scholarly journals Genetic Association ofMMP10,MMP14, andMMP16with Dental Caries

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
D. D. Lewis ◽  
J. R. Shaffer ◽  
E. Feingold ◽  
M. Cooper ◽  
M. M. Vanyukov ◽  
...  
Keyword(s):  
Dental Caries ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Extracellular Proteins ◽  
Caries Experience ◽  
Caries Risk ◽  
Physiological Processes ◽  
Genome Wide ◽  
A Genome ◽  
White Adults

Matrix metalloproteinases (MMPs), which degrade extracellular proteins as part of a variety of physiological processes, and their inhibitors have been implicated in the dental caries process. Here we investigated 28 genetic variants spanning theMMP10,MMP14, andMMP16genes to detect association with dental caries experience in 13 age- and race-stratified (n=3,587) samples from 6 parent studies. Analyses were performed separately for each sample, and results were combined across samples by meta-analysis. Two SNPs (rs2046315 and rs10429371) upstream ofMMP16were significantly associated with caries in an individual sample of white adults and via meta-analysis across 8 adult samples after gene-wise adjustment for multiple comparisons. Noteworthy is SNP rs2046315 (p=8.14×10-8) association with caries in white adults. This SNP was originally nominated in a genome-wide-association study (GWAS) of dental caries in a sample of white adults and yielded associations in a subsequent GWAS of surface level caries in white adults as well. Therefore, in our study, we were able to recapture the association between rs2046315 and dental caries in white adults. Although we did not strengthen evidence thatMMPs 10,14, and16influence caries risk,MMP16is still a likely candidate gene to pursue.

Abstract 16003: Genetic Variation Associated With Favorable Exercise Response in Patients With Systolic Heart Failure: A Hf-action Trial Substudy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sara Coles ◽  
Stephanie Giamberardino ◽  
Carol Haynes ◽  
Ruicong She ◽  
Hongsheng Gui ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Trial ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Systolic Heart Failure ◽  
Genome Wide Association ◽  
Supervised Exercise ◽  
Genome Wide ◽  
A Genome ◽  
Response To Exercise

Background: Exercise has shown benefit in patients with systolic heart failure, including in the clinical trial Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION). There is heterogeneity in who derives benefit from exercise, and the biologic mechanisms of favorable response to exercise in systolic heart failure are not well understood. Hypothesis: Genetic variation is an underlying factor influencing heterogeneity in response to exercise in patients with systolic heart failure. Methods: The HF-ACTION trial randomized individuals with systolic heart failure (left ventricular ejection fraction <35%) to supervised exercise versus usual care. In this study, we performed a genome wide association study (GWAS) in the HF-ACTION biorepository using the Axiom Biobank1 genotyping array (13,403,591 single nucleotide polymorphisms [SNPs] after quality control on directly genotyped and 1000 genomes imputed data), in N=377 study subjects who completed the supervised exercise arm. Using change in peak VO2 as our outcome, we ran within-ancestry GWASes, modeling SNP effects as both additive and dominant, and conducted across-ancestry meta-analysis within each genetic model. Results: Five loci met genome-wide significance in the European ancestry analyses, 5 loci in the African ancestry, and 8 in the meta-analyses. The two most significantly associated loci across both additive and dominant meta-analysis models were rs111577308 located in the histone acetylation for transcription elongator complex 3 gene ( ELP3, p=1.212x10 -9 ) and rs75444785 located in the phosphodiesterase 4D gene ( PDE4D , p=1.565x10 -9 ). ELP3 is responsible for histone modifications related to DNA transcription factor complexes, and PDE4D is involved in cyclic AMP cell signaling. In silico analysis of these loci showed that they are in linkage with regions associated with skeletal muscle and peripheral vascular disease phenotypes. Conclusions: Using a genome-wide association study in a well-phenotyped clinical trial of exercise in systolic heart failure, we found common genetic variants in genes involved in DNA transcription histone modification and cyclic AMP cell signaling that are associated with a more favorable response to exercise.

