scholarly journals Charcot-Marie-Tooth type 4B2 demyelinating neuropathy in miniature Schnauzer dogs caused by a novel splicingSBF2 (MTMR13)genetic variant: a new spontaneous clinical model

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7983 ◽  
Author(s):  
Nicolas Granger ◽  
Alejandro Luján Feliu-Pascual ◽  
Charlotte Spicer ◽  
Sally Ricketts ◽  
Rebekkah Hitti ◽  
...  
Keyword(s):  
Genetic Variant ◽  
Chromosome 21 ◽  
Genome Wide Association ◽  
Splice Donor Site ◽  
Positional Candidate ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Genome Wide ◽  
A Genome ◽  
Tooth Disease

BackgroundCharcot-Marie-Tooth (CMT) disease is the most common neuromuscular disorder in humans affecting 40 out of 100,000 individuals. In 2008, we described the clinical, electrophysiological and pathological findings of a demyelinating motor and sensory neuropathy in Miniature Schnauzer dogs, with a suspected autosomal recessive mode of inheritance based on pedigree analysis. The discovery of additional cases has followed this work and led to a genome-wide association mapping approach to search for the underlying genetic cause of the disease.MethodsFor genome wide association screening, genomic DNA samples from affected and unaffected dogs were genotyped using the Illumina CanineHD SNP genotyping array.SBF2and its variant were sequenced using primers and PCRs. RNA was extracted from muscle of an unaffected and an affected dog and RT-PCR performed. Immunohistochemistry for myelin basic protein was performed on peripheral nerve section specimens.ResultsThe genome-wide association study gave an indicative signal on canine chromosome 21. Although the signal was not of genome-wide significance due to the small number of cases, theSBF2(also known asMTMR13)gene within the region of shared case homozygosity was a strong positional candidate, as 22 genetic variants in the gene have been associated with demyelinating forms of Charcot-Marie-Tooth disease in humans. Sequencing ofSBF2in cases revealed a splice donor site genetic variant, resulting in cryptic splicing and predicted early termination of the protein based on RNA sequencing results.ConclusionsThis study reports the first genetic variant in Miniature Schnauzer dogs responsible for the occurrence of a demyelinating peripheral neuropathy with abnormally folded myelin. This discovery establishes a genotype/phenotype correlation in affected Miniature Schnauzers that can be used for the diagnosis of these dogs. It further supports the dog as a natural model of a human disease; in this instance, Charcot-Marie-Tooth disease. It opens avenues to search the biological mechanisms responsible for the disease and to test new therapies in a non-rodent large animal model. In particular, recent gene editing methods that led to the restoration of dystrophin expression in a canine model of muscular dystrophy could be applied to other canine models such as this before translation to humans.

scholarly journals Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study

2019 ◽  
Vol 6 (2) ◽  
pp. 201-211 ◽  
Author(s):  
Feifei Tao ◽  
Gary W. Beecham ◽  
Adriana P. Rebelo ◽  
Susan H. Blanton ◽  
John J. Moran ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Disease Type ◽  
Modifier Gene ◽  
Genome Wide Association ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Genome Wide ◽  
Tooth Disease

scholarly journals Identifying Pleiotropic Effects: A Two-Stage Approach Using Genome-Wide Association Meta-Analysis Data

2017 ◽  
Author(s):  
Xing Chen ◽  
Yi-Hsiang Hsu
Keyword(s):  
Genetic Variant ◽  
Density Lipoprotein ◽  
Pleiotropic Effects ◽  
Genome Wide Association ◽  
Two Stage ◽  
Individual Level ◽  
Multiple Phenotypes ◽  
Genome Wide ◽  
A Genome ◽  
Wide Scale

