November 2023
Volume 64, Issue 14
Open Access
Genetics  |   November 2023
Association of APOE Haplotypes With Common Age-Related Ocular Diseases in 412,171 Individuals
Author Affiliations & Notes
  • Perttu J. Liuska
    Eye Genetics Group, Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, Helsinki, Finland
  • Joel T. Rämö
    Institute for Molecular Medicine Finland (FIMM), HiLIFE, PL 20, University of Helsinki, Finland
    The Broad Institute of MIT and Harvard, Stanley Building, Cambridge, Massachusetts, United States
  • Susanna Lemmelä
    Institute for Molecular Medicine Finland (FIMM), HiLIFE, PL 20, University of Helsinki, Finland
    Finnish Institute for Health and Welfare, PL 30, Helsinki, Finland
  • Kai Kaarniranta
    Department of Ophthalmology, Kuopio University Hospital and University of Eastern Finland, KYS, Finland
  • Hannu Uusitalo
    TAYS Eye Center, Tampere University and Tampere University Hospital, PL 2000, Tampere, Finland
  • Elisa Lahtela
    Institute for Molecular Medicine Finland (FIMM), HiLIFE, PL 20, University of Helsinki, Finland
  • Mark J. Daly
    Institute for Molecular Medicine Finland (FIMM), HiLIFE, PL 20, University of Helsinki, Finland
    The Broad Institute of MIT and Harvard, Stanley Building, Cambridge, Massachusetts, United States
  • Mika Harju
    Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4C, Helsinki, Finland
  • Aarno Palotie
    Institute for Molecular Medicine Finland (FIMM), HiLIFE, PL 20, University of Helsinki, Finland
    The Broad Institute of MIT and Harvard, Stanley Building, Cambridge, Massachusetts, United States
  • Joni A. Turunen
    Eye Genetics Group, Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, Helsinki, Finland
    Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4C, Helsinki, Finland
  • Correspondence: Perttu Liuska, Department of Ophthalmology, Helsinki University Hospital, Haartmaninkatu 4C, PL220, FI-00029 HUS, Helsinki, Finland; [email protected]
  • Footnotes
     Related online manuscript file.
  • Footnotes
     PJL and JTR contributed equally to the work.
Investigative Ophthalmology & Visual Science November 2023, Vol.64, 33. doi:https://doi.org/10.1167/iovs.64.14.33
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      Perttu J. Liuska, Joel T. Rämö, Susanna Lemmelä, Kai Kaarniranta, Hannu Uusitalo, Elisa Lahtela, Mark J. Daly, Mika Harju, Aarno Palotie, Joni A. Turunen, for the FinnGen Study†; Association of APOE Haplotypes With Common Age-Related Ocular Diseases in 412,171 Individuals. Invest. Ophthalmol. Vis. Sci. 2023;64(14):33. https://doi.org/10.1167/iovs.64.14.33.

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Abstract

Purpose: Apolipoprotein E4 (APOE4), a known risk factor for Alzheimer's disease, has controversially been associated with reduced risk of primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD). Here, we sought to systematically quantify the associations of APOE haplotypes with age-related ocular diseases and to assess their scope and age-dependency.

Methods: We included genetic and registry data from 412,171 Finnish individuals in the FinnGen study. Disease endpoints were defined using nationwide registries. APOE genotypes were directly genotyped using Illumina and Affymetrix arrays or imputed using a custom Finnish reference panel. We evaluated the disease associations of APOE genotypes containing ε2 (without ε4) and ε4 (without ε2) compared with the ε3ε3 genotype using logistic regressions stratified by age.

Results: APOE ε4 enriched haplotypes were inversely associated with overall glaucoma (odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.92–0.99, P = 0.0047), and its subtypes POAG (OR = 0.95, P = 0.027), normal-tension glaucoma (OR = 0.87, P = 0.0058), and suspected glaucoma (OR = 0.95, P = 0.014). Individuals with the ε4 allele also had lower odds for AMD (OR = 0.80, 95% CI = 0.76–0.84, P < 0.001), seen both in dry and neovascular subgroups. A slight negative association was also detected in senile cataract, but this was not reproducible in age-group analyses.