scholarly journals Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples

2018 ◽  
Vol 214 (1) ◽  
pp. 36-41 ◽  
Author(s):  
Chiara Fabbri ◽  
Siegfried Kasper ◽  
Alexander Kautzky ◽  
Lucie Bartova ◽  
Markus Dold ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Adenosine Monophosphate ◽  
Research Support ◽  
Antidepressant Treatments ◽  
Advisory Boards ◽  
Gene Sets ◽  
Genome Wide ◽  
A Genome ◽  
Resistant Depression

BackgroundTreatment-resistant depression (TRD) is the most problematic outcome of depression in terms of functional impairment, suicidal thoughts and decline in physical health.AimsTo investigate the genetic predictors of TRD using a genome-wide approach to contribute to the development of precision medicine.MethodA sample recruited by the European Group for the Study of Resistant Depression (GSRD) including 1148 patients with major depressive disorder (MDD) was characterised for the occurrence of TRD (lack of response to at least two adequate antidepressant treatments) and genotyped using the Infinium PsychArray. Three clinically relevant patient groups were considered: TRD, responders and non-responders to the first antidepressant trial, thus outcomes were based on comparisons of these groups. Genetic analyses were performed at the variant, gene and gene-set (i.e. functionally related genes) level. Additive regression models of the outcomes and relevant covariates were used in the GSRD participants and in a fixed-effect meta-analysis performed between GSRD, STAR*D (n = 1316) and GENDEP (n = 761) participants.ResultsNo individual polymorphism or gene was associated with TRD, although some suggestive signals showed enrichment in cytoskeleton regulation, transcription modulation and calcium signalling. Two gene sets (GO:0043949 and GO:0000183) were associated with TRD versus response and TRD versus response and non-response to the first treatment in the GSRD participants and in the meta-analysis, respectively (corrected P = 0.030 and P = 0.027).ConclusionsThe identified gene sets are involved in cyclic adenosine monophosphate mediated signal and chromatin silencing, two processes previously implicated in antidepressant action. They represent possible biomarkers to implement personalised antidepressant treatments and targets for new antidepressants.Declaration of interestD.S. has received grant/research support from GlaxoSmithKline and Lundbeck; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck. S.M. has been a consultant or served on advisory boards for: AstraZeneca, Bristol-Myers Squibb, Forest, Johnson & Johnson, Leo, Lundbeck, Medelink, Neurim, Pierre Fabre, Richter. S.K. has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen and Novartis; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, Pierre Fabre, Janssen and Neuraxpharm. J.Z. has received grant/research support from Lundbeck, Servier, Brainsway and Pfizer, has served as a consultant or on advisory boards for Servier, Pfizer, Abbott, Lilly, Actelion, AstraZeneca and Roche and has served on speakers' bureaus for Lundbeck, Roch, Lilly, Servier, Pfizer and Abbott. J.M. is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. A.S. is or has been consultant/speaker for: Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. C.M.L. receives research support from RGA UK Services Limited.

scholarly journals A genome-wide meta-analysis identifies 53 sequence variants associating with carpal tunnel syndrome

2022 ◽  
Author(s):  
Astros Skuladottir ◽  
Gyda Bjornsdottir ◽  
Egil Ferkingstad ◽  
Gudmundur Einarsson ◽  
Lilja Stefansdottir ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Carpal Tunnel Syndrome ◽  
Carpal Tunnel ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Missense Variant ◽  
Sequence Variants ◽  
Genome Wide ◽  
A Genome ◽  
Tunnel Syndrome

Abstract Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (Ncases = 48,843, Ncontrols = 1,190,837), we found 53 sequence variants at 50 loci that associate with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10−24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in recurrent/persistent cases than nonrecurrent/nonresistant cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

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 &lt; 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 A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women

Bone Reports ◽  
2016 ◽  
Vol 5 ◽  
pp. 233-242 ◽  
Author(s):  
Kira C. Taylor ◽  
Daniel S. Evans ◽  
Digna R. Velez Edwards ◽  
Todd L. Edwards ◽  
Tamar Sofer ◽  
...  
Keyword(s):  
African American ◽  
Association Study ◽  
African American Women ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
American Women ◽  
Clinical Fracture ◽  
Genome Wide ◽  
A Genome

