scholarly journals A missense variant in IFT122 associated with a canine model of retinitis pigmentosa

2021 ◽  
Author(s):  
Maria Kaukonen ◽  
Inka-Tuulevi Pettinen ◽  
Kaisa Wickström ◽  
Meharji Arumilli ◽  
Jonas Donner ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Genome Wide Association Study ◽  
Retinal Dystrophy ◽  
Intraflagellar Transport ◽  
Missense Variant ◽  
Canine Model ◽  
Progressive Retinal Atrophy ◽  
Inherited Retinal Dystrophies ◽  
A Genome ◽  
Causes Of Disease

AbstractRetinitis pigmentosa (RP) is a blinding eye disease affecting nearly two million people worldwide. Dogs are affected with a similar illness termed progressive retinal atrophy (PRA). Lapponian herders (LHs) are affected with several types of inherited retinal dystrophies, and variants in PRCD and BEST1 genes have been associated with generalized PRA and canine multifocal retinopathy 3 (cmr3), respectively. However, all retinal dystrophy cases in LHs are not explained by these variants, indicating additional genetic causes of disease in the breed. We collected DNA samples from 10 PRA affected LHs, with known PRCD and BEST1 variants excluded, and 34 unaffected LHs. A genome-wide association study identified a locus on CFA20 (praw = 2.4 × 10–7, pBonf = 0.035), and subsequent whole-genome sequencing of an affected LH revealed a missense variant, c.3176G>A, in the intraflagellar transport 122 (IFT122) gene. The variant was also found in Finnish Lapphunds, in which its clinical relevancy needs to be studied further. The variant interrupts a highly conserved residue, p.(R1059H), in IFT122 and likely impairs its function. Variants in IFT122 have not been associated with retinal degeneration in mammals, but the loss of ift122 in zebrafish larvae impaired opsin transport and resulted in progressive photoreceptor degeneration. Our study establishes a new spontaneous dog model to study the role of IFT122 in RP biology, while the affected breed will benefit from a genetic test for a recessive condition.

scholarly journals A missense Variant in IFT122 Associated with a Canine Model of Retinitis Pigmentosa

2021 ◽  
Author(s):  
Maria Kaukonen ◽  
Inka-Tuulevi Pettinen ◽  
Kaisa Wickström ◽  
Meharji Arumilli ◽  
Jonas Donner ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Genome Wide Association Study ◽  
Retinal Dystrophy ◽  
Intraflagellar Transport ◽  
Missense Variant ◽  
Canine Model ◽  
Progressive Retinal Atrophy ◽  
Inherited Retinal Dystrophies ◽  
A Genome ◽  
Causes Of Disease

Abstract Retinitis pigmentosa (RP) is a blinding eye disease affecting nearly two million people worldwide. Dogs are affected with a similar illness termed progressive retinal atrophy (PRA). Lapponian Herders (LHs) are affected with several types of inherited retinal dystrophies, and variants in PRCD and BEST1 genes have been associated with generalized PRA and canine multifocal retinopathy 3 (cmr3), respectively. However, all retinal dystrophy cases in LHs are not explained by these variants, indicating additional genetic causes of disease in the breed. We collected DNA samples from 10 PRA-affected LHs, with known PRCD and BEST1 variants excluded, and 34 unaffected LHs. A genome-wide association study identified a locus on CFA20 (praw=2.4x10-7, pBonf=0.035), and subsequent whole-genome sequencing of an affected LH revealed a missense variant, c.3176G>A, in the intraflagellar transport 122 (IFT122) gene. The variant was also found in Finnish Lapphunds, in which its clinical relevancy needs to be studied further. The variant interrupts a highly conserved residue, p.(R1059H), in IFT122 and likely impairs its function. Variants in IFT122 have not been associated with retinal degeneration in mammals, but the loss of ift122 in zebrafish larvae impaired opsin transport and resulted in progressive photoreceptor degeneration. Our study establishes a new spontaneous dog model to study the role of IFT122 in RP biology, while the affected breed will benefit from a genetic test for a recessive condition.

