In the majority of late age-related macular degeneration (AMD) cases, genetic risk variants are a major contribution, and lifestyle factors turned out to have a “strong influence” on genetic risk outcome, according to the EYE-RISK consortium, a large European study published in Ophthalmology.

The study, a pooled analysis of cross-sectional data of 17,174 people who were 45 years or older from the E3 consortium, looked at the genetic distribution of AMD-associated risk variants by calculating attributable, pathway-specific genetics risks and how lifestyle impacted genetic outcomes. Late AMD was considered to be cases that involved geographic atrophy or choroidal neovascularization.

They diagnosed and graded AMD by fundus photographs, harmonizing and collecting data on genetics, lifestyle, and diet as needed. In addition, they calculated minor allele frequencies and population attributable fraction (PAF) per single nucleotide polymorphism (SNP). They constructed the total genetic risk score (GRS) and pathway-specific risk scores (complement, lipid, extra-cellular matrix, other) from dosage of SNPs and conditional beta’s; the study’s lifestyle score was created from smoking and dietary intake.


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They found that the genetic risk variants with the biggest influence in between late AMD cases and controls and the highest population attributable fractions were located in ARMS2 (rs3750846) and CHF (rs570618 and rs10922109). Risk increasing and protective variants also had the highest population attributable fractions. When they combined all genetic variants, they found the total genetic risk score was in the range of 3.50 to 4.63, and was normally distributed and increased with severity of AMD.

The majority of late AMD cases (89%) had a positive total genetic risk score. “The complement pathway and ARMS2 were by far the most prominent genetic pathways contributing to late AMD (positive GRS 90% of late cases), but risk in 3 pathways was most frequent (35% of late cases),” according to investigators.

In addition, they found that lifestyle was “a strong determinant of the outcome in each genetic risk category; unfavorable lifestyle increased the risk of late AMD at least twofold.”

“This large European consortium showed that genetic risk of AMD is highly prevalent in the population at large, and that risk variants in the complement pathway are by far the lead drivers of late AMD. Nevertheless, late AMD is mostly a result of multiple genetic pathways and lifestyle. The frequency and risk estimates provided by this study can lay the foundation for future intervention studies which are tailored to pathways,” according to investigators.

Reference

Colijn JM, Meester M, Verzijden T, EYE-RISK Consortium. Genetic risk, lifestyle, and AMD in Europe. The EYE-RISK consortium. Ophthalmol. Published online November 27, 2020. doi:10.1016/j.ophtha.2020.11.024