Conclusions: Our results support prior evidence of the inverse association of APOE ε4 with glaucoma, but the association was weaker than for AMD. We could not show an association with exfoliation glaucoma, supporting the hypothesis that APOE may be involved in regulating retinal ganglion cell degeneration rather than intraocular pressure.

Apolipoprotein E (APOE), the major lipoprotein in the brain and a lipid transport protein, is strongly associated with late-onset Alzheimer's disease (AD) – the leading cause of dementia in the elderly – and cardiovascular disease.1 It has also emerged as a potential regulator of age-related macular degeneration (AMD), and, more recently, glaucoma, which together account for up to 49.8% of blindness in developed, high-income countries.13 
The APOE gene normally encodes a 299-aminoacid lipoprotein which regulates plasma lipid levels and acts as a ligand for low-density lipoprotein (LDL) receptors. APOE has three alleles (ε2, ε3, and ε4), defined by two single-nucleotide polymorphisms (SNPs), rs429358 and rs7412. Thus, six different genotypes are formed by the combination of these three alleles (ε2/ε2, ε3/ε3, ε4/ε4, ε2/ε3, ε3/ε4, and ε2/ε4), encoding different isoforms of the APOE protein, affecting lipid processing, transport, and clearance from the circulation.4 The ε3 allele is the most common and constitutes a baseline risk for AD, whereas ε4 is a major risk allele and ε2 is protective for AD in an allele-dose dependent manner.5,6 
Primary open-angle glaucoma (POAG; MIM 137760), the leading cause of irreversible blindness in the world, is a group of neurodegenerative diseases characterized by the loss of retinal ganglion cells (RGCs) and their axons in the optic nerve. Intraocular pressure (IOP) remains the only modifiable risk factor for POAG and there are no neuroprotective therapies to promote RGC survival.7 Interestingly, the APOE ε4 allele has recently been associated with a reduced risk of POAG (odds ratio [OR] = 0.83, 95% confidence interval [CI] = 0.74–0.94, P = 0.0022) in an inverse association compared with AD.1 This protective effect was found in both high-tension and normal-tension glaucoma (NTG) groups. Furthermore, in a Brazilian cohort, carrying the APOE ε2 allele (OR = 1.516, P = 0.04) or the ε2ε3 genotype (OR = 1.655, P = 0.02) was associated with a greater risk for POAG when compared to ε3ε3 reference genotype.8 A small negative association between APOE ε4 and glaucoma was also observed in a recent study within the UK Biobank, but this was not reproducible in two other replication cohorts in the study set, and the authors suggested that the association might only reflect glaucoma underdiagnosis in the APOE ε4 carriers.9 
AMD (MIM 603075), identified by progressive degeneration of photoreceptors and the underlying retinal pigment epithelium (RPE) cells in the macula region of the retina, is the second leading cause of acquired visual impairment in the elderly population, and it is estimated to affect almost 30% of European individuals over 75 years of age.2,10 It can be clinically classified into two major subtypes: the dry form, accounting for approximately 80% of the cases, and the wet form.11 The early hallmark of AMD are inflammatory cellular debris called drusen in or under the RPE. The dry form of AMD is also characterized by pigment irregularities or geographic atrophy in the RPE (without angiogenesis), whereas the wet form is marked by choroidal neovascularization.3 An inverse association between the APOE ε4 allele and AMD was identified in early candidate gene studies,12 and the APOE locus has since been identified in meta-analyses and genome-wide association studies of AMD with high statistical confidence.3,13,14 
Despite increasing interest, the statistical evidence for a causal association of APOE with glaucoma remains weaker than for AMD.9 Several studies have reported conflicting results regarding the risk profiles of different APOE haplotypes with glaucoma,1519 whereas others have detected no association.2025 Many previous reports are based on small to moderately sized case-control datasets and have not examined other diseases as negative controls to reveal possible bias in the study design. APOE ε4 is a major determinant of cardiovascular disease and dementia, and a leading genetic cause of mortality and disability worldwide.26,27 The association of APOE genotypes with life span and functional capacity in old age can bias associations of diseases primarily affecting the elderly population. Non-neurodegenerative diseases affecting a large proportion of the elderly population, such as senile age-related cataract,28 can be analyzed as probable negative outcome controls to assess the likelihood of bias. 
