome Wide Association Study ◽

Susceptibility Gene ◽

Biological Traits ◽

Nucleotide Polymorphisms ◽

Ann Model ◽

Neural Network Approach ◽

A Genome ◽

Increased Risk ◽

Artificial Neural

AbstractVenous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its potential fatal form, pulmonary embolism (PE). While PE is observed in ~ 40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (rs1424597: p = 5.3 × 10–7) at the PLXNA4 locus. Homozygote carriers for the rs1424597-A allele were then more frequently observed in PE than in DVT patients from the MARTHA (2% vs. 0.4%, p = 0.005) and the EOVT (3% vs. 0%, p = 0.013) studies. In a sample of 112 COVID-19 patients known to have endotheliopathy leading to acute lung injury and an increased risk of PE, decreased PLXNA4 levels were associated (p = 0.025) with worsened respiratory function. Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.

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Lifestyle factors and genetic variants on two biological age measures: evidence from 94,443 Taiwan Biobank participants

The Journals of Gerontology Series A ◽

10.1093/gerona/glab251 ◽

2021 ◽

Author(s):

Wan-Yu Lin

Keyword(s):

Genetic Variants ◽

Genome Wide Association Study ◽

Lifestyle Factors ◽

Biological Age ◽

Biological Aging ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome ◽

The Uk

Abstract Background Biological age (BA) can be estimated by phenotypes and is useful for predicting lifespan and healthspan. Levine et al. proposed a PhenoAge and a BioAge to measure BA. Although there have been studies investigating the genetic predisposition to BA acceleration in Europeans, little has been known regarding this topic in Asians. Methods I here estimated PhenoAgeAccel (age-adjusted PhenoAge) and BioAgeAccel (age-adjusted BioAge) of 94,443 Taiwan Biobank (TWB) participants, wherein 25,460 TWB1 subjects formed a discovery cohort and 68,983 TWB2 individuals constructed a replication cohort. Lifestyle factors and genetic variants associated with PhenoAgeAccel and BioAgeAccel were investigated through regression analysis and a genome-wide association study (GWAS). Results A unit (kg/m 2) increase of BMI was associated with a 0.177-year PhenoAgeAccel (95% C.I. = 0.163~0.191, p = 6.0×) and 0.171-year BioAgeAccel (95% C.I. = 0.165~0.177, p = 0). Smokers on average had a 1.134-year PhenoAgeAccel (95% C.I. = 0.966~1.303, p = 1.3×) compared with non-smokers. Drinkers on average had a 0.640-year PhenoAgeAccel (95% C.I. = 0.433~0.847, p = 1.3×) and 0.193-year BioAgeAccel (95% C.I. = 0.107~0.279, p = 1.1×) relative to non-drinkers. A total of 11 and 4 single-nucleotide polymorphisms (SNPs) were associated with PhenoAgeAccel and BioAgeAccel (p<5× in both TWB1 and TWB2), respectively. Conclusions A PhenoAgeAccel-associated SNP (rs1260326 in GCKR) and two BioAgeAccel-associated SNPs (rs7412 in APOE; rs16998073 near FGF5) were consistent with the finding from the UK Biobank. The lifestyle analysis shows that prevention from obesity, cigarette smoking, and alcohol consumption is associated with a slower rate of biological aging.

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Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

Multiple Sclerosis Journal ◽

10.1177/1352458518763089 ◽

2018 ◽

Vol 25 (4) ◽

pp. 565-573 ◽

Cited By ~ 4

Author(s):

Dorothea Buck ◽

Till FM Andlauer ◽

Wilmar Igl ◽

Eva-Maria Wicklein ◽

Mark Mühlau ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genetic Variants ◽

Neutralizing Antibodies ◽

Genome Wide Association Study ◽

Phase Iii ◽

Interferon Β ◽

Hla Alleles ◽

Genome Wide ◽

A Genome ◽

Increased Risk

Background: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β. Objective: To validate the proposed genetic markers and to identify new markers. Methods: Associations of genetic candidate markers with antibody presence and development were examined in a post hoc analysis in 941 patients treated with interferon β-1b in the Betaferon® Efficacy Yielding Outcomes of a New Dose (BEYOND) and BEtaseron®/BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) prospective phase III trials. All patients were treated with interferon β-1b for at least 6 months. In addition, a genome-wide association study was conducted to identify new genetic variants. Results: We confirmed an increased risk for carriers of HLA-DRB1*04:01 (odds ratio (OR) = 3.3, p = 6.9 × 10−4) and HLA-DRB1*07:01 (OR = 1.8, p = 3.5 × 10−3) for developing neutralizing antibodies (NAbs). Several additional, previously proposed HLA alleles and genetic variants showed nominally significant associations. In the exploratory analysis, variants in the HLA region were associated with NAb development at genome-wide significance (OR = 2.6, p = 2.30 × 10−15). Conclusion: The contribution of HLA alleles and HLA-associated single-nucleotide polymorphisms (SNPs) to the development and titer of antibodies against interferon β was confirmed in the combined analysis of two multi-national, multi-center studies.