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.

scholarly journals A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs

BMC Genetics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Rebekkah J. Hitti-Malin ◽  
Louise M. Burmeister ◽  
Sally L. Ricketts ◽  
Thomas W. Lewis ◽  
Louise Pettitt ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Retinal Disease ◽  
Photoreceptor Cells ◽  
Causal Variant ◽  
Sequencing Analysis ◽  
Sequencing Data ◽  
Progressive Retinal Atrophy ◽  
Dna Test ◽  
A Genome ◽  
The Uk

Abstract Background Canine progressive retinal atrophies are a group of hereditary retinal degenerations in dogs characterised by depletion of photoreceptor cells in the retina, which ultimately leads to blindness. PRA in the Lhasa Apso (LA) dog has not previously been clinically characterised or described in the literature, but owners in the UK are advised to have their dog examined through the British Veterinary Association/ Kennel Club/ International Sheep Dog Society (BVA/KC/ISDS) eye scheme annually, and similar schemes that are in operation in other countries. After the exclusion of 25 previously reported canine retinal mutations in LA PRA-affected dogs, we sought to identify the genetic cause of PRA in this breed. Results Analysis of whole-exome sequencing data of three PRA-affected LA and three LA without signs of PRA did not identify any exonic or splice site variants, suggesting the causal variant was non-exonic. We subsequently undertook a genome-wide association study (GWAS), which identified a 1.3 Mb disease-associated region on canine chromosome 33, followed by whole-genome sequencing analysis that revealed a long interspersed element-1 (LINE-1) insertion upstream of the IMPG2 gene. IMPG2 has previously been implicated in human retinal disease; however, until now no canine PRAs have been associated with this gene. The identification of this PRA-associated variant has enabled the development of a DNA test for this form of PRA in the breed, here termed PRA4 to distinguish it from other forms of PRA described in other breeds. This test has been used to determine the genotypes of over 900 LA dogs. A large cohort of genotyped dogs was used to estimate the allele frequency as between 0.07–0.1 in the UK LA population. Conclusions Through the use of GWAS and subsequent sequencing of a PRA case, we have identified a LINE-1 insertion in the retinal candidate gene IMPG2 that is associated with a form of PRA in the LA dog. Validation of this variant in 447 dogs of 123 breeds determined it was private to LA dogs. We envisage that, over time, the developed DNA test will offer breeders the opportunity to avoid producing dogs affected with this form of PRA.

scholarly journals Genetic studies of accelerometer-based sleep measures in 85,670 individuals yield new insights into human sleep behaviour

2018 ◽  
Author(s):  
Samuel E. Jones ◽  
Vincent T. van Hees ◽  
Diego R. Mazzotti ◽  
Pedro Marques-Vidal ◽  
Séverine Sabia ◽  
...  
Keyword(s):  
Sleep Quality ◽  
Sleep Duration ◽  
Genome Wide Association Study ◽  
Missense Variant ◽  
Causal Variant ◽  
Self Report ◽  
Accelerometer Data ◽  
Genetic Associations ◽  
A Genome ◽  
The Uk

ABSTRACTSleep is an essential human function but its regulation is poorly understood. Identifying genetic variants associated with quality, quantity and timing of sleep will provide biological insights into the regulation of sleep and potential links with disease. Using accelerometer data from 85,670 individuals in the UK Biobank, we performed a genome-wide association study of 8 accelerometer-derived sleep traits, 5 of which are not accessible through self-report alone. We identified 47 genetic associations across the sleep traits (P<5×10-8) and replicated our findings in 5,819 individuals from 3 independent studies. These included 26 novel associations for sleep quality and 10 for nocturnal sleep duration. The majority of newly identified variants were associated with a single sleep trait, except for variants previously associated with restless legs syndrome that were associated with multiple sleep traits. Of the new associated and replicated sleep duration loci, we were able to fine-map a missense variant (p.Tyr727Cys) in PDE11A, a dual-specificity 3’,5’-cyclic nucleotide phosphodiesterase expressed in the hippocampus, as the likely causal variant. As a group, sleep quality loci were enriched for serotonin processing genes and all sleep traits were enriched for cerebellar-expressed genes. These findings provide new biological insights into sleep characteristics.

scholarly journals ALDH2 p.E504K Variation and Sex Are Major Factors Associated with Current and Quitting Alcohol Drinking in Japanese Oldest Old

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 799
Author(s):  
Takashi Sasaki ◽  
Yoshinori Nishimoto ◽  
Takumi Hirata ◽  
Yukiko Abe ◽  
Toru Takebayashi ◽  
...  
Keyword(s):  
Alcohol Drinking ◽  
Genome Wide Association Study ◽  
Oldest Old ◽  
Drinking Behavior ◽  
Missense Variant ◽  
Depression Score ◽  
Smoking History ◽  
Factors Associated ◽  
Logistic Analysis ◽  
A Genome