Here, we report the association and age dependency of APOE haplotypes with common age-related ocular diseases, glaucoma, AMD, and senile cataract in 412,171 Finnish individuals. 
Methods
FinnGen (https://www.finngen.fi/en) is a public-private partnership research project combining genotype data of currently 429,209 individuals (Data Freeze 10) from Finnish biobanks, prospective epidemiological cohorts (initiated as far back as 1992), and disease-based cohorts with digital health record data from national health registries. The samples were linked by a unique national personal identification number assigned to all Finnish citizens and residents. Recruitment of samples to FinnGen was initiated in August 2017, and the data analysis was performed between December 2022 and April 2023. 
The FINRISK study is a large Finnish population survey on risk factors for chronic, noncommunicable diseases. The survey was carried out for 40 years since 1972 every 5 years using independent, random, and representative population samples from different parts of Finland, as described earlier.29 The Health 2000 Survey was carried out in the years 2000 to 2001, capturing a nationally representative sample of more than 8000 persons aged 30 years and over living in mainland Finland. The National FINRISK Study and Health 2000 Survey were joined to form a new population study, the National FinHealth Study. The data were transferred to THL Biobank in July 2015 and subsequently incorporated into FinnGen. 
The FinnGen samples were genotyped using Illumina and Affymetrix arrays (Illumina Inc., San Diego, CA, USA, and Thermo Fisher Scientific, Santa Clara, CA, USA), as detailed previously.30 Genotypes were imputed based on a population-specific SISu v4 imputation reference panel comprised of 8557 whole genomes. Non-Finnish outliers, twin, and duplicate samples were removed, as detailed previously,30 and the remaining 412,171 participants were included in genotype analyses. The two SNPs forming the APOE alleles, rs429358 and rs7412, were identified either by direct genotyping or imputation. 
The FinnGen study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Review Board of the Hospital District of Helsinki and Uusimaa (HUS/990/2017; Online-Only Supplement). Individuals gave written informed consent based on the Finnish Biobank Act or separate research cohort protocols. All DNA samples and data in this study were pseudonymized. 
The disease endpoints were defined using nationwide registries for deaths, hospital discharges, outpatient specialist appointments, harmonizing over the International Classification of Diseases (ICD) revisions 8, 9, and 10, procedure codes (NOMESCO), Finnish-specific Social Insurance Institute (KELA) drug reimbursement codes and Anatomic Therapeutic Chemical (ATC) codes. Glaucoma-related operations included trabeculectomy and iridectomy, glaucoma shunt operation, non-penetrating glaucoma surgery, and other filtering operations. The definitions of clinical endpoints used in this study are presented in Supplementary Table S1 and control groups are provided in detail at https://www.finngen.fi/en/researchers/clinical-endpoints
Statistical Analysis
APOE genotypes were identified from haplotypes of the two non-synonymous SNPs, rs429358 and rs7412, forming the corresponding alleles of ε2, ε3, and ε4. Logistic regression in R (version 4.2.2; http://www.r-project.org) was used to analyze the association of genotypes with ocular disease, with covariates including genotypic sex, age at end of follow-up or death,2 first 10 genotypic principal components (PCs), and genotyping array. All participants were included in the analyses, and the APOE ε3ε3 was used as the reference unless otherwise stated. A Wald test was used to evaluate the statistical significance of the coefficients. We additionally evaluated the disease associations of the rs429358 and rs7412 genotypes with 2405 binary endpoints and 3 quantitative endpoints using the additive model as implemented in Regenie version 2.24, with genotypic sex, age at end of follow-up or death, first 10 PCs, genotyping array, and genotyping batch as fixed-effect covariates.31 All tests were two-tailed. Because this study followed up previously reported associations, and the examined phenotypes and genotypes were correlated, multiple testing correction was not considered appropriate. The analyses were performed between December 2022 and April 2023. 
Results
Study Characteristics
Altogether, 412,171 individuals from FinnGen passing genotype quality control were included (Table 1). Of those, 230,307 (55.9%) were female subjects, and 181,864 (44.1%) were male subjects. The mean age at the end of the follow-up period was 60.3 (SD = 17.9) years. The number of individuals with different disease endpoints are presented in Table 2
Table 1.
 
