TY - JOUR
T1 - An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity
AU - Qassim, Ayub
AU - Souzeau, Emmanuelle
AU - Siggs, Owen M.
AU - Hassall, Mark M.
AU - Han, Xikun
AU - Griffiths, Helen L.
AU - Frost, N. Andrew
AU - Vallabh, Neeru A
AU - Kirwan, James F.
AU - Menon, Geeta
AU - Cree, Angela J.
AU - Galanopoulos, Anna
AU - Agar, Ashish
AU - Healey, Paul R.
AU - Graham, Stuart L.
AU - Landers, John
AU - Casson, Robert J.
AU - Gharahkhani, Puya
AU - Willoughby, Colin E.
AU - Hewitt, Alex W.
AU - Lotery, Andrew J.
AU - MacGregor, Stuart
AU - Craig, Jamie E.
PY - 2020/7
Y1 - 2020/7
N2 - PurposeTo
examine the combined effects of common genetic variants associated with
intraocular pressure (IOP) on primary open-angle glaucoma (POAG)
phenotype using a polygenic risk score (PRS) stratification.DesignCross-sectional study.ParticipantsFor
the primary analysis, we examined the glaucoma phenotype of 2154 POAG
patients enrolled in the Australian and New Zealand Registry of Advanced
Glaucoma, including patients recruited from the United Kingdom. For
replication, we examined an independent cohort of 624 early POAG
patients.MethodsUsing
IOP genome-wide association study summary statistics, we developed a
PRS derived solely from IOP-associated variants and stratified POAG
patients into 3 risk tiers. The lowest and highest quintiles of the
score were set as the low- and high-risk groups, respectively, and the
other quintiles were set as the intermediate risk group.Main Outcome MeasuresClinical
glaucoma phenotype including maximum recorded IOP, age at diagnosis,
number of family members affected by glaucoma, cup-to-disc ratio, visual
field mean deviation, and treatment intensity.ResultsA
dose–response relationship was found between the IOP PRS and the
maximum recorded IOP, with the high genetic risk group having a higher
maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the
low genetic risk group (P = 0.006). Compared with the low
genetic risk group, the high genetic risk group had a younger age of
diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1–2.0; P =
0.007). No statistically significant difference was found in mean
deviation. We further replicated the maximum IOP, number of family
members affected by glaucoma, and treatment intensity (number of
medications) results in the early POAG cohort (P ≤ 0.01).ConclusionsThe
IOP PRS was correlated positively with maximum IOP, disease severity,
need for surgery, and number of affected family members. Genes acting
via IOP-mediated pathways, when considered in aggregate, have clinically
important and reproducible implications for glaucoma patients and their
close family members.
AB - PurposeTo
examine the combined effects of common genetic variants associated with
intraocular pressure (IOP) on primary open-angle glaucoma (POAG)
phenotype using a polygenic risk score (PRS) stratification.DesignCross-sectional study.ParticipantsFor
the primary analysis, we examined the glaucoma phenotype of 2154 POAG
patients enrolled in the Australian and New Zealand Registry of Advanced
Glaucoma, including patients recruited from the United Kingdom. For
replication, we examined an independent cohort of 624 early POAG
patients.MethodsUsing
IOP genome-wide association study summary statistics, we developed a
PRS derived solely from IOP-associated variants and stratified POAG
patients into 3 risk tiers. The lowest and highest quintiles of the
score were set as the low- and high-risk groups, respectively, and the
other quintiles were set as the intermediate risk group.Main Outcome MeasuresClinical
glaucoma phenotype including maximum recorded IOP, age at diagnosis,
number of family members affected by glaucoma, cup-to-disc ratio, visual
field mean deviation, and treatment intensity.ResultsA
dose–response relationship was found between the IOP PRS and the
maximum recorded IOP, with the high genetic risk group having a higher
maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the
low genetic risk group (P = 0.006). Compared with the low
genetic risk group, the high genetic risk group had a younger age of
diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1–2.0; P =
0.007). No statistically significant difference was found in mean
deviation. We further replicated the maximum IOP, number of family
members affected by glaucoma, and treatment intensity (number of
medications) results in the early POAG cohort (P ≤ 0.01).ConclusionsThe
IOP PRS was correlated positively with maximum IOP, disease severity,
need for surgery, and number of affected family members. Genes acting
via IOP-mediated pathways, when considered in aggregate, have clinically
important and reproducible implications for glaucoma patients and their
close family members.
KW - Intraocular Pressure
KW - Polygenic Risk Score
KW - Open-Angle Glaucoma
UR - http://www.scopus.com/inward/record.url?scp=85079519439&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1107098
UR - http://purl.org/au-research/grants/NHMRC/1116360
UR - http://purl.org/au-research/grants/NHMRC/1116495
UR - http://purl.org/au-research/grants/NHMRC/1023911
U2 - 10.1016/j.ophtha.2019.12.025
DO - 10.1016/j.ophtha.2019.12.025
M3 - Article
AN - SCOPUS:85079519439
SN - 0161-6420
VL - 127
SP - 901
EP - 907
JO - Ophthalmology
JF - Ophthalmology
IS - 7
ER -