scholarly journals Novel EDGE encoding method enhances ability to identify genetic interactions

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009534
Author(s):  
Molly A. Hall ◽  
John Wallace ◽  
Anastasia M. Lucas ◽  
Yuki Bradford ◽  
Shefali S. Verma ◽  
...  
Keyword(s):  
Intergenic Region ◽  
Genome Wide Association Study ◽  
Genetic Model ◽  
False Positive Rate ◽  
Genetic Interactions ◽  
Genetic Models ◽  
Age Related Macular Degeneration ◽  
Genetic Encoding ◽  
Age Related ◽  
Snp Interaction

Assumptions are made about the genetic model of single nucleotide polymorphisms (SNPs) when choosing a traditional genetic encoding: additive, dominant, and recessive. Furthermore, SNPs across the genome are unlikely to demonstrate identical genetic models. However, running SNP-SNP interaction analyses with every combination of encodings raises the multiple testing burden. Here, we present a novel and flexible encoding for genetic interactions, the elastic data-driven genetic encoding (EDGE), in which SNPs are assigned a heterozygous value based on the genetic model they demonstrate in a dataset prior to interaction testing. We assessed the power of EDGE to detect genetic interactions using 29 combinations of simulated genetic models and found it outperformed the traditional encoding methods across 10%, 30%, and 50% minor allele frequencies (MAFs). Further, EDGE maintained a low false-positive rate, while additive and dominant encodings demonstrated inflation. We evaluated EDGE and the traditional encodings with genetic data from the Electronic Medical Records and Genomics (eMERGE) Network for five phenotypes: age-related macular degeneration (AMD), age-related cataract, glaucoma, type 2 diabetes (T2D), and resistant hypertension. A multi-encoding genome-wide association study (GWAS) for each phenotype was performed using the traditional encodings, and the top results of the multi-encoding GWAS were considered for SNP-SNP interaction using the traditional encodings and EDGE. EDGE identified a novel SNP-SNP interaction for age-related cataract that no other method identified: rs7787286 (MAF: 0.041; intergenic region of chromosome 7)–rs4695885 (MAF: 0.34; intergenic region of chromosome 4) with a Bonferroni LRT p of 0.018. A SNP-SNP interaction was found in data from the UK Biobank within 25 kb of these SNPs using the recessive encoding: rs60374751 (MAF: 0.030) and rs6843594 (MAF: 0.34) (Bonferroni LRT p: 0.026). We recommend using EDGE to flexibly detect interactions between SNPs exhibiting diverse action.

scholarly journals A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 179
Author(s):  
Laurence Klipfel ◽  
Marie Cordonnier ◽  
Léa Thiébault ◽  
Emmanuelle Clérin ◽  
Frédéric Blond ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Age Related Macular Degeneration ◽  
Lactate Transport ◽  
Ips Cell ◽  
Risk Alleles ◽  
Age Related ◽  
A Genome

Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci. We are studying the possible implication of a metabolic imbalance associated with risk alleles within the SLC16A8 gene that encodes for a retinal pigment epithelium (RPE)-specific lactate transporter MCT3 and its consequences for vision. As a first approach, we report here the deficit in transepithelial lactate transport of a rare SLC16A8 allele identified during a genome-wide association study. We produced induced pluripotent stem cells (iPSCs) from the unique patient in our cohort that carries two copies of this allele. After in vitro differentiation of the iPSCs into RPE cells and their characterization, we demonstrate that the rare allele results in the retention of intron 2 of the SLC16A8 gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport.

scholarly journals Genome-wide association analyses identify two susceptibility loci for pachychoroid disease central serous chorioretinopathy

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Yoshikatsu Hosoda ◽  
Masahiro Miyake ◽  
Rosa L. Schellevis ◽  
Camiel J. F. Boon ◽  
Carel B. Hoyng ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Central Serous Chorioretinopathy ◽  
Genome Wide Association Study ◽  
Risk Allele ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association ◽  
Susceptibility Loci ◽  
Association Analyses ◽  
Age Related ◽  
Genome Wide

AbstractThe recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13,029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10−13; rs6061548, odds ratio = 1.63, P = 5.36 × 10−15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD.

TIMP3 mutation in Sorsby's fundus dystrophy: molecular insights

2005 ◽  
Vol 7 (24) ◽  
pp. 1-15 ◽  
Author(s):  
Zheng Li ◽  
Michael P. Clarke ◽  
Michael D. Barker ◽  
Norman McKie
Keyword(s):  
Peripheral Vision ◽  
Genetic Model ◽  
Single Gene ◽  
The Elderly ◽  
Developed Countries ◽  
Biochemical Properties ◽  
Age Related Macular Degeneration ◽  
Autosomal Dominant Disorder ◽  
Age Related ◽  
Sorsby's Fundus Dystrophy