Characteristics of Study Participants (n = 412,171) and Prevalence of the APOE Haplotypes
Table 1.
 
Characteristics of Study Participants (n = 412,171) and Prevalence of the APOE Haplotypes
Table 2.
 
Disease Prevalence and Association of the APOE ε4 Allele Containing Genotypes (ε3ε4 and ε4ε4 Genotypes) Compared With the Reference Genotype ε3ε3 With Different Types of Glaucoma, Age-Related Macular Degeneration, Myopia, Senile Cataract, and Alzheimer's Disease in the FinnGen Biobank Cohort With 412,171 Individuals
Table 2.
 
Disease Prevalence and Association of the APOE ε4 Allele Containing Genotypes (ε3ε4 and ε4ε4 Genotypes) Compared With the Reference Genotype ε3ε3 With Different Types of Glaucoma, Age-Related Macular Degeneration, Myopia, Senile Cataract, and Alzheimer's Disease in the FinnGen Biobank Cohort With 412,171 Individuals
The distribution of individuals with different APOE genotypes are tabulated in Table 1. The phenome-wide association study plots of the two APOE alleles forming the haplotypes, rs429358 and rs7412, are supplied in Supplementary Figure S1
Associations of the APOE Genotypes With AD and Ocular Diseases
First, we tested the known association of APOE genotypes with AD in our sample. The OR for genotypes with ε4 but without ε2 (i.e. ε3ε4 and ε4ε4) compared to the ε3ε3 reference genotype was 3.06 (95% CI = 2.93–3.20, P < 0.001) for AD. We subsequently investigated the association between the APOE genotypes with glaucoma endpoints and AMD. The APOE ε4 allele demonstrated an inverse association with all glaucoma endpoints (overall glaucoma, glaucoma suspects, POAG, NTG, and glaucoma operations) except XFG (see Table 2). The APOE ε4 allele also had a negative association with AMD with an OR of 0.80 (95% CI = 0.76–0.84, P < 0.001). To serve as a negative control, we also tested for associations among the APOE genotypes, myopia, and senile cataract. The APOE ε4 allele was not associated with myopia but there was an association with senile cataract (OR = 0.95, 95% CI = 0.93–0.97, P < 0.001). 
The OR for genotypes with ε4 but without ε2 (i.e. ε3ε4 and ε4ε4) compared with all other genotypes was 0.93 (95% CI = 0.88–0.98, P = 0.011) for overall glaucoma; for POAG 0.86 (95% CI = 0.79–0.93, P < 0.001); for NTG 0.79 (95% CI = 0.68–0.93, P = 0.0030); and 0.92 (95% CI = 0.86–0.99, P = 0.022) for suspected glaucoma. The OR was 0.75 for AMD (95% CI = 0.69–0.81, P < 0.001); and 0.93 for senile cataract (95% CI = 0.89–0.96, P < 0.001). The associations of ε3ε4 and ε4ε4 genotypes with XFG (95% CI = 0.82–1.06, P = 0.30) or glaucoma-related surgery (95% CI = 0.73–1.08, P = 0.23) were not significant. 
When comparing the less common ε2 allele containing genotypes ε2ε2 and ε2ε3 with the ε3ε3 reference genotype, we observed a slight positive association with POAG (OR = 1.12, 95% CI = 1.03–1.20, P = 0.0046), but we did not observe statistically significant associations with any other glaucoma phenotypes (Supplementary Table S2). 
Prevalences of Ocular Diseases by APOE Genotypes
The prevalence of glaucoma-related diseases among carriers of the APOE ε4ε4 and the reference ε3ε3 genotypes were 4.1% and 5.2%, respectively, for overall glaucoma; 1.5% and 2.1% for POAG; 0.66% and 0.84% for XFG; 0.38% and 0.58% for NTG; 2.3% and 3.0% for suspected glaucoma; and 0.25% and 0.39% for glaucoma-related surgery. The prevalence among carriers of the APOE ε4ε4 and the ε3ε3 genotypes were 1.4% and 2.6% for AMD; 0.71% and 1.4% for wet AMD; 0.95% and 1.8% for dry AMD; and 12.4% and 16.3% for senile cataract. The genotype prevalences in disease endpoints are presented in the Figure
Figure.
 
