Macular thickness varies with age-related macular degeneration genetic risk variants in the UK Biobank cohort.
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SUBMITTER: Kaye RA
PROVIDER: S-EPMC8636487 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To evaluate potential diagnostic and therapeutic biomarkers for age-related macular degeneration (AMD), we identified 8433 UK Biobank participants with rare complement Factor I gene (CFI) variants, 579 with optical coherence tomography-derived macular thickness data. We stratified these variants by predicted gene expression and measured their association with retinal pigment epithelium-Bruch's membrane (RPE-BM) complex and retinal thicknesses at nine macular subfields, as well as AMD risk, using multivariable regression models adjusted for the common complement Factor H gene (CFH) p.Y402H and age-related maculopathy susceptibility protein 2 gene (ARMS2) p.A69S risk genotypes. CFI variants associated with low Factor I levels predicted a thinner mean RPE-BM (95% confidence interval [CI] -1.66 to -0.37 μm, P = 0.002) and retina (95% CI -5.88 to -0.13 μm, P = 0.04) and a higher AMD risk (odds ratio [OR] = 2.26, 95% CI 1.56 to 3.27, P < 0.001). CFI variants associated with normal Factor I levels did not impact mean RPE-BM/retinal thickness (P = 0.28; P = 0.99) or AMD risk (P = 0.97). CFH p.Y402H was associated with a thinner RPE-BM (95% CI -0.31 to -0.18 μm, P < 0.001 heterozygous; 95% CI -0.62 to -0.42 μm, P < 0.001 homozygous) and retina (95% CI -0.73 to -0.12 μm, P = 0.007 heterozygous; 95% CI -1.08 to -0.21 μm, P = 0.004 homozygous). ARMS2 p.A69S did not influence RPE-BM (P = 0.80 heterozygous; P = 0.12 homozygous) or retinal thickness (P = 0.75 heterozygous; P = 0.07 homozygous). p.Y402H and p.A69S exhibited a significant allele-dose response with AMD risk. Thus, CFI rare variants associated with low Factor I levels are robust predictors of reduced macular thickness and AMD. The observed association between macular thickness and CFH p.Y402H, but not ARMS2 p.A69S, highlights the importance of complement dysregulation in early pathogenesis.
| S-EPMC9402241 | biostudies-literature
Project description:PurposeThe prevalence of age-related macular degeneration (AMD) increases dramatically with age. This large collaborative study investigates the effects of 51 late-AMD-associated genetic variants in different ages, focusing on individuals above the age of 90 years.MethodsThe study included 27,996 individuals of the International AMD Genomics Consortium; 14,539 showed late AMD (51.9%) and 13,457 were controls (48.1%). Four age groups were compiled: 60 to 69 years, n = 6514, AMD = 2210 (33.9%); 70 to 79 years, n = 12228, AMD = 6217 (51.7%); 80 to 89 years, n = 8285, AMD = 5326 (64.3%); and ≥90 years, n = 969, AMD = 686 (70.8%). The effect sizes of 51 AMD-associated genetic variants were calculated for all age groups and were compared among the age groups.ResultsSix variants were associated with late AMD in individuals ≥ 90 years of age (P ≤ 0.0006). For rs10922109 and rs570618 (both in CFH), the minor allele (MA) was protective, and minor allele frequency (MAF) increased with age in cases and controls. For rs116503776 in C2/CFB/SKIV2L, the MA was protective, and MAF increased in cases. For rs3750846 in ARMS2/HTRA1, the MA increased risk, and MAF was lower in cases with increasing age. For rs6565597 in NPLOC4/TSPAN10, the MA increased risk. For rs5754227 in SYN3/TIMP3, the MA was protective, and there was no consistent variation in MAF with age. Variants in CFH and ARMS2 showed lower effect sizes at greater age. Interaction analysis showed strong age-related effects for rs570618 (P = 2.24 × 10-7) and rs3750846 (P = 0.001). Total genetic risk was lower in individuals ≥ 90 years old (area under the curve [AUC], 0.795) than in those 70 to 79 years old (AUC, 0.831; P = 0.03).ConclusionsEffect sizes and MAF of genetic risk factors for late AMD differed among the age groups. These results could guide future work on AMD risk assessment in older individuals.