This study identified the factors associated with current and quitting alcohol drinking in the Oldest Old to better understand the associated factors and mechanisms underlying drinking behaviors in this age group. Results of a questionnaire for drinking behavior in 1015 Japanese Oldest Old citizens aged 85 to 89 years revealed that 56.0% of men and 24.0% of women were current drinkers. A genome-wide association study revealed that the rs671 G > A variation, which corresponds to the aldehyde dehydrogenase 2 (ALDH2) p.E504K missense variant, was significantly associated with current drinking (odds ratio: 3.8, p = 3.33 × 10−31). Variable selection with 41 factors and multivariate regression logistic analysis for current drinking indicated that the rs671 genotype and sex were the most significant factors in the Oldest Old. Further analysis revealed that the rs671 genotype, alcohol-associated biomarkers, a history of heart or kidney disease, and frailty score are factors associated with quitting drinking in the Oldest Old men, whereas smoking history, walking time, and depression score were factors associated with quitting drinking in the Oldest Old women. These results indicate that the ALDH2 p.E504K variation is a major factor associated with current and quitting drinking in the Japanese Oldest Old.

scholarly journals A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

2016 ◽  
Vol 98 (4) ◽  
pp. 744-754 ◽  
Author(s):  
Elizabeth J. Leslie ◽  
Huan Liu ◽  
Jenna C. Carlson ◽  
John R. Shaffer ◽  
Eleanor Feingold ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Missense Variant ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

scholarly journals LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity

2020 ◽  
Author(s):  
Nellie Y. Loh ◽  
Senthil K. Vasan ◽  
Manu Verma ◽  
Agata Wesolowska-Andersen ◽  
Matt J. Neville ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Fat Mass ◽  
Genome Wide Association Study ◽  
Missense Variant ◽  
Mineral Density ◽  
High Bone Mass ◽  
Genome Wide ◽  
A Genome

ABSTRACTWNT signalling is a developmental pathway which plays an important role in post-natal bone accrual. We have previously shown, that in addition to exhibiting extreme high bone mass, subjects with rare gain-of-function (GoF) mutations in the WNT co-receptor LRP5 also display increased lower-body fat mass. Here, we demonstrate using human physiological studies in GoF LRP5 mutation carriers and glucose uptake assays in LRP5 knockdown (KD) adipocytes that LRP5 promotes adipocyte insulin sensitivity. We also show that a low frequency missense variant in LRP5 shown to be associated with low heel bone mineral density in a genome wide association study meta-analysis, is associated with reduced leg fat mass. Finally, using genome wide transcriptomic analyses and in vitro functional studies in LRP5-KD adipose progenitors (APs) we demonstrate that LRP5 plays an essential role in maintaining AP fitness i.e. functional characteristics. Pharmacological activation of LRP5 signalling in adipose tissue provides a promising strategy to prevent the redistribution of adipose tissue and metabolic sequela associated with obesity and ageing.

scholarly journals Retinitis Pigmentosa withEYSMutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Yuuki Arai ◽  
Akiko Maeda ◽  
Yasuhiko Hirami ◽  
Chie Ishigami ◽  
Shinji Kosugi ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Direct Sequencing ◽  
Retinal Dystrophy ◽  
In Silico Analysis ◽  
Japanese Patients ◽  
Sequence Variants ◽  
Stargardt Disease ◽  
Identification Rate ◽  
Inherited Retinal Dystrophies ◽  
Inherited Retinal Dystrophy

The aim of this study was to gain information about disease prevalence and to identify the responsible genes for inherited retinal dystrophies (IRD) in Japanese populations. Clinical and molecular evaluations were performed on 349 patients with IRD. For segregation analyses, 63 of their family members were employed. Bioinformatics data from 1,208 Japanese individuals were used as controls. Molecular diagnosis was obtained by direct sequencing in a stepwise fashion utilizing one or two panels of 15 and 27 genes for retinitis pigmentosa patients. If a specific clinical diagnosis was suspected, direct sequencing of disease-specific genes, that is,ABCA4for Stargardt disease, was conducted. Limited availability of intrafamily information and decreasing family size hampered identifying inherited patterns. Differential disease profiles with lower prevalence of Stargardt disease from European and North American populations were obtained. We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%. This study found 43 novel sequence variants. In silico analysis suggests that 20 of 25 novel missense variants are pathogenic.EYSmutations had the highest prevalence at 23.5%. c.4957_4958insA and c.8868C>A were the two majorEYSmutations identified in this cohort.EYSmutations are the most prevalent among Japanese patients with IRD.

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