A GENOME-WIDE ASSOCIATION STUDY IN PROGRESSIVE SUPRANUCLEAR PALSY

2015 ◽  
Vol 86 (11) ◽  
pp. e4.68-e4
Author(s):  
Zhongbo Chen ◽  
Aleksey Shatunov ◽  
Gilbert Bensimon ◽  
Christine Payan ◽  
Albert Ludolph ◽  
...  
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Chromosome 17 ◽  
Gene Variants ◽  
Genome Wide ◽  
Mapt Gene ◽  
Common Genetic Variants ◽  
A Genome

BackgroundProgressive supranuclear palsy (PSP) is a debilitating Parkinsonian movement disorder characterised by tau protein burden. We aimed to identify common genetic variants influencing PSP susceptibility through a genome-wide association analysis (GWAS) of a multi-centre European study, Neuroprotection and Natural History in Parkinson's Plus Syndromes (NNIPPS), recruiting clinically well-characterised patients. We combined this with a meta-analysis of previously-identified gene variants.MethodsWe genotyped 275,684 single nucleotide polymorphisms using Illumina microarrays in 212 PSP cases from the UK, Germany and France, and compared these with 4,707 matched controls. GWAS was performed using PLINK. Meta-analysis was performed with METAL. Genome-wide significance was defined as p<5×10^–8.ResultsWe observed multiple associations on chromosome 17 within or close to the MAPT gene, a well-established risk locus for PSP, confirming the sample and method validity. Of nine other previously reported associations, meta-analysis only confirmed that the MOBP variation (rs1768208) modified PSP risk (p=3.29×10^–13).ConclusionIn the GWAS and meta-analysis, we found the chromosome 17 inversion region to be associated with PSP susceptibility. Furthermore, we have shown that MOBP can modify the risk of PSP, possibly through influencing oligodendrocyte tau inclusions. These identified gene variants provide novel insights into the underlying genetics of sporadic PSP.

scholarly journals Genome-wide association meta-analysis of PR interval identifies 47 novel loci associated with atrial and atrioventricular electrical activity

2018 ◽  
Author(s):  
Jessica van Setten ◽  
Jennifer A. Brody ◽  
Yalda Jamshidi ◽  
Brenton R. Swenson ◽  
Anne M. Butler ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Electrical Activity ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Regulatory Regions ◽  
European Descent ◽  
Genome Wide ◽  
A Genome ◽  
Pr Interval

ABSTRACTElectrocardiographic PR interval measures atrial and atrioventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. We performed a genome-wide association study in over 92,000 individuals of European descent and identified 44 loci associated with PR interval (34 novel). Examination of the 44 loci revealed known and novel biological processes involved in cardiac atrial electrical activity, and genes in these loci were highly over-represented in several cardiac disease processes. Nearly half of the 61 independent index variants in the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with one or more missense variants. Cardiac regulatory regions of the genome as measured by cardiac DNA hypersensitivity sites were enriched for variants associated with PR interval, compared to non-cardiac regulatory regions. Joint analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation identified additional new pleiotropic loci. The majority of associations discovered in European-descent populations were also present in African-American populations. Meta-analysis examining over 105,000 individuals of African and European descent identified additional novel PR loci. These additional analyses identified another 13 novel loci. Together, these findings underscore the power of GWAS to extend knowledge of the molecular underpinnings of clinical processes.

scholarly journals A regulatory variant of CHRM3 is associated with cannabis-induced hallucinations in European Americans

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhongshan Cheng ◽  
Chureerat Phokaew ◽  
Yi-Ling Chou ◽  
Dongbing Lai ◽  
Jacquelyn L. Meyers ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Collaborative Study ◽  
Risk Genes ◽  
European Americans ◽  
Genome Wide ◽  
Nominal Significance ◽  
A Genome ◽  
Regulatory Variant

AbstractCannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs (n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 (P = 1.66 × 10−10), rs74722579 (P = 2.81 × 10−9), and rs1938228 (P = 1.57 × 10−8); signals were GWS in Yale-Penn 1 EAs (n = 1092) and nominally significant in Yale-Penn 2 EAs (n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs’ association signals were increased (meta-P-values 1.32 × 10−10 and 2.60 × 10−9, respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis (n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes (GABAG2, CHRNA4, and HRH3) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait.

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