| S-EPMC7745630 | biostudies-literature
Project description:The macula, located near the center of the retina in the human eye, is responsible for providing critical functions, such as central, sharp vision. Structural changes in the macula are associated with many ocular diseases, including age-related macular degeneration (AMD) and glaucoma. Although macular thickness is a highly heritable trait, there are no prior reported genome-wide association studies (GWASs) of it. Here we describe the first GWAS of macular thickness, which was measured by spectral-domain optical coherence tomography using 68 423 participants from the UK Biobank cohort. We identified 139 genetic loci associated with macular thickness at genome-wide significance (P < 5 × 10-8). The most significant loci were LINC00461 (P = 5.1 × 10-120), TSPAN10 (P = 1.2 × 10-118), RDH5 (P = 9.2 × 10-105) and SLC6A20 (P = 1.4 × 10-71). Results from gene expression demonstrated that these genes are highly expressed in the retina. Other hits included many previously reported AMD genes, such as NPLOC4 (P = 1.7 × 10-103), RAD51B (P = 9.1 × 10-14) and SLC16A8 (P = 1.7 × 10-8), further providing functional significance of the identified loci. Through cross-phenotype analysis, these genetic loci also exhibited pleiotropic effects with myopia, neurodegenerative diseases (e.g. Parkinson's disease, schizophrenia and Alzheimer's disease), cancer (e.g. breast, ovarian and lung cancers) and metabolic traits (e.g. body mass index, waist circumference and type 2 diabetes). Our findings provide the first insight into the genetic architecture of macular thickness and may further elucidate the pathogenesis of related ocular diseases, such as AMD.
| S-EPMC6423416 | biostudies-literature
Project description:PurposeDespite widespread use of OCT, an early-stage imaging biomarker for age-related macular degeneration (AMD) has not been identified. Pathophysiologically, the timing of drusen accumulation in relationship to photoreceptor degeneration in AMD remains unclear, as are the inherited genetic variants contributing to these processes. Herein, we jointly analyzed OCT, electronic health record data, and genomic data to characterize the time sequence of changes in retinal layer thicknesses in AMD, as well as epidemiologic and genetic associations between retinal layer thicknesses and AMD.DesignCohort study.ParticipantsForty-four thousand eight hundred twenty-three individuals from the UK Biobank (enrollment age range, 40-70 years; 54% women; median follow-up, 10 years).MethodsThe Topcon Advanced Boundary Segmentation algorithm was used for retinal layer segmentation. We associated 9 retinal layer thicknesses with prevalent AMD (present at enrollment) in a logistic regression model and with incident AMD (diagnosed after enrollment) in a Cox proportional hazards model. Next, we associated AMD-associated genetic alleles, individually and as a polygenic risk score (PRS), with retinal layer thicknesses. All analyses were adjusted for age, age-squared (age2), sex, smoking status, and principal components of ancestry.Main outcome measuresPrevalent and incident AMD.ResultsPhotoreceptor segment (PS) thinning was observed throughout the lifespan of individuals analyzed, whereas retinal pigment epithelium (RPE) and Bruch's membrane (BM) complex thickening started after 57 years of age. Each standard deviation (SD) of PS thinning and RPE-BM complex thickening was associated with incident AMD (PS: hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.23-1.47; P = 3.7 × 10-11; RPE-BM complex: HR, 1.14; 95% CI, 1.06-1.22; P = 0.00024). The AMD PRS was associated with PS thinning (β, -0.21 SD per twofold genetically increased risk of AMD; 95% CI, -0.23 to -0.19; P = 2.8 × 10-74), and its association with RPE-BM complex was U-shaped (thinning with AMD PRS less than the 92nd percentile and thickening with AMD PRS more than the 92nd percentile). The loci with strongest support for genetic correlation were AMD risk-raising variants Complement Factor H (CFH):rs570618-T, CFH:rs10922109-C, and Age-Related Maculopathy Susceptibility 2 (ARMS2)/High-Temperature Requirement Serine Protease 1 (HTRA1):rs3750846-C on PS thinning and SYN3/Tissue Inhibitor of Metalloprotease 3 (TIMP3):rs5754227-T on RPE-BM complex thickening.ConclusionsEpidemiologically, PS thinning precedes RPE-BM complex thickening by decades and is the retinal layer most strongly predictive of future AMD risk. Genetically, AMD risk variants are associated with decreased PS thickness. Overall, these findings support PS thinning as an early-stage biomarker for future AMD development.
