Mark M Hassall1, Ayub Qassim1, Xikun Han2, Emmanuelle Souzeau1, Ivan Goldberg3, Paul R Healey3, Stuart L Graham4, Jonathan Ruddle5, Robert J Casson6, David A Mackey7, Alex Hewitt8, Stuart MacGregor2, Jamie E Craig1
Purpose: To improve the quantiﬁcation of family history risk estimation in glaucoma.
Method: Positive family history is one of the stron- gest risk factors for developing glaucoma. We devel- oped a glaucoma polygenic risk score (PRS) by characterizing glaucoma endophenotypes on 67,040 UK Biobank (UKBB) and performing genome-wide association study (GWAS). The vertical cup to disc ratio (VCDR) and vertical disc diameter (VDD) were measured form digital retinal photographs. These endophenotypes were then then combined with intraocular pressure (IOP) and glaucoma GWAS data using multi-trait analysis of GWAS (MTAG). We then related the resulting PRS to self-reported family history of glaucoma in the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG; n = 1398). We also analyzed PRS in early glaucoma patients (n = 939).
Results: In ANZRAG, increasing PRS was strongly associated with an increasing number of affected family members (P = 3.46e-09). The patients in the lowest decile of PRS genetic risk had lower mean number of affected family members (0.94, [95CI 0.74, 1.13]) than those patients in the top decile (1.95,[95CI 1.66, 2.25]).
In early glaucoma patients, increasing PRS was signif- icantly associated with increasing number of affected family members (P = 1.01e-06), with similar differ- ences in mean family members between the deciles.
Conclusion: Our novel polygenic risk score predicts self-reported family history. Risk stratiﬁcation and cascade clinical screening of family members of glaucoma probands could be more accurately guided by the PRS of the family member or affected patient, as self-reported family history is known to suffer from inaccurate recall and underestimation.