Jiemin Liao

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10−8 for rs6445055), two on chromosome 9 (P = 2.80 × 10−11 for rs2472493 near ABCA1 and P = 6.39 × 10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10−11 for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1

In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene; P = 1.67 × 10−9) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P = 4.25 × 10−8). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P = 0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer.

Ethnic Differences of Intraocular Pressure and Central Corneal Thickness: The Singapore Epidemiology of Eye Diseases Study

PURPOSE To determine the ethnic differences in the distribution of intraocular pressure (IOP) and central corneal thickness (CCT) in a multi-ethnic Asian population by self-reported ethnicity and genetic ancestry. DESIGN Population-based, cross-sectional study. PARTICIPANTS A total of 10 033 adults (3353 Chinese, 3280 Malays, and 3400 Indians) aged >40 years. METHODS Participants underwent standardized systemic and ocular examinations and interviewer-administered questionnaires for risk factor assessment. The IOP readings were obtained by Goldmann applanation tonometry (Haag-Streit, Konig, Switzerland) before pupil dilation. The CCT was measured with ultrasound pachymetry. Genetic ancestry was derived using principal component (PC) analysis. Regression models were used to investigate the association of IOP and CCT with potential risk factors and genetic ancestry. MAIN OUTCOME MEASURES Intraocular pressure and CCT. RESULTS After excluding participants with a history of glaucoma surgery or medication, refractive surgery, corneal edema, or corneal dystrophy, IOP and CCT readings were available for 3251 Chinese, 3232 Malays, and 3317 Indians. The mean IOP readings in the Chinese, Malay, and Indian participants were 14.3±3.1, 15.3±3.7, and 15.8±2.9 mmHg, respectively (P < 0.001). The prevalence of participants with IOP ≥21 mmHg was 2.6% in Chinese, 6.2% in Malays, and 4% in Indians (P < 0.001). In the multivariate regression analysis, the Malay and Indian participants on average had 0.81 and 1.43 mmHg higher IOP levels, respectively, than Chinese (P < 0.001). The mean CCT reading was 552.3±33.4 μm in Chinese, 540.9±33.6 μm in Malays, and 540.4±33.6 μm in Indians (P < 0.001). The percentage of participants with CCT <555 μm was 52.8% in Chinese, 68.5% in Malays, and 66.2% in Indians (P < 0.001). The IOP and CCT levels are significantly correlated with genetic ancestry in our South East Asian population. CONCLUSIONS Chinese have the thickest CCT but lowest IOP among the 3 major ethnic groups. In addition, there is a higher proportion of Malays with IOP ≥21 mmHg and CCT <555 μm compared with the Chinese or Indians. This disparity across ethnic groups should be taken into account by future studies investigating IOP and CCT as risk factors or diagnostic tests for glaucoma in Asian populations.

Glaucoma in Asia: regional prevalence variations and future projections

Purpose To evaluate glaucoma prevalence and disease burden across Asian subregions from 2013 to 2040. Methods We conducted a systematic review and meta-analysis of 23 population-based studies of 1318 primary open angle glaucoma (POAG) cases in 66 800 individuals and 691 primary angle closure glaucoma (PACG) cases in 72 767 individuals in Asia. Regions in Asia were defined based on United Nations’ (UN) classification of macro-geographic regions. PubMed, Medline and Web of Science databases were searched for population-based glaucoma prevalence studies using standardised criteria published to 31 December 2013. Pooled glaucoma prevalence for individuals aged 40–80 years was calculated using hierarchical Bayesian approaches. Prevalence differences by geographic subregion, subtype and habitation were examined with random effects meta-regression models. Estimates of individuals with glaucoma from 2013 to 2040 were based on the UN World Population Prospects. Results In 2013, pooled overall glaucoma prevalence was 3.54% (95% credible interval (CrI) 1.83 to 6.28). POAG (2.34%, 95% CrI 0.96 to 4.55) predominated over PACG (0.73%, 95% CrI 0.18 to 1.96). With age and gender adjustment, PACG prevalence was higher in East than South East Asia (OR 5.55, 95% CrI 1.52 to 14.73), and POAG prevalence was higher in urban than rural populations (OR 2.11, 95% CrI 1.57 to 2.38). From 2013 to 2040, South Central Asia will record the steepest increase in number of glaucoma individuals from 17.06 million to 32.90 million compared with other Asian subregions. In 2040, South-Central Asia is also projected to overtake East Asia for highest overall glaucoma and POAG burden, while PACG burden remains highest in East Asia. Conclusions Across the Asian subregions, there was greater glaucoma burden in South-Central and East Asia. Sustainable public health strategies to combat glaucoma in Asia are needed.

Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians.

Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10−23], HBS1L/MYB [8.5 × 10−15], MYO9B [9.0 × 10−12], and CYBA [1.1 × 10−8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (≥6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.

Determinants of Macular Thickness using Spectral Domain Optical Coherence Tomography in Healthy Eyes: the Singapore Chinese Eye Study

PURPOSE We determined ocular and systemic factors influencing macular thickness measured by spectral-domain optical coherence tomography (SD-OCT) in a population-based sample of healthy eyes. METHODS We recruited 490 healthy Chinese adults, aged 40 to 80 years, from the Singapore Chinese Eye Study, a population-based survey. All participants underwent a comprehensive eye examination and a standardized interview. The SD-OCT (Cirrus HD-OCT, software version 6.0) was used to measure a range of macular thickness parameters (central foveal subfield thickness, average inner macular thickness, average outer macular thickness, overall average macular thickness, and overall macular cube volume). Linear regression analyses were performed to examine the effects of various ocular and systemic factors on macular thickness. RESULTS The mean (standard deviation) age of the subjects was 53.17 (6.14) years and 50.0% of them were male. The mean central foveal subfield, average inner, and average outer macular thicknesses were 250.38 (20.58), 319.33 (14.40), and 276.67 (11.94) μm, respectively. The overall average macular thickness was 280.25 (11.42) μm and overall macular cube volume was 10.09 (0.41) mm(3). Sex, age, and axial length (AL) are the factors that influenced macular thicknesses. Thinner overall average macular thickness was associated with female sex (4.46 μm thinner compared to males, P < 0.001), older age (0.38 μm decrease per each year increase in age, P < 0.001), and longer AL (2.34-μm decrease per each mm increase in AL, P < 0.001), whereas thinner central foveal subfield thickness was associated with female sex (13.5 μm thinner compared to males, P < 0.001) and shorter AL (3.33-μm decrease per each mm increase in AL, P < 0.001). CONCLUSIONS Female sex, older age, and longer AL were associated independently with thinner overall average macular thickness, whereas female sex and shorter AL were associated with thinner central foveal thickness in ethnic Chinese. These factors should be taken into consideration when interpreting macular thickness measurements with SD-OCT.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Assessment of Iris Surface Features and Their Relationship with Iris Thickness in Asian Eyes

PURPOSE To assess iris surface features in Asian eyes and examine their associations with iris thickness measured by anterior segment optical coherence tomography (AS OCT). DESIGN Cross-sectional study. PARTICIPANTS We recruited 250 subjects from the Singapore Malay Eye Study. METHODS We obtained standardized slit-lamp photographs and developed a grading system assessing iris crypts (by number and size), furrows (by number and circumferential extent), and color (higher grade denoting darker iris). Vertical and horizontal cross-sections of the anterior chamber were imaged using AS OCT. Intragrader and intergrader agreements in the grading of iris surface were assessed by weighted κ (κ(w)) statistic. Associations of the average iris thickness with the grade of iris features were assessed using linear regression analysis. MAIN OUTCOME MEASURES Frequency and size of iris crypts, furrows, and color; iris thickness at 750 μm (IT750) and 2000 μm (IT2000) from the scleral spur; and maximum iris thickness (ITM) averaged from the 4 quarters. RESULTS Three hundred sixty-four eyes had complete and gradable data for crypts and color; 330 eyes were graded for furrows. The grading scheme showed good intragrader (crypt κ(w) = 0.919, furrow κ(w) =0.901, color κ(w) = 0.925) and intergrader (crypt κ(w) = 0.775, furrow κ(w) = 0.836, color κ(w) = 0.718) agreements. Higher crypt grade was associated independently with thinner IT750 (β [change in iris thickness per grade higher] = -0.007; P = 0.029), IT2000 (β = -0.018; P < 0.001), and ITM (β = -0.012; P < 0.001). More extensive furrows were associated with thicker IT750 (β = 0.022; P < 0.001). Darker iris was also associated with thicker IT750 (β = 0.014; P = 0.001). CONCLUSIONS Iris surface features, assessed and measured from slit-lamp photographs, correlate well with iris thickness. Irises with more crypts are thinner; irises with more extensive furrows and darker color are thicker peripherally. These findings may provide another means to assess angle closure risk based on iris features.