| S-EPMC9134644 | biostudies-literature
Project description:Background: The aim of this paper was to determine the frequency of SIRT1 rs3818292, rs3758391, rs7895833 single nucleotide polymorphism genotypes and SIRT1 serum levels associated with age-related macular degeneration (AMD) in the Lithuanian population. Methods: Genotyping of SIRT1 rs3818292, rs3758391 and rs7895833 was performed using RT-PCR. SIRT1 serum level was determined using the ELISA method. Results: We found that rs3818292 and rs7895833 were associated with an increased risk of developing exudative AMD. Additional sex-differentiated analysis revealed only rs7895833 was associated with an increased risk of developing exudative AMD in women after strict Bonferroni correction. The analysis also revealed that individuals carrying rs3818292, rs3758391 and rs7895833 haplotype G-T-G are associated with increased odds of exudative AMD. Still, the rare haplotypes were associated with the decreased odds of exudative AMD. After performing an analysis of serum SIRT1 levels and SIRT1 genetic variant, we found that carriers of the SIRT1 rs3818292 minor allele G had higher serum SIRT1 levels than the AA genotype. In addition, individuals carrying at least one SIRT1 rs3758391 T allele also had elevated serum SIRT1 levels compared with individuals with the wild-type CC genotype. Conclusions: Our study showed that the SIRT1 polymorphisms rs3818292 and rs7895833 and rs3818292-rs3758391-rs7895833 haplotype G-T-G could be associated with the development of exudative AMD. Also, two SNPs (rs3818292 and rs3758391) are associated with elevated SIRT1 levels.
| S-EPMC9148058 | biostudies-literature
Project description:To identify rare genetic variants in early age-related macular degeneration (AMD) utilizing whole-exome sequencing (WES). Eight non-related early-AMD families of different Jewish ethnicities were ascertained. Initial mutation screening (phase-1) included common complement factor-H (CFH) p.Y402H; and age relatedmaculopathy susceptibility 2 (ARMS2) p.A69S; and rare variants complement factor-I (CFI) p.V412M; and hemicentin1 (HMCN1) c.4163delC identified previously in our population. Four families, whose initial screening for the aforementioned variants was negative, underwent WES (phase-2). Bioinformatics filtering was based on functionality (from a panel of 234 genes with proven or presumed association to AMD); predicted severity; and frequency (rare variants with minor allele frequency <1%). When applicable, further screening for specific rare variants was carried out on additional cases of similar ethnicities and phenotypes (phase-3). Phase-1 identified three families carrying CFI p.V412M mutation. WES analysis detected probable disease-related variants in three out of the remaining families. These included: a family with a variant in PLEKHA1 gene p.S177N; a family with previously reported variant p.R1210C in CFH gene; and two families with the C3 p.R735W variant. Rare, high-penetrance variants have a profound contribution to early-AMD pathogenesis. Utilization of WES in genetic research of multifactorial diseases as AMD, allows a thorough comprehensive analysis with the identification of previously unreported rare variants.
| S-EPMC6826738 | biostudies-literature
Project description:ObjectiveTo compare prevalent and incident morbidity and mortality between those with the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) and those with no p.C282Y mutations, in a large UK community sample of European descent.DesignCohort study.Setting22 centres across England, Scotland, and Wales in UK Biobank (2006-10).Participants451 243 volunteers of European descent aged 40 to 70 years, with a mean follow-up of seven years (maximum 9.4 years) through hospital inpatient diagnoses and death certification.Main outcome measureOdds ratios and Cox hazard ratios of disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components. The sexes were analysed separately as morbidity due to iron excess occurs later in women.ResultsOf 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), haemochromatosis was diagnosed in 21.7% (95% confidence interval 19.5% to 24.1%, 281/1294) of men and 9.8% (8.4% to 11.2%, 156/1596) of women by end of follow-up. p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed haemochromatosis (odds ratio 411.1, 95% confidence interval 299.0 to 565.3, P<0.001), liver disease (4.30, 2.97 to 6.18, P<0.001), rheumatoid arthritis (2.23, 1.51 to 3.31, P<0.001), osteoarthritis (2.01, 1.71 to 2.36, P<0.001), and diabetes mellitus (1.53, 1.16 to 1.98, P=0.002), versus no p.C282Y mutations (n=175 539). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (P<0.001) with no p.C282Y mutations (women 10.1% v 3.4%, P<0.001). Haemochromatosis diagnoses were more common in p.C282Y/p.H63D heterozygotes, but excess morbidity was modest.ConclusionsIn a large community sample, HFE p.C282Y homozygosity was associated with substantial prevalent and incident clinically diagnosed morbidity in both men and women. As p.C282Y associated iron overload is preventable and treatable if intervention starts early, these findings justify re-examination of options for expanded early case ascertainment and screening.
