Expressive

rs11200638 (HTRA1): Wet AMD Risk Variant

Key takeaways

  • rs11200638 sits in the HTRA1 gene promoter and is one of the strongest known genetic risk factors for wet AMD
  • The homozygous risk genotype carries an estimated 10-fold higher wet AMD likelihood compared with the wild-type
  • The chromosome 10q26 region specifically marks AMD patients who develop reticular pseudodrusen, with no such signal from the complement system locus on chromosome 1
  • A neighboring long non-coding RNA, HTRA1-AS1, shows a strong expression signal in retinal tissue concentrated at the photoreceptor outer segment layer
  • AMD association has been confirmed in Thai and Taiwanese populations alongside the original Chinese discovery

Key takeaways

  • rs11200638 sits in the promoter of HTRA1 (a serine protease gene at chromosome 10q26) and ranks among the strongest known genetic risk factors for wet age-related macular degeneration (AMD)
  • The homozygous risk genotype was estimated to carry roughly 10 times the likelihood of developing wet AMD compared with the wild-type genotype
  • The chromosome 10q26 region specifically distinguishes AMD patients who develop reticular pseudodrusen from those who do not, while the chromosome 1 complement factor H locus shows no such subtype-specific signal
  • A long non-coding RNA within this region, HTRA1-AS1, shows a strong expression-QTL signal in retinal tissue concentrated at the parafoveal photoreceptor outer segment layer
  • AMD association has been confirmed in Thai and Taiwanese populations alongside its original Chinese discovery, supporting relevance across East Asian ancestries

What the research says A whole-genome association study in a Chinese population first identified rs11200638 - in the promoter of HTRA1, a serine protease (protein-cleaving enzyme) on chromosome 10q26 - as a major risk factor for wet AMD, reporting P<10^-¹¹ and estimating approximately 10-fold higher disease likelihood for the risk genotype relative to wild-type PMID 17053109. Independent GWAS in a Thai cohort (377 cases, 1,074 controls) and a Taiwanese cohort (4,039 AMD cases, 16,488 controls) confirmed the 10q26 locus at genome-wide significance, replicating the association across East Asian ancestries. A 2025 RPD-specific international consortium (n=13,985 across 14 cohorts) found the 10q26 locus uniquely distinguishing AMD+/RPD+ from AMD+/RPD- participants, with the chromosome 1 complement factor H locus notably absent from that comparison, and identified HTRA1-AS1 - a long non-coding RNA at this locus - as carrying a strong retinal eQTL (expression quantitative trait locus: a genetic variant that influences how much of a gene is produced in tissue) signal localised to the parafoveal (near-foveal, the central high-acuity zone of the retina) photoreceptor outer segment layer and co-localizing with retinal thickness markers.

Reported associations

  • Wet (neovascular) AMD: Major risk locus identified in a Chinese population; risk genotype estimated at ~10-fold higher disease likelihood vs wild-type; P<10^-¹¹ PMID 17053109
  • Neovascular AMD (Thai population): Genome-wide significant replication in 377 cases and 1,074 controls; confirmed alongside ARMS2 rs10490924 and CFH rs800292 as one of three major AMD loci in this ancestry group
  • AMD at the HTRA1-ARMS2 region (Taiwanese population): One of 31 AMD-associated variants on chromosome 10q26 in a GWAS of 4,039 AMD patients and 16,488 controls; the neighboring SNP rs11200630 at this locus showed 1.31-fold increased AMD risk per risk allele (95% CI: 1.20-1.43)
  • Reticular pseudodrusen (RPD) AMD subtype: The 10q26 locus significantly differentiates AMD+/RPD+ (n=2,165) from AMD+/RPD- (n=4,181) participants in an international consortium of 13,985 total participants; whole-genome sequencing of phenotypically extreme RPD cases showed even stronger enrichment for the chromosome 10 risk genotype

Evidence quality Evidence for rs11200638 as an AMD risk variant is strong and consistently replicated. The original discovery reached P<10^-¹¹ with an estimated ~10-fold odds for the risk homozygote in a Chinese population PMID 17053109. Independent replication in a Thai GWAS (n=1,451) and a Taiwanese GWAS (n=20,527) both achieved genome-wide significance at the same locus. The 2025 RPD-specific consortium (n=13,985 from 14 international cohorts combining individual-level genotyping and summary statistics) adds subtype resolution without conflicting with prior findings. No conflicting evidence is reported across the four studies reviewed. The HTRA1-AS1 retinal eQTL signal provides a plausible mechanistic pathway but is an observational finding and does not establish causation.

Tissue-specific expression effects

  • ARMS2: The alternate allele is associated with reduced expression in testis GTEx Portal
  • HTRA1-AS1 (ENSG00000285955): The alternate allele is associated with increased expression across multiple tissues, including brain cortex, unexposed and sun-exposed skin, cultured fibroblasts, pituitary, tibial artery, and subcutaneous adipose tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is the HTRA1 gene?

HTRA1 is a gene on chromosome 10q26 that encodes a serine protease, a type of enzyme that cleaves other proteins. Variants in its promoter region are among the strongest known genetic risk factors for wet age-related macular degeneration.

Is rs11200638 linked to macular degeneration?

Yes. Multiple genome-wide association studies in Chinese, Thai, and Taiwanese populations have confirmed rs11200638 as a major risk variant for wet (neovascular) AMD. The risk genotype was estimated to carry roughly 10-fold higher disease likelihood compared with the wild-type genotype.

What are reticular pseudodrusen?

Reticular pseudodrusen are deposits that form in the subretinal space, above the retinal pigment epithelium, and are found in up to 60% of late-stage AMD cases. Research has found that the chromosome 10q26 region around HTRA1 specifically differentiates AMD patients who develop these deposits from those who do not, with no equivalent signal from the complement system on chromosome 1.

What is HTRA1-AS1?

HTRA1-AS1 (ENSG00000285955) is a long non-coding RNA located near HTRA1 on chromosome 10q26. It carries a strong expression-QTL signal in retinal tissue, particularly in the parafoveal photoreceptor outer segment layer, suggesting a functional role in retinal biology at this locus.

Is rs11200638 relevant outside East Asian populations?

The studies reviewed examined Chinese, Thai, and Taiwanese populations, all of which confirmed strong AMD associations at this locus. The available evidence does not directly address AMD risk for rs11200638 in non-East Asian populations.