Prevalences of the APOE genotypes in different types of glaucoma, age-related macular degeneration, senile cataract, and Alzheimer's disease in FinnGen. The prevalence of each APOE genotype with respect to disease status was evaluated using logistic regression, with the respective APOE genotype as the outcome and disease status, genotypic sex, age at the end of follow-up or death2, first 10 PCs, and genotyping array as independent predictors. A Wald test was used to evaluate the statistical significance (*** indicates P < 0.001, **P < 0.01, and *P < 0.05). Abbreviations: POAG = primary open-angle glaucoma, NTG = normal-tension glaucoma, AMD = age-related macular degeneration.
Figure.
 
Prevalences of the APOE genotypes in different types of glaucoma, age-related macular degeneration, senile cataract, and Alzheimer's disease in FinnGen. The prevalence of each APOE genotype with respect to disease status was evaluated using logistic regression, with the respective APOE genotype as the outcome and disease status, genotypic sex, age at the end of follow-up or death2, first 10 PCs, and genotyping array as independent predictors. A Wald test was used to evaluate the statistical significance (*** indicates P < 0.001, **P < 0.01, and *P < 0.05). Abbreviations: POAG = primary open-angle glaucoma, NTG = normal-tension glaucoma, AMD = age-related macular degeneration.
Age-Dependent Associations of APOE Genotypes With Ocular Diseases
We also evaluated associations of APOE haplotypes with the disease endpoints in different age groups by age at disease onset: <70 years, <60 years, and <50 years (i.e. all individuals diagnosed before the age limit; Table 3). The association of the ε4 allele containing genotypes compared with the reference ε3ε3 genotype was statistically significant with POAG in all age groups (see Table 3). Similarly, we observed a significant association between APOE haplotypes and overall glaucoma in all age groups, and the association was more pronounced in the younger age groups (OR = 0.96, P = 0.047; and OR = 0.90, P = 0.0098 for individuals <70 and <50 years of age by disease onset, respectively; see Table 3). However, we could not repeat significant associations with AMD or senile cataract in any of these age groups. Myopia was not associated with APOE haplotypes in any age group. The results were similar in additional sensitivity analyses stratified by age at the end of the follow-up (Supplementary Table S3). 
Table 3.
 
Age-Related Odds Ratios (ORs) of APOE ε4 Allele (ε3ε4 and ε4ε4 Genotypes) Compared to the Reference ε3ε3 Genotype in Different Ophthalmic Diseases, and Alzheimer's Disease in FinnGen Data Freeze 10 (n = 412,171) by Age at Disease Onset
Table 3.
 
