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:ImportanceRisk score models predicting the progression of age-related macular degeneration (AMD) to its advanced forms may be useful for targeting high-risk individuals for lifestyle changes that reduce risk for AMD progression, helping with differential diagnosis of AMD and its subtypes, identifying high-risk subjects for participation in clinical trials, and selecting appropriate therapies.ObjectiveTo develop and validate a predictive model for progression to advanced stages of AMD in 2 independent cohorts. DESIGN Participants in a validation cohort and an independent derivation population were classified into 5 stages of AMD based on ocular examination and fundus photographs at baseline. Progression was defined as either eye progressing from stage 1, 2, or 3 to either stage 4 or stage 5 at any follow-up visit to the end of the study. Cox proportional hazards models were used for progression analyses. Covariates included demographic and environmental factors, 6 variants in 5 genes, and baseline AMD grades in both eyes. The algorithm developed with the derivation sample was assessed for calibration and discrimination in the validation data set.SettingClinic populations and referrals.ParticipantsThe derivation population comprised 2914 subjects with 809 progressors. The independent validation cohort comprised 980 individuals with no, early, or intermediate AMD in at least one eye at baseline, of whom 294 progressed to advanced stages of geographic atrophy or neovascular disease.Main outcome measureProgression to advanced AMD. RESULTS For the model with all nongenetic and genetic factors, the respective C statistics for progression to advanced AMD in the derivation and validation samples were 0.858 and 0.750 at 5 years and 0.884 and 0.809 at 10 years, and models also discriminated risk for progression to geographic atrophy and neovascular disease separately. For unilateral or bilateral intermediate AMD, 5-year cumulative incidence rates of progression to advanced AMD were 10% with the low-risk score and 50% with the high-risk score; for unilateral advanced disease, the progression rates were 22% and 80% for the fellow eye.Conclusions and relevanceThe risk prediction model was validated in an independent study of progression from no, early, or intermediate stages to advanced subtypes of AMD and will be useful for research, clinical trials, and personalized medicine.

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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.

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