AbstractPleiotropic effects occur when a single genetic variant independently influences multiple phenotypes. In genetic epidemiological studies, multiple endo-phenotypes or correlated traits are commonly tested separately in a univariate statistical framework to identify associations with genetic determinants. Subsequently, a simple look-up of overlapping univariate results is applied to identify pleiotropic genetic effects. However, this strategy offers limited power to detect pleiotropy. In contrast, combining correlated traits into a composite test provides a powerful approach for detecting pleiotropic genes. Here, we propose a two-stage approach to identify potential pleiotropic effects by utilizing aggregated results from large-scale genome-wide association (GWAS) meta-analyses. In the first stage, we developed two novel approaches (direct linear combining, dLC; and empirical combining, eLC) combining correlated univariate test statistics to screen potential pleiotropic variants on a genome-wide scale, using either individual-level or aggregated data. Our simulations indicated that dLC and eLC outperform other popular multivariate approaches (such as principal component analysis (PCA), multivariate analysis of variance (MANOVA), canonical correlation (CCA), generalized estimation equations (GEE), linear mixed effects models (LME) and O’Brien combining approach). In particular, eLC provides a notable increase in power when the genetic variant exhibits both protective and deleterious effects. In the second stage, we developed a unique approach, conditional pleiotropy testing (cPLT), to examine pleiotropic effects using individual-level data for candidate variants identified in Stage 1. Simulation demonstrated reduced type 1 error for cPLT in identifying pleiotropic genetic variants compared to the typical conditional strategy. We validated our two-stage approach by performing a bivariate GWA study on two correlated quantitative traits, high-density lipoprotein (HDL) and triglycerides (TG), in the Genetic Analysis Workshop 16 (GAW16) simulation dataset. In summary, the proposed two-stage approach allows us to leverage aggregated summary statistics from univariate GWAS and improves the power to identify potential pleiotropy while maintaining valid false-positive rates.Author SummaryPleiotropy, occurring when a single genetic variant contributes to multiple phenotypes, remains difficult to identify in genome-wide association studies (GWAS). To leverage data for multiple phenotypes and incorporate univariate GWAS summary results, we propose a novel two-stage approach for discovering potential pleiotropic variants. In the first stage, two novel combining approaches were developed to screen potential pleiotropic variants on a genome-wide scale. Simulations demonstrated the superior statistical power of these approaches over other multivariate methods. In the second stage, our approach was used to identify potential pleiotropy in the candidate marker sets generated from the first stage. The proposed two-stage approach was applied to the GAW16 simulation dataset to discover pleiotropic variants associated with high-density lipoprotein and triglycerides. In summary, we demonstrate that the proposed two-stage approach can be applied as a viable and robust strategy to accommodate phenotypic and genetic heterogeneity for discovering potential pleiotropy on genome-wide scale.

scholarly journals Genome-wide association study of phenotypes measuring progression from first cocaine or opioid use to dependence reveals novel risk genes

2021 ◽  
Author(s):  
Richard Sherva ◽  
Congcong Zhu ◽  
Leah Wetherill ◽  
Howard J. Edenberg ◽  
Emma Johnson ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Chromosome 21 ◽  
Genome Wide Association ◽  
Chromosome 1 ◽  
Opioid Use ◽  
Discovery Sample ◽  
Genome Wide ◽  
A Genome

Aim: Substance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively). A genome-wide association study of OD and CD related phenotypes reflecting the time between first self-reported use of these substances and a first DSM-IV dependence diagnosis was conducted. Methods: Cox proportional hazards regression in a discovery sample of 6,188 African-Americans (AAs) and 6,835 European-Americans (EAs) participants in a genetic study of multiple substance dependence phenotypes were used to test for association between genetic variants and these outcomes. The top findings were tested for replication in two independent cohorts. Results: In the discovery sample, three independent regions containing variants associated with time to dependence at P < 5 x 10-8 were identified, one (rs61835088 = 1.03 x 10-8) for cocaine in the combined EA-AA meta-analysis in the gene FAM78B on chromosome 1, and two for opioids in the AA portion of the sample in intergenic regions of chromosomes 4 (rs4860439, P = 1.37 x 10-8) and 9 (rs7032521, P = 3.30 x 10-8). After meta-analysis with data from the replication cohorts, the signal at rs61835088 improved (HR = 0.87, P = 3.71 x 10-9 and an intergenic SNP on chromosome 21 (rs2825295, HR = 1.14, P = 2.57 x 10-8) that missed the significance threshold in the AA discovery sample became genome-wide significant (GWS) for CD. Conclusions: Although the two GWS variants are not in genes with obvious links to SUD biology and have modest effect sizes, they are statistically robust and show evidence for association in independent samples. These results may point to novel pathways contributing to disease progression and highlight the utility of related phenotypes to better understand the genetics of SUDs.