Age-Related Odds Ratios (ORs) of APOE ε4 Allele (ε3ε4 and ε4ε4 Genotypes) Compared to the Reference ε3ε3 Genotype in Different Ophthalmic Diseases, and Alzheimer's Disease in FinnGen Data Freeze 10 (n = 412,171) by Age at Disease Onset
Associations of APOE Genotypes With Ocular Diseases in Population Surveys
We performed an additional sensitivity analysis using the representative, randomly selected National FinHealth Study subpopulation in FinnGen with 35,599 individuals (Supplementary Table S4). The inverse association of the APOE ε4 allele with different types of AMD remained significant. Although we did not detect statistically significant associations with glaucoma endpoints in this smaller sample, effect estimates were comparable to those observed in the entire FinnGen cohort (Supplementary Table S5). 
Discussion
Here, we systematically evaluated the associations of APOE haplotypes with common age-related ocular diseases, with a particular focus on glaucoma subtypes and AMD. We build upon previous findings of a protective association of APOE ε4 with glaucoma by including genotype and registry data from 412,171 Finnish individuals. We demonstrate that the APOE ε4 enriched haplotypes were inversely associated with overall glaucoma, NTG, POAG, and suspected glaucoma. They were also inversely associated with both dry and neovascular AMD. Interestingly, a slight negative association was also shown in senile cataract. 
In earlier studies, the most pronounced protective effect of APOE ε4 has been observed in NTG or populations with a high proportion of NTG.1,16,17 Margeta et al. speculated that this is because APOE has a role in regulating RGC degeneration rather than IOP.1 In our study, the effect was also most pronounced in the NTG group (OR = 0.79 compared with all other genotypes, P = 0.0030). We could not show an association with XFG, a relatively common cause of secondary glaucoma in the Nordics,32 which is in line with this hypothesis. In exfoliation syndrome, extracellular fibrillary material can be discovered in the anterior segment of the eye supposedly hindering the outflow of the aqueous humor and increasing IOP. Thus, the pathogenesis of XFG differs from that of primary glaucoma. 
Some other studies and meta-analyses have also reported contradictory results, suggesting either a lack of association of these alleles or a positive association of APOE ε4 with glaucoma.9,33,34 A recent study within the UK Biobank, including 13,988 individuals with glaucoma, observed similar results to our analysis, but could not replicate the results in other cohorts and the authors proposed that the association may represent an artifact of glaucoma underdiagnosis in APOE ε4 carriers.9 Considering the possible ethnic differences, the differences in the pathogenesis of different types of glaucoma, and false positive results when conducting targeted genetic association studies, the role of APOE with glaucoma has remained debatable. An additional confounding element arises from the observation that AD has an impact on the retina both molecularly and structurally.35,36 The APOE ε4 allele has been associated with faster retinal nerve fiber layer thinning,37 introducing a potential source of bias in imaging-based studies. Our results do not exclude a general role for APOE in glaucoma and support differential associations for glaucoma subtypes. 
An important observation is the presence of a negative association between APOE ε4 allele-containing genotypes and senile cataract, a presumed negative control outcome. A similar association was also recently detected in the UK Biobank.9 This association could reflect a genuine pathophysiological role of APOE in lens degeneration, or perhaps more likely, confounding. Because APOE ε4 is linked with greater disability and mortality, as well as with recruitment to biobank studies, this may distort the association with senile cataract in a large data set reliant on digital health registries for disease endpoints. Supporting this hypothesis, we observed that the association with cataract was no longer significant in age groups <70 years of age despite a considerable number of cases (see Table 3, Supplementary Table S3). In contrast, we observed significant associations of the ε4 allele containing genotypes with glaucoma in younger age groups. 
We also carried out additional sensitivity analyses using representative and randomly selected population samples within the FinHealth Study subsample in FinnGen. In this subsample of 35,599 individuals, the associations of the APOE ε4 allele with AMD subtypes and AD remained significant, but we could not repeat significant associations with different types of glaucoma or senile cataract (see Supplementary Table S5). Nevertheless, the effect size of the APOE ε4 with respect to glaucoma endpoints remained consistent with the original analyses, and less robust associations may have been obscured by smaller sample sizes. 
The exact mechanism by which APOE may affect the risk of glaucoma and AMD remains unclear. Although APOE is expressed widely in different cell types, APOE is also shown to be synthesized in retinal Müller cells, secreted into the vitreous, and transported into the optic nerve by RGCs.38 APOE is upregulated in mouse models of neurodegenerative diseases, such as AD, amyotrophic lateral sclerosis, and multiple sclerosis; and it seems to be a regulator of microglial neurodegeneration.39,40 Microglia are the resident immune cells in the central nervous system that play a vital role in brain homeostasis but lose their homeostatic function in neurodegenerative diseases.39 Margeta et al. showed in two mouse models that the microglial transition from homeostatic to neurodegenerative is characterized by upregulation of APOE and LGALS3 (galectin-3), which were also upregulated in glaucomatous human retinas.41 This transition to neurodegenerative microglia seems to be controlled by APOE and triggering receptor expressed on myeloid cells 2 (TREM2) signaling.39 In human glaucoma, the activated microglia colocalize in the optic nerve with proinflammatory cytokines, including tumor necrosis factor α.42 Furthermore, a recent study found that APOE and galectin-3 levels were significantly elevated in the aqueous humor of human eyes with glaucoma.43 In mouse models, mice carrying the human APOE4 allele or targeted deletion of Apoe were protected from RGC loss and did not upregulate neurodegeneration associated genes including LGALS3.41 Thus, APOE4 may act as a loss-of-function isoform, preserving RGCs by impairing microglial activation.41 