| S-EPMC6334179 | biostudies-literature
Project description:PurposeTo compare plasma levels of oxidative stress biomarkers in patients with age-related macular degeneration (AMD) and controls and to evaluate a potential relationship between biochemical markers of oxidative stress and AMD susceptibility genotypes.DesignProspective case-control study.MethodsPlasma levels of oxidative stress biomarkers were determined in 77 AMD patients and 75 controls recruited from a clinical practice. Cysteine, cystine (CySS), glutathione, isoprostane, and isofuran were measured, and participants were genotyped for polymorphisms in the complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes.ResultsCySS was elevated in cases compared with controls (P = .013). After adjustment for age, sex, and smoking, this association was not significant. In all participants, CySS levels were associated with the CFH polymorphism rs3753394 (P = .028) as well as an 8-allele CFH haplotype (P = .029) after correction for age, gender, and smoking. None of the other plasma markers was related to AMD status in our cohort.ConclusionsOur investigation of the gene-environment interaction involved in AMD revealed a relationship between a plasma biomarker of oxidative stress, CySS, and CFH genotype. These data suggest a potential association between inflammatory regulators and redox status in AMD pathogenesis.
| S-EPMC3288635 | biostudies-literature
Project description:PurposeFor OCT retinal thickness measurements to be used as a prodromal age-related macular degeneration (AMD) risk marker, the 3-dimensional (3D) topographic variation of the relationship between genetic susceptibility to AMD and retinal thickness needs to be assessed. We aimed to evaluate individual retinal layer thickness changes and topography at the macula that are associated with AMD genetic susceptibility.DesignGenetic association study.ParticipantsA total of 1579 healthy participants (782 Chinese, 353 Malays, and 444 Indians) from the multiethnic Singapore Epidemiology of Eye Diseases study were included.MethodsSpectral-domain OCT and automatic segmentation of individual retinal layers were performed to produce 10 retinal layer thickness measurements at each ETDRS subfield, producing 3D topographic information. Age-related macular degeneration genetic susceptibility was represented via single nucleotide polymorphisms (SNPs) and aggregated via whole genome (overall) and pathway-specific age-related macular degeneration polygenic risk score (PRSAMD).Main outcome measuresAssociations of individual SNPs, overall PRSAMD, and pathway-specific PRSAMD with retinal thickness were analyzed by individual retinal layer and ETDRS subfield.ResultsCFH rs10922109, ARMS2-HTRA1 rs3750846, and LIPC rs2043085 were the top AMD susceptibility SNPs associated with retinal thickness of individual layers (P < 1.67 × 10-3), all at the central subfield. The overall PRSAMD was most associated with thinner L9 (outer segment photoreceptor/retinal pigment epithelium complex) thickness at the central subfield (β = -0.63 μm; P = 5.45 × 10-9). Pathway-specific PRSAMD for the complement cascade (β = -0.53 μm; P = 9.42 × 10-7) and lipoprotein metabolism (β = -0.05 μm; P = 0.0061) were associated with thinner photoreceptor layers (L9 and L7 [photoreceptor inner/outer segments], respectively) at the central subfield. The mean PRSAMD score was larger among Indians compared with that of the Chinese and had the thinnest thickness at the L9 central subfield (β = -1.00 μm; P = 2.91 × 10-7; R2 = 5.5%). Associations at other retinal layers and ETDRS regions were more heterogeneous.ConclusionsOverall genetic susceptibility to AMD and the aggregate effects of the complement cascade and lipoprotein metabolism pathway are associated most significantly with L7 and L9 photoreceptor thinning at the central macula in healthy individuals. Photoreceptor thinning has potential to be a prodromal AMD risk marker, and topographic variation should be considered.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
| S-EPMC10630670 | biostudies-literature
Project description:Age-related macular degeneration (AMD) is a complex multifactorial disease with at least 34 loci contributing to genetic susceptibility. To gain functional understanding of AMD genetics, we generated transcriptional profiles of retina from 453 individuals including both controls and cases at distinct stages of AMD. We integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at over 9 million common single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets. Cis-eQTL analysis revealed 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. We then integrated the AMD-genome-wide association studies (GWAS) data with eQTLs and ascertained target genes at six loci. Furthermore, using transcriptome wide association analysis (TWAS), we identified 23 additional AMD-associated genes, including RLBP1, HIC1 and PARP12. Our studies expand the genetic landscape of AMD leading to direct targets for biological evaluation and establish the Genotype-Retina Expression (GREx) database as a resource for post-GWAS interpretation of retina-associated traits including glaucoma and diabetic retinopathy.
2019-02-11 | GSE115828 | GEO