Aggregate Effects of Intraocular Pressure and Cup-to-Disc Ratio Genetic Variants on Glaucoma in a Multiethnic Asian Population

PURPOSE High intraocular pressure (IOP) and large vertical cup-to-disc ratio (VCDR) are important risk factors of glaucoma. Recent genome-wide association studies have discovered several genetic variants associated with IOP and VCDR. In this study, we examined the aggregate effects of these IOP-, VCDR-associated variants on glaucoma. DESIGN Case-control genetic association study. PARTICIPANTS A total of 6881 participants, including 194 glaucoma and 158 primary open-angle glaucoma (POAG) cases in the Singapore Epidemiology of Eye Diseases Study. METHODS We first identified IOP and VCDR risk single nucleotide polymorphisms (SNPs) that were located in previously discovered IOP, VCDR genetic loci and showed strongest associations with IOP and VCDR in our study. We then constructed multi-locus IOP-, VCDR-specific genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on glaucoma. Associations between tertiles of IOP- and VCDR-specific GRSs with glaucoma and POAG were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES Odds ratios on glaucoma. RESULTS Participants in the top tertile of IOP-specific GRS were 2.00 (95% CI, 1.32-3.03, P = 1.1×10(-3)) and 2.50 times (95% CI, 1.54-4.02, P = 2.0×10(-4)) likely to have glaucoma and POAG, respectively, compared with those in the bottom. Participants in the top tertile of VCDR-specific GRS were 2.09 (95% CI, 1.43-3.07, P = 1.6×10(-4)) and 2.31 times (95% CI, 1.50-3.55, P = 1.4×10(-4)) likely to have glaucoma and POAG, respectively. Participants with both GRSs in the top tertile were 5.54 (95% CI, 2.57-11.93, P = 1.1×10(-5)) and 7.77 times (95% CI, 3.03-19.93, P = 2.0×10(-5)) likely to have glaucoma and POAG, respectively, compared with participants with both GRSs in bottom tertiles. The GRSs improved AUC for glaucoma modestly when added to traditional factors (AUC difference = 0.03, P = 0.06). CONCLUSIONS Higher IOP-, VCDR-specific GRSs were associated with greater risk of glaucoma. Participants with both GRSs in the top tertiles had a 5.5-fold increased risk of glaucoma compared with those in the bottom tertiles. These findings may provide insights into the genetic pathogenesis of glaucoma.

Glaucoma and Associated Visual Acuity and Field Loss Significantly Affect Glaucoma-Specific Psychosocial Functioning

OBJECTIVE To examine the impact of glaucoma and visual acuity (VA) and visual field (VF) losses on psychosocial functioning (PF). DESIGN Cross-sectional study. PARTICIPANTS We compared PF between 192 participants with bilateral glaucoma with VA or VF losses and 40 controls from a tertiary eye hospital clinic in Singapore. METHODS Glaucoma was defined using the Hodapp-Anderson-Parish criteria. Four psychosocial outcomes of the Glaucoma Quality of Life 36 questionnaire were psychometrically assessed using Rasch analysis. Multivariate regression was performed to determine the independent impact of glaucoma and VA and VF losses on PF. The impact of VA and VF on PF were evaluated by restricted cubic spline analysis. MAIN OUTCOME MEASURES Anxiety, self-image, psychological well-being, and confidence in health care. RESULTS The mean age of participants was 66.2±11.0 years, and 63% were male. In the better eye, VA and mean deviation were Snellen 20/25 and -8.89±6.52 dB, respectively. In multivariate models, glaucoma patients had 63.0% greater anxiety (95% confidence interval [CI], -66.0% to -61.2%; P<0.001), 71.0% lower self-image (95% CI, -74.1% to -68.5%; P<0.001), 38.3% less psychological well-being (95% CI, -37.4% to -39.0%; P<0.001), and 32.4% reduced confidence in health care than patients without glaucoma. The worst VA and VF categories had the most reduced PF (range, 26.0% to 81.5%; P<0.001 for all associations) compared with controls. With worsening VA, there was a linear increase in anxiety (P=0.009) and decrease in self-image (P=0.005). With worsening VF from 0 to -12.1 dB (P=0.003), anxiety increased before plateauing. Self-image decreased as VF worsened from 0 to -10 dB (P<0.001), and confidence in health care decreased when VF worsened from 0 to -9.3 dB (P=0.008). However, self-image and confidence in health care actually improved at greater levels of VF loss beyond these thresholds. CONCLUSION Glaucoma negatively affects PF. Early stage glaucoma with mild VF loss adversely affects anxiety, self-image, and confidence in health care. As VA worsens in advanced glaucoma, anxiety further increases and self-image deteriorates. Ophthalmologists and glaucoma patients need to be aware that both VA and VF losses at different stages of glaucoma negatively impact PF.