APOE also plays a significant role in neuroinflammatory response in AMD. AMD is associated with a breakdown of the subretinal immunosuppressive system and chronic accumulation of mononuclear phagocytes, which express high levels of APOE, interleukin-6 (IL-6) and CC chemokine ligand 2.44,45 Moreover, APOE can activate the innate immunity receptor cluster and induce inflammatory cytokines including IL-6 and promote the survival of mononuclear phagocytes.44 Notably, IL-6 levels are associated with AMD incidence.46 The APOE ε4 allele is associated with lower plasma and brain tissue APOE concentrations, whereas ε2 associates with higher concentrations.47 AMD is characterized by drusen, which contain considerable amounts of APOE and its cargo, and thus, a causal inverse association of APOE4 with AMD is plausible.47 
Strengths and Limitations
A strength of the current study is the ability to evaluate multiple diseases, including subtypes of glaucoma and AMD, simultaneously within a large cohort. Glaucoma endpoints in FinnGen are based on both inpatient and outpatient diagnosis and operation codes reported by eye care specialists, which may decrease bias, compared with data from hospital admissions and self-report in cohorts such as the UK Biobank. Enrichment of the APOE ε4 allele in the Nordics also increases the power to evaluate disease associations.48 The two SNPs forming the APOE alleles, rs429358 and rs7412, both had very high-quality imputation INFO scores of 99.9% (ranges = 0.86-1.0 and 0.90-1.0, respectively). 
Our study had several limitations. FinnGen is not a truly healthy population-based sample, as many biobanks collected consent from individuals during hospital visits, potentially inflating estimates of disease prevalence and presenting a challenge in determining accurate ORs. The study relied on reported codes in national health registries, which could result in undiagnosed or unreported individuals and overlapping diagnoses. It is also estimated that 50% of patients with glaucoma remain undiagnosed,49,50 and we speculate that some diseases, such as senile cataract, might also be more likely diagnosed in the presence of other ophthalmic comorbidities. Finally, individuals with a high disease burden or disability may be less likely to participate in biobank studies compared with healthy individuals. 
Conclusions
Our results corroborate prior evidence of an inverse association of the APOE ε4 allele with glaucoma and its subtypes POAG, NTG, and suspected glaucoma. Furthermore, in age-stratified analyses, we were able to validate these results in younger age groups. We could not demonstrate an association with XFG, which supports the hypothesis that APOE may be involved in regulating RGC degeneration rather than IOP. We also observed a nominally significant association of the APOE ε2 allele with POAG. However, the associations with different types of glaucoma appear to be markedly weaker than that observed with AMD, and the causality of these associations remains unresolved. Our study highlights the necessity to systematically assess the associations detected in genetic association studies considering false positive associations and the complex pleiotropy of many genetic loci. 
Acknowledgments
Supported by grants from the Glaukooma Tukisäätiö Lux Foundation, the Mary and Georg C. Ehrnrooth Foundation, the Evald and Hilda Nissi Foundation, and the Finnish Medical Foundation. We want to acknowledge the participants and investigators of the FinnGen study. The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme LCC, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim International GmbH. The following biobanks are acknowledged for delivering biobank samples to FinnGen: Auria Biobank (www.auria.fi/biopankki), THL Biobank (www.thl.fi/biobank), Helsinki Biobank (www.helsinginbiopankki.fi), Biobank Borealis of Northern Finland (https://www.ppshp.fi/Tutkimus-ja-opetus/Biopankki/Pages/Biobank-Borealis-briefly-in-English.aspx), Finnish Clinical Biobank Tampere (www.tays.fi/en-US/Research_and_development/Finnish_Clinical_Biobank_Tampere), Biobank of Eastern Finland (www.ita-suomenbiopankki.fi/en), Central Finland Biobank (www.ksshp.fi/fi-FI/Potilaalle/Biopankki), Finnish Red Cross Blood Service Biobank (www.veripalvelu.fi/verenluovutus/biopankkitoiminta), Terveystalo Biobank (www.terveystalo.com/fi/Yritystietoa/Terveystalo-Biopankki/Biopankki/), and Arctic Biobank (https://www.oulu.fi/en/university/faculties-and-units/faculty-medicine/northern-finland-birth-cohorts-and-arctic-biobank). All Finnish Biobanks are members of BBMRI.fi infrastructure (www.bbmri.fi). Finnish Biobank Cooperative -FINBB (https://finbb.fi/) is the coordinator of BBMRI-ERIC operations in Finland. The Finnish biobank data can be accessed through the Fingenious services (https://site.fingenious.fi/en/) managed by FINBB. 
The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. 
Perttu Liuska, Folkhälsan Research Center; and Joel Rämö, The Broad Institute of MIT and Harvard, conducted and are responsible for the data analysis. 
Perttu Liuska and Joel Rämö had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. 
Data Availability: Summary-level genome-wide association study data from FinnGen is subjected to a one-year embargo and thereafter made available online (https://www.finngen.fi/en/access_results). Any researcher can apply for health register data from the Finnish Data Authority Findata and individual-level genotype data via the Fingenious portal (https://site.fingenious.fi/en/) hosted by the Finnish Biobank Cooperative FinBB (https://finbb.fi/en/). 
Disclosure: P.J. Liuska, None; J.T. Rämö, None; S. Lemmelä, None; K. Kaarniranta, None; H. Uusitalo, None; E. Lahtela, None; M.J. Daly, None; M. Harju, None; A. Palotie, None; J.A. Turunen, None 
References
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Figure.
 
