Dataset Information

Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.

ABSTRACT:

Purpose

To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes.

Design

Sibling correlation study and genome-wide association study (GWAS).

Participants

For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls.

Methods

Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.

Main outcome measures

Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.

Results

The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis).

Conclusions

Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.

SUBMITTER: Sobrin L

PROVIDER: S-EPMC3899891 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Publications

Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.

Sobrin Lucia L Ripke Stephan S Yu Yi Y Fagerness Jesen J Bhangale Tushar R TR Tan Perciliz L PL Souied Eric H EH Buitendijk Gabriëlle H S GH Merriam Joanna E JE Richardson Andrea J AJ Raychaudhuri Soumya S Reynolds Robyn R Chin Kimberly A KA Lee Aaron Y AY Leveziel Nicolas N Zack Donald J DJ Campochiaro Peter P Smith R Theodore RT Barile Gaetano R GR Hogg Ruth E RE Chakravarthy Usha U Behrens Timothy W TW Uitterlinden André G AG van Duijn Cornelia M CM Vingerling Johannes R JR Brantley Milam A MA Baird Paul N PN Klaver Caroline C W CC Allikmets Rando R Katsanis Nicholas N Graham Robert R RR Ioannidis John P A JP Daly Mark J MJ Seddon Johanna M JM

Ophthalmology 20120615 9

<h4>Purpose</h4>To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes.<h4>Design</h4>Sibling correlation study and genome-wide association study (GWAS).<h4>Participants</h4>For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants ...[more]

PMID: 22705344

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Project description:ImportanceRecent reports suggest that cilioretinal arteries (CRAs) confer protection against developing advanced age-related macular degeneration (AMD).ObjectiveTo further characterize the association between the presence of a CRA and incidence of geographic atrophy (GA) or choroidal neovascularization (CNV).DesignThis cohort study constituted an ad hoc secondary analysis of data from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and was performed at 44 clinical centers in the United States among participants in CATT with CNV in the study eye and without advanced AMD in the fellow eye at baseline. The presence of a CRA was determined by 2 graders, masked to clinical data, using color fundus photographs, red-free fundus photographs, and fluorescein angiography. The proportion with CRAs at baseline between the study eye with CNV and fellow eye without CNV was first compared. The association of a CRA with incidence of CNV or GA at 5 years among fellow eyes and with incidence of GA among study (treated) eyes was then assessed. In addition, the association of CRAs with the Age-Related Eye Disease Study severity scale among the fellow eyes at baseline was assessed. Data were collected from February 1, 2008, through April 30, 2015, and analyzed from July 1, 2018, through April 30, 2019.ExposuresPresence of a CRA.Main outcomes and measuresThe association between the presence of a CRA and incidence of CNV or GA at 5 years of follow-up.ResultsA total of 350 patients (700 eyes) (230 [65.7% women; mean [SD] age, 77 [7.2] years) were included in the analysis. Cilioretinal arteries were present in 67 of 345 (19.4%) fellow eyes without baseline CNV and 73 of 349 (20.9%) study eyes with baseline CNV (P = .60). Cilioretinal arteries in fellow eyes were not associated with incidence of CNV at 5 years (125 of 278 [45.0%] among eyes without CRAs and 30 of 67 [44.8%] among eyes with CRAs; P = .99) or with incidence of GA at 5 years (110 of 278 [39.6%] among eyes without CRAs and 25 of 67 [37.3%] among eyes with CRAs; P = .89). Cilioretinal arteries in study eyes were not associated with incidence of GA at 5 years (105 of 276 [38.0%] study eyes without CRAs and 26 of 73 [35.6%] study eyes with CRAs; P = .72).Conclusions and relevanceThe analysis did not find a protective association between CRAs and incidence of CNV or GA among CATT participants who had unilateral exudative AMD. Why these findings were different from those of previous publications is unclear but may be partially explained by the different techniques used to detect CRAs or by the baseline advanced disease in CATT participants.Trial registrationClinicalTrials.gov identifier: NCT00593450.

Project description:BackgroundAdvanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD.MethodsTo identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants.ResultsAltogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10- 8), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism).ConclusionsOur GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

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Dataset Information

Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.

Purpose

Design

Participants

Methods

Main outcome measures

Results

Conclusions

Publications

Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes.

Similar Datasets

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