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Evidence for Genetic Association of CARD9 and SNAPC4 with Ankylosing Spondylitis in a Chinese Han Population

The Journal of Rheumatology ◽

10.3899/jrheum.130519 ◽

2013 ◽

Vol 41 (2) ◽

pp. 318-324 ◽

Cited By ~ 11

Author(s):

Xiaochun Ma ◽

Yongchao Liu ◽

Hua Zhang ◽

Rongfang Qiu ◽

Hailing Zhao ◽

...

Keyword(s):

Ankylosing Spondylitis ◽

Mrna Expression ◽

Genome Wide Association Study ◽

Chinese Han Population ◽

Healthy Controls ◽

Nucleotide Polymorphisms ◽

Chinese Han ◽

Han Population ◽

A Genome ◽

Increased Risk

Objective.A genome-wide association study and 2 replication studies identified 2 single-nucleotide polymorphisms (SNP) of caspase recruitment domain-containing protein 9 (CARD9) and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) at Chr 9q34.3 associated with ankylosing spondylitis (AS) in whites. We explored a possible association of SNP in CARD9 and SNAPC4 and AS in a Chinese Han population from Shandong.Methods.The study included 1150 patients with AS and 1120 healthy controls who underwent genotyping for 4 SNP of CARD9 and 2 of SNAPC4; we replicated the results in another 490 patients and 380 healthy controls of Ningxia Han Chinese during the same time. We used quantitative real-time PCR (qRT-PCR) to measure CARD9 and SNAPC4 mRNA expression in peripheral leukocytes from 44 patients and 36 controls and allele-specific mRNA expression of CARD9 and SNAPC4 in leukocytes from 130 controls.Results.We validated that an SNP in SNAPC4, rs11145835, was significantly associated with AS in our Chinese Han population (p = 0.001) and replicated the association in samples from the Chinese Ningxia Han population (p = 0.002). Carrying the G allele of rs11145835 was associated with increased risk of AS (OR 1.34, 95% CI 1.12–1.59) and with decreased expression of CARD9 (p = 0.001) and SNAPC4 (p = 0.02) in leukocytes. SNAPC4 mRNA expression was lower in leukocytes from patients than from controls (p = 0.0002).Conclusion.Our study confirmed that an SNP rs11145835 in 9q34.3 that harbors CARD9 and SNAPC4 is associated with AS in a Chinese Han population, and rs11145835 in SNAPC4 is a potential causal variant.

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Correction: Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma: A Genome-Wide Association Study

PLoS ONE ◽

10.1371/journal.pone.0130109 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0130109 ◽

Cited By ~ 1

Author(s):

Giuseppe Matullo ◽

Simonetta Guarrera ◽

Marta Betti ◽

Giovanni Fiorito ◽

Daniela Ferrante ◽

...

Keyword(s):

Association Study ◽

Malignant Pleural Mesothelioma ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Pleural Mesothelioma ◽

Genome Wide ◽

A Genome ◽

Increased Risk

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Association between Polymorphisms in the IL-1β, TNFRSF11B, CASP1, and IL-6 Genes and Orthodontic-Induced External Apical Root Resorption

Journal of Clinical Medicine ◽

10.3390/jcm10184166 ◽

2021 ◽

Vol 10 (18) ◽

pp. 4166

Author(s):

Agata Ciurla ◽

Crystal Marruganti ◽

Tiziana Doldo ◽

Jolanta Szymańska

Keyword(s):

