June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Spatial modeling of variants in complement genes associated with age-related macular degeneration
Author Affiliations & Notes
  • Michelle Grunin
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Braun School of Public Health and Community Medicine, Hebrew University of Jerusalem, Jerusalem, Jerusalem, Israel
  • Sarah de Jong
    Department of Ophthalmology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
  • Ellen Palmer
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States
  • Bowen Jin
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States
  • David Rinker
    Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, United States
  • Christopher Moth
    Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States
  • John A Capra
    Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States
    Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, United States
  • Jonathan L Haines
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States
  • William S Bush
    Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States
    Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States
  • Anneke I Den Hollander
    AbbVie Inc, North Chicago, Illinois, United States
  • Footnotes
    Commercial Relationships   Michelle Grunin None; Sarah de Jong None; Ellen Palmer None; Bowen Jin None; David Rinker None; Christopher Moth None; John Capra None; Jonathan Haines None; William Bush None; Anneke Den Hollander Abbvie Pharmaceuticals, Code E (Employment)
  • Footnotes
    Support  IAMDGC: NIH 1X01HG006934–01 and R01 EY022310, Michelle Grunin: Bright Focus Postdoctoral Fellow in Macular Degeneration Research
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 2627. doi:
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    • Get Citation

      Michelle Grunin, Sarah de Jong, Ellen Palmer, Bowen Jin, David Rinker, Christopher Moth, John A Capra, Jonathan L Haines, William S Bush, Anneke I Den Hollander; Spatial modeling of variants in complement genes associated with age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2627.

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

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  • Supplements
Abstract

Purpose : Genetic variants in complement genes are associated with age-related macular degeneration (AMD). However, the functional impact of the majority of missense variants is unknown. We evaluated spatial placement on protein structure, using the International AMD Genomics Consortium(IAMDGC) data(16,144 cases/17,832 controls).

Methods : The IAMDGC data was imputed using the HRC, with a 30% improvement over the original. Missense variants were extracted for CFH,CFI,CFB,C9,& C3 genes. We evaluated variants’ placement in protein structure space: spatial proximity in the protein, and AMD association. We compared the spatial proximity of known AMD variants(KAV) to unassociated, assessed variants’ likelihood of protein destabilization, and performed gene-based testing. Gene-based tests included: all variants; variants near KAV; and variants predicted to destabilize proteins. SKAT testing was used to confirm spatial associations. Logistic regression on KAV in CFI identified variants leading to >50% reduction in protein expression compared to wild type in vitro. These results were compared to functional impact scores, showing if a variant has a functional impact genome wide.

Results : Multiple destabilizing variants were found. Gene-based tests using all variants identified significant associations of the C3,C9,CFB,andCFH genes with AMD risk after controlling for age and sex(P=3.22x10-5;7.58x10-6;2.1x10-3;1.2x10-31). Filtering on protein destabilization and SKAT-O tests found several missense variants in CFI and CFH associated with AMD(P=CFH:0.05,CFI:0.01, threshold<0.05).We identified spatial associations for AMD risk in structures for C3,C9,CFB,CFH,and CFI at P<0.05. Both structural and functional scores were predictive of reduced CFI protein expression, and ROC curve analyses suggest structural scores are a better predictor(AUCs of 0.76 and 0.69).

Conclusions : We demonstrate missense variants in complement genes cluster spatially and are associated with AMD status. Using this method, we can identify CFI and CFH variants previously classified as unknown significance, but are predicted to destabilize proteins. This method can predict in-vitro tested CFI protein expression changes, indicating that it is a useful tool for selecting variants for functional follow-up. Further investigation is needed to validate the models for additional variants in other complement and AMD-associated genes.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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