Prevalences of the APOE genotypes in different types of glaucoma, age-related macular degeneration, senile cataract, and Alzheimer's disease in FinnGen. The prevalence of each APOE genotype with respect to disease status was evaluated using logistic regression, with the respective APOE genotype as the outcome and disease status, genotypic sex, age at the end of follow-up or death2, first 10 PCs, and genotyping array as independent predictors. A Wald test was used to evaluate the statistical significance (*** indicates P < 0.001, **P < 0.01, and *P < 0.05). Abbreviations: POAG = primary open-angle glaucoma, NTG = normal-tension glaucoma, AMD = age-related macular degeneration.
Figure.
 
Prevalences of the APOE genotypes in different types of glaucoma, age-related macular degeneration, senile cataract, and Alzheimer's disease in FinnGen. The prevalence of each APOE genotype with respect to disease status was evaluated using logistic regression, with the respective APOE genotype as the outcome and disease status, genotypic sex, age at the end of follow-up or death2, first 10 PCs, and genotyping array as independent predictors. A Wald test was used to evaluate the statistical significance (*** indicates P < 0.001, **P < 0.01, and *P < 0.05). Abbreviations: POAG = primary open-angle glaucoma, NTG = normal-tension glaucoma, AMD = age-related macular degeneration.
Table 1.
 
Characteristics of Study Participants (n = 412,171) and Prevalence of the APOE Haplotypes
Table 1.
 
Characteristics of Study Participants (n = 412,171) and Prevalence of the APOE Haplotypes
Table 2.
 
Disease Prevalence and Association of the APOE ε4 Allele Containing Genotypes (ε3ε4 and ε4ε4 Genotypes) Compared With the Reference Genotype ε3ε3 With Different Types of Glaucoma, Age-Related Macular Degeneration, Myopia, Senile Cataract, and Alzheimer's Disease in the FinnGen Biobank Cohort With 412,171 Individuals
Table 2.
 
Disease Prevalence and Association of the APOE ε4 Allele Containing Genotypes (ε3ε4 and ε4ε4 Genotypes) Compared With the Reference Genotype ε3ε3 With Different Types of Glaucoma, Age-Related Macular Degeneration, Myopia, Senile Cataract, and Alzheimer's Disease in the FinnGen Biobank Cohort With 412,171 Individuals
Table 3.
 
Age-Related Odds Ratios (ORs) of APOE ε4 Allele (ε3ε4 and ε4ε4 Genotypes) Compared to the Reference ε3ε3 Genotype in Different Ophthalmic Diseases, and Alzheimer's Disease in FinnGen Data Freeze 10 (n = 412,171) by Age at Disease Onset
Table 3.
 
Age-Related Odds Ratios (ORs) of APOE ε4 Allele (ε3ε4 and ε4ε4 Genotypes) Compared to the Reference ε3ε3 Genotype in Different Ophthalmic Diseases, and Alzheimer's Disease in FinnGen Data Freeze 10 (n = 412,171) by Age at Disease Onset
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