Genome-wide association study of non-tuberculous mycobacterial pulmonary disease

Thorax ◽  
2020 ◽  
pp. thoraxjnl-2019-214430
Author(s):  
Jaeyoung Cho ◽  
Kyungtaek Park ◽  
Sun Mi Choi ◽  
Jinwoo Lee ◽  
Chang-Hoon Lee ◽  
...  
Keyword(s):  
Association Study ◽  
Pulmonary Disease ◽  
Genetic Variant ◽  
Genome Wide Association Study ◽  
Causal Effect ◽  
Genome Wide Association ◽  
Mendelian Randomisation ◽  
Eqtl Analysis ◽  
Genome Wide ◽  
A Genome

BackgroundThe prevalence of non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in South Korea and many parts of the world. However, the genetic factors underlying susceptibility to this disease remain elusive.MethodsTo identify genetic variants in patients with NTM-PD, we performed a genome-wide association study with 403 Korean patients with NTM-PD and 306 healthy controls from the Healthy Twin Study, Korea cohort. Candidate variants from the discovery cohort were subsequently validated in an independent cohort. The Genotype-Tissue Expression (GTEx) database was used to identify expression quantitative trait loci (eQTL) and to conduct Mendelian randomisation (MR).ResultsWe identified a putatively significant locus on chromosome 7p13, rs849177 (OR, 2.34; 95% CI, 1.71 to 3.21; p=1.36×10−7), as the candidate genetic variant associated with NTM-PD susceptibility. Its association was subsequently replicated and the combined p value was 4.92×10−8. The eQTL analysis showed that a risk allele at rs849177 was associated with lower expression levels of STK17A, a proapoptotic gene. In the MR analysis, a causal effect of STK17A on NTM-PD development was identified (β, −4.627; 95% CI, −8.768 to −0.486; p=0.029).ConclusionsThe 7p13 genetic variant might be associated with susceptibility to NTM-PD in the Korean population by altering the expression level of STK17A.

scholarly journals A genome-wide association study reveals novel genomic regions and positional candidate genes for fat deposition in broiler chickens

BMC Genomics ◽  
2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Gabriel Costa Monteiro Moreira ◽  
Clarissa Boschiero ◽  
Aline Silva Mello Cesar ◽  
James M. Reecy ◽  
Thaís Fernanda Godoy ◽  
...  
Keyword(s):  
Association Study ◽  
Candidate Genes ◽  
Broiler Chickens ◽  
Genome Wide Association Study ◽  
Fat Deposition ◽  
Genome Wide Association ◽  
Positional Candidate ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Regions

scholarly journals Genome-wide association study of phenotypes measuring progression from first cocaine or opioid use to dependence reveals novel risk genes

2021 ◽  
Author(s):  
Richard Sherva ◽  
Congcong Zhu ◽  
Leah Wetherill ◽  
Howard J. Edenberg ◽  
Emma Johnson ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Chromosome 21 ◽  
Genome Wide Association ◽  
Chromosome 1 ◽  
Opioid Use ◽  
Discovery Sample ◽  
Genome Wide ◽  
A Genome

Aim: Substance use disorders (SUD) result in substantial morbidity and mortality worldwide. Opioids, and to a lesser extent cocaine, contribute to a large percentage of this health burden. Despite their high heritability, few genetic risk loci have been identified for either opioid or cocaine dependence (OD or CD, respectively). A genome-wide association study of OD and CD related phenotypes reflecting the time between first self-reported use of these substances and a first DSM-IV dependence diagnosis was conducted. Methods: Cox proportional hazards regression in a discovery sample of 6,188 African-Americans (AAs) and 6,835 European-Americans (EAs) participants in a genetic study of multiple substance dependence phenotypes were used to test for association between genetic variants and these outcomes. The top findings were tested for replication in two independent cohorts. Results: In the discovery sample, three independent regions containing variants associated with time to dependence at P < 5 × 10−8 were identified, one (rs61835088 = 1.03 × 10−8) for cocaine in the combined EA-AA meta-analysis in the gene FAM78B on chromosome 1, and two for opioids in the AA portion of the sample in intergenic regions of chromosomes 4 (rs4860439, P = 1.37 × 10−8) and 9 (rs7032521, P = 3.30 × 10−8). After meta-analysis with data from the replication cohorts, the signal at rs61835088 improved (HR = 0.87, P = 3.71 × 10−9 and an intergenic SNP on chromosome 21 (rs2825295, HR = 1.14, P = 2.57 × 10−8) that missed the significance threshold in the AA discovery sample became genome-wide significant (GWS) for CD. Conclusions: Although the two GWS variants are not in genes with obvious links to SUD biology and have modest effect sizes, they are statistically robust and show evidence for association in independent samples. These results may point to novel pathways contributing to disease progression and highlight the utility of related phenotypes to better understand the genetics of SUDs.

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