Sorsby's fundus dystrophy (SFD) is a rare autosomal dominant disorder that results in degeneration of the macular region of the retina, with onset usually in the fourth to fifth decade of life. It leads to the rapid loss of central vision, often followed by further loss of peripheral vision. SFD shares several pathological features commonly found in the ‘wet’ or exudative form of age-related macular degeneration (AMD), the most common cause of blindness in the elderly in developed countries. These phenotypic similarities have led to SFD being proposed as an acceptable genetic model for AMD. Whereas AMD appears to have a complex aetiology, with both genetic and environmental factors playing a role, SFD has been shown to be a single-gene disorder, linked to mutations in exon 5 of the tissue inhibitor of metalloproteinases 3 (TIMP3) gene on chromosome 22q12-q13. This review confines itself to a discussion of the known biochemical properties of the wild-type and SFD TIMP3 proteins and attempts to relate these to the pathology encountered in SFD patients. We also discuss briefly how, despite the lack of inherited mutations in the structural gene, the TIMP3 protein might play a role in the onset and progression of AMD.

scholarly journals Sensitivity, Specificity, and Limitations of Optical Coherence Tomography Angiography in Diagnosis of Polypoidal Choroidal Vasculopathy

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Yi-Ming Huang ◽  
Ming-Hung Hsieh ◽  
An-Fei Li ◽  
Shih-Jen Chen
Keyword(s):  
Optical Coherence Tomography ◽  
Sensitivity And Specificity ◽  
Polypoidal Choroidal Vasculopathy ◽  
Optical Coherence Tomography Angiography ◽  
False Positive Rate ◽  
Correct Diagnosis ◽  
Age Related Macular Degeneration ◽  
Optical Coherence ◽  
Age Related ◽  
Choroidal Vasculopathy

Purpose. To evaluate the sensitivity and specificity of optical coherence tomography angiography (OCTA) in differentiating polypoidal choroidal vasculopathy (PCV) from age-related macular degeneration (AMD). Methods. Fundus color photographs, spectral-domain optical coherence tomography, and fluorescein angiography (step 1) and OCTA (step 2) of 50 eyes that had PCV or AMD were presented to two ophthalmologists. The final diagnoses of PCV were masked. Sensitivity and specificity were calculated and compared to the 2-step approach (before and after OCTA) in detecting PCV. The limitations were also evaluated. Results. Of the 50 eyes, 31 were PCV and 19 were non-PCV. The sensitivity increased from 69.5% to 90% after OCTA; however, there was no significant improvement in specificity after OCTA. 70.9% of the eyes with PCV had clear or obvious branching vascular nets (BVNs) in OCTA with high sensitivity (97.5%) after OCTA. Contrarily, 29.1% had insignificant BVNs with a low sensitivity (72.5%) after OCTA. 27% of the occult choroidal neovascularization (CNV) cases were overdiagnosed as PCV when OCTA was applied. Conclusions. OCTA based on clear BVNs at the choroidal level increased sensitivity of diagnosis of PCV by 20%. However, the false-positive rate also increased in occult CNV. Several limitations for a correct diagnosis of PCV were noted.

scholarly journals A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

2015 ◽  
Vol 48 (2) ◽  
pp. 134-143 ◽  
Author(s):  
Lars G Fritsche ◽  
Wilmar Igl ◽  
Jessica N Cooke Bailey ◽  
Felix Grassmann ◽  
Sebanti Sengupta ◽  
...  
Keyword(s):  
Association Study ◽  
Macular Degeneration ◽  
Genome Wide Association Study ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association ◽  
Common Variants ◽  
Large Genome ◽  
Age Related ◽  
Genome Wide

scholarly journals CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy

2018 ◽  
Vol 115 (24) ◽  
pp. 6261-6266 ◽  
Author(s):  
Yoshikatsu Hosoda ◽  
Munemitsu Yoshikawa ◽  
Masahiro Miyake ◽  
Yasuharu Tabara ◽  
Jeeyun Ahn ◽  
...  
Keyword(s):  
Central Serous Chorioretinopathy ◽  
Choroidal Thickness ◽  
Vision Loss ◽  
Genome Wide Association Study ◽  
Age Related Macular Degeneration ◽  
Common Disease ◽  
Susceptibility Loci ◽  
Case Control Studies ◽  
Age Related ◽  
A Genome

Central serous chorioretinopathy (CSC) is a common disease affecting younger people and may lead to vision loss. CSC shares phenotypic overlap with age-related macular degeneration (AMD). As recent studies have revealed a characteristic increase of choroidal thickness in CSC, we conducted a genome-wide association study on choroidal thickness in 3,418 individuals followed by TaqMan assays in 2,692 subjects, and we identified two susceptibility loci: CFH rs800292, an established AMD susceptibility polymorphism, and VIPR2 rs3793217 (P = 2.05 × 10−10 and 6.75 × 10−8, respectively). Case–control studies using patients with CSC confirmed associations between both polymorphisms and CSC (P = 5.27 × 10−5 and 5.14 × 10−5, respectively). The CFH rs800292 G allele is reportedly a risk allele for AMD, whereas the A allele conferred risk for thicker choroid and CSC development. This study not only shows that susceptibility genes for CSC could be discovered using choroidal thickness as a defining variable but also, deepens the understanding of differences between CSC and AMD pathophysiology.

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