September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
AMD-associated SNPs in the ARMS2/HTRA1 locus influence local gene expression in multiple human tissues
Author Affiliations & Notes
  • Sha-Mei Liao
    Novartis, Cambridge, Massachusetts, United States
  • casey lewis
    Novartis, Cambridge, Massachusetts, United States
  • Omar Delgado
    Novartis, Cambridge, Massachusetts, United States
  • Maura Crowley
    Novartis, Cambridge, Massachusetts, United States
  • Natasha Buchanan
    Novartis, Cambridge, Massachusetts, United States
  • Wei Zheng
    Novartis, Cambridge, Massachusetts, United States
  • Thaddeus P Dryja
    Novartis, Cambridge, Massachusetts, United States
  • Bruce D Jaffee
    Novartis, Cambridge, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Sha-Mei Liao, Novartis (F); casey lewis, Novartis (F); Omar Delgado, novartis (F); Maura Crowley, Novartis (F); Natasha Buchanan, Novartis (F); Wei Zheng, novartis (F); Thaddeus Dryja, Novartis (F); Bruce Jaffee, Novartis (F)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2629. doi:
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      Sha-Mei Liao, casey lewis, Omar Delgado, Maura Crowley, Natasha Buchanan, Wei Zheng, Thaddeus P Dryja, Bruce D Jaffee; AMD-associated SNPs in the ARMS2/HTRA1 locus influence local gene expression in multiple human tissues. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2629.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Genome-wide association studies successfully identified a number of age-related macular degeneration (AMD) risk or protective variants. To assess allele-specific gene expression, we evaluated the cis-effect of one major AMD susceptibility locus ARMS2/HTRA1 on local gene transcription using the Genotype-Tissue Expression (GTEx) database.

Methods : AMD risk variants rs104909242-T and rs11200638-A on chromosome 10 ARMS2/HTRA1 locus were used to search for nearby gene expression in the GTEx portal Version 6. Messenger RNA levels are expressed as rank normalized gene expression. The effect size quantifies the strength of expression variation (positive number = increase in mRNA level, negative number = decrease).

Results : Human testis expressed the highest level of ARMS2 mRNA compared to other tissues. The rs10490929-T allele, one of the major AMD risk variants in the ARMS2 coding region, was associated with a marked reduction in ARMS2 mRNA level (effect size -0.79, p=7.5x10-24) in testis as well as in many other tissues. Another AMD risk variant in the HTRA1 promoter region, rs1120638-A, was also associated with a marked reduction in ARMS2 mRNA levels (effect size -0.76, p=8.3x10-20) in testis. PLEKHA1 is the gene upstream of ARMS2. Its mRNA level was reduced by both rs10490924-T and rs11200638-A in ovary (effect size -0.43, p=3.2-3.8x10-5), but not in testis. The transcript level of HTRA1, the gene downstream of ARMS2, was increased (effect size 0.39-0.40, p=1.5-4.9x10-7) in testis by both genetic variants. No other genes within 1 mega base pairs around the ARMS2/HTRA1 locus were affected in transcription by these two variants.

Conclusions : Both AMD risk variants, rs14090924-T and rs1120638-A, are associated with a significant reduction of ARMS2 gene expression in a variety of tissues. PLEKHA1 mRNA levels are also reduced by these two variants in a number of human tissues, but not in testis. In contrast, rs14090924-T and rs1120638-A are associated with increased HTRA1 mRNA levels in several tissues including testis.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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