Orthodontic Treatment ◽

Root Resorption ◽

Predictive Ability ◽

Accurate Method ◽

Nucleotide Polymorphisms ◽

Severe Condition ◽

Apical Root Resorption ◽

Level Model ◽

External Apical Root Resorption ◽

Multi Level

Orthodontic-induced external apical root resorption (EARR) is a severe condition affecting the roots of the teeth, whose genetic causes have been inconclusive to date. The aim of the present study was to assess the influence of selected single nucleotide polymorphisms (SNPs) IL-1β, TNFRSF11B, CASP1, and IL-6 genes on post-orthodontic EARR. A sample of 101 patients with clearly assessable orthopantomograms and lateral cephalometric radiographs taken before and at the end of the orthodontic treatment was used to evaluate the presence of EARR. The association between genetic polymorphisms and EARR was assessed with the Chi2 test. A binary logistic multi-level model was built to evaluate the ability of patient- and tooth-level variables to predict EARR occurrence. The overall prevalence of EARR resulted to be around 40%. Within the limitations of this study, a significant association was found between EARR presence and the SNP for the IL-1β gene but not for the TNFRSF11B, CASP1, and the IL-6 genes. The final multi-level model demonstrated that the SNP for the IL-1β gene increases the odds of developing EARR by around four times. Since there is currently no accurate method to determine which patients will develop EARR prior to orthodontic treatment, further studies are needed to investigate the predictive ability of further genetic variants on EARR development.

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A Genome-Wide Association Study of Novel Genetic Variants Associated With Anthropometric Traits in Koreans

Frontiers in Genetics ◽

10.3389/fgene.2021.669215 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hye-Won Cho ◽

Hyun-Seok Jin ◽

Yong-Bin Eom

Keyword(s):

Genetic Variants ◽

Genetic Factors ◽

Genome Wide Association Study ◽

Association Studies ◽

Fat Distribution ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

A Genome

Most previous genome-wide association studies (GWAS) have identified genetic variants associated with anthropometric traits. However, most of the evidence were reported in European populations. Anthropometric traits such as height and body fat distribution are significantly affected by gender and genetic factors. Here we performed GWAS involving 64,193 Koreans to identify the genetic factors associated with anthropometric phenotypes including height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip ratio. We found nine novel single-nucleotide polymorphisms (SNPs) and 59 independent genetic signals in genomic regions that were reported previously. Of the 19 SNPs reported previously, eight genetic variants at RP11-513I15.6 and one genetic variant at the RP11-977G19.10 region and six Asian-specific genetic variants were newly found. We compared our findings with those of previous studies in other populations. Five overlapping genetic regions (PAN2, ANKRD52, RNF41, HGMA1, and C6orf106) had been reported previously but none of the SNPs were independently identified in the current study. Seven of the nine newly found novel loci associated with height in women revealed a statistically significant skeletal expression of quantitative trait loci. Our study provides additional insight into the genetic effects of anthropometric phenotypes in East Asians.

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Association of common genetic variants in the CPSF7 and SDHAF2 genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier

10.1101/2020.04.14.030486 ◽

2020 ◽

Author(s):

Ignazio S. Piras ◽

Christiane Bleul ◽

Ashley Siniard ◽

Amanda J. Wolfe ◽

Matthew D. De Both ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Nucleotide Polymorphisms ◽

The West ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome ◽

Fibrotic Lung Disease

AbstractCanine Idiopathic Pulmonary Fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a Genome-Wide Association Study (GWAS) in the WHWT using Whole Genome Sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide™ DNA library prep kit. After quality controls, 28 affected, 44 unaffected and 1,843,695 informative Single Nucleotide Polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the CPSF7 and SDHAF2 genes (adjusted p = 0.016 and p = 0.025, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389, however it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma further highlighting the potential relevance of our results since IPF and lung cancer share several pathological mechanisms.

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Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach

Blood ◽

10.1182/blood-2008-11-190389 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5298-5303 ◽

Cited By ~ 194

Author(s):

David-Alexandre Trégouët ◽

Simon Heath ◽

Noémie Saut ◽

Christine Biron-Andreani ◽

Jean-François Schved ◽

...

Keyword(s):

Complex Disease ◽

Genetic Factors ◽

Genome Wide Association Study ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

A Genome ◽

Increased Risk ◽

Fv Leiden ◽

Gwas Approach

Abstract Venous thromboembolism (VTE) is a complex disease that has a major genetic component of risk. To identify genetic factors that may modify the risk of VTE, we conducted a genome-wide association study by analyzing approximately 317 000 single nucleotide polymorphisms (SNPs) in 453 VTE cases and 1327 controls. Only 3 SNPs located in the FV and ABO blood group genes were found associated with VTE at a genome-wide significant level of 1.7 × 10−7. Detailed analysis of these SNPs in additional cohorts of more than 1700 cases and 1400 controls revealed that the association observed at the FV locus was the result of the increased risk mediated by the FV Leiden mutation, whereas O and A2 blood groups were found to be at lower risk for VTE. Apart from the FV and ABO loci, no other locus was found strongly associated with VTE. However, using this large cohort of subjects, we were able to replicate the mild effects of 2 nonsynonymous SNPs, rs1613662 in GP6 and rs13146272 in CYP4V2, recently suspected to be associated with VTE.

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