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Introduction
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Publications
Publications (109)
Background
With the advance of next-generation sequencing, various gene-based rare variant association tests have been developed, particularly for binary and continuous phenotypes. In contrast, fewer methods are available for traits not following binomial or normal distributions. To address this, we previously proposed a set of burden- and kernel-b...
We investigated whether the effect of lipid-lowering drugs (LLDs) on age-related macular degeneration (AMD) differs according to the main complement genetic variants in Singapore Epidemiology of Eye Diseases (SEED) (n = 5,579) and UK Biobank studies (n = 445,727). The effect of LLD was determined for each stratum of 20 complement genetic variants....
Creativity is one defining characteristic of human species. There have been mixed findings on how creativity relates to well-being, and little is known about its relationship with career success. We conduct a large-scale genome-wide association study to examine the genetic architecture of occupational creativity, and its genetic correlations with w...
Neovascular age-related macular degeneration (nAMD), along with its clinical subtype known as polypoidal choroidal vasculopathy (PCV), are among the leading causes of vision loss in elderly Asians. In a genome-wide association study (GWAS) comprising 3,128 nAMD (1,555 PCV and 1,573 typical nAMD), and 5,493 controls of East Asian ancestry, we identi...
Purpose
For OCT retinal thickness measurements to be used as a prodromal age-related macular degeneration (AMD) risk marker, the 3-dimensional (3D) topographic variation of the relationship between genetic susceptibility to AMD and retinal thickness needs to be assessed. We aimed to evaluate individual retinal layer thickness changes and topography...
Background:
High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER...
Purpose:
To identify genetic alleles associated with differences in choroidal thickness (CT) in a population-based multiethnic Asian cohort.
Methods:
A population-based multiethnic Asian cohort without retinal pathology was subjected to spectral-domain OCT (SD-OCT) and genotyping of risk alleles in CFH, VIPR2, ARMS2, and CETP. Subfoveal choroida...
Refractive error, measured here as mean spherical equivalent (SER), is a complex eye condition caused by both genetic and environmental factors. Individuals with strong positive or negative values of SER require spectacles or other approaches for vision correction. Common genetic risk factors have been identified by genome-wide association studies...
Purpose
Observational studies suggest that myopic eyes carry a greater risk of primary open angle glaucoma (POAG), however the evidence for this association is inconsistent. This may be due to confounding factors that arise from myopia, which complicate clinical tests for glaucoma. This study uses Mendelian randomization (MR) analysis to determine...
Objective
We hypothesized that the effect of blood lipid-related metabolites on POAG would differ according to specific lipoprotein particles and lipid sub-fractions. We thus investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG.
Design
Cross-sectional study.
Participants
Individuals recruited fo...
In recent years, a number of literatures published large-scale genome-wide association studies (GWASs) for human diseases or traits while adjusting for other heritable covariate. However, it is known that these GWASs are biased, which may lead to biased genetic estimates or even false positives. In this study, we provide a method called “BTOB” whic...
Importance
Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk...
Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h² = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studi...
p>Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26...
Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 ar...
Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between...
Multiple correlated phenotypes are frequently collected in genome‐wide association studies (GWASs), and a systematic, simultaneous analysis of multiple phenotypes can integrate the signals from single phenotypes, therefore increasing the power of detecting genetic signals. However, fundamental questions remain open, including the conditions and rea...
Purpose
To identify genes and genetic markers associated with corneal astigmatism.
Methods
A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as hav...
Bilateral neovascular age-related macular degeneration (AMD) causes much more handicaps for patients than unilateral neovascular AMD. Although several AMD-susceptibility genes have been evaluated for their associations to bilaterality, genome-wide association study (GWAS) on bilaterality has been rarely reported. In the present study, we performed...
Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic varia...
Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization (MR) approach. We pooled genome-wide association studies summary statistics from 18 studies for 2 DR phenotypes: any DR (N=...
Background:
Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated wi...
Cohort information, genotyping, quality control (QC), glycated hemoglobin (HbA1c), analysis and covariates.
(XLSX)
Genome-wide significant SNPs identified in the genetic discovery analysis.
(XLSX)
Proportion of additional variance explained over age and sex in measured glycated hemoglobin (HbA1c) by erythryocytic genetic variants and by all genome-wide significant genetic variants by ethnicity.
(XLSX)
Mean difference in glycated hemoglobin (HbA1c) between the top and bottom 5 percentile of genetic score-total (GS-Total) by ancestry.
(XLSX)
Additional analyses on the association of rs1050828, G6PD variant G202A, with glycated hemoglobin (HbA1c).
(XLSX)
Association of lead glycated hemoglobin (HbA1c) variants with glycemic and erythrocytic traits from publicly available association results.
(XLSX)
Attenuation of glycated hemoglobin variant (HbA1c) effect size in association models conditioned on fasting glucose (FG), 2hr glucose (2hrGlu), hemoglobin level (Hb), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) for the lead HbA1c-associated variants.
(XLSX)
Baseline characteristics among those who developed incident type 2 diabetes (T2D) during follow-up and among those who did not, by cohort and ethnicity.
(XLSX)
Net reclassification index of type 2 diabetes (T2D) status by measured glycated hemoglobin (HbA1c) ≥ 6.5% compared to fasting glucose (FG) ≥ 7 mmol/L with and without accounting for erythrocytic genetic variants by ancestry.
(XLSX)
Association of genetic score-glycemic (GS-G) and genetic score erythrocytic (GS-E) with incident type 2 diabetes (T2D) over a decade-long follow-up period by cohort and ancestry.
(XLSX)
Mean difference in glycated hemoglobin (HbA1c) between the top and bottom 5 percentile of genetic score-erythrocytic (GS-E) by ancestry.
(XLSX)
Diagram describing the flow of our study.
(PDF)
Overview of the classification of genetic variants as glycemic, erythrocytic, or unclassified.
(PDF)
Estimated number of African Americans with type 2 diabetes (T2D) in the US whose diagnosis would be missed due to the glycose-6-phosphate dehydrogenase (G6PD) variant if screened with glycated hemoglobin (HbA1c).
(XLSX)
Overview of participants included in the genetic discovery analysis.
(PDF)
Forest plot of association between erythrocytic genetic score with incident type 2 diabetes (T2D) over a decade-long follow-up period adjusted for glycated hemoglobin (HbA1c) as a continuous variable by ancestry.
(PDF)
Authors’ funding information.
(DOCX)
Background:
Dyslipidemia, particularly high-density lipoprotein cholesterol (HDL-C), has recently been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss. However, epidemiological studies have yielded conflicting results.
Methods:
We investigated the causal role of plasma lipid levels in AM...
Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD) more frequently seen in East Asians, has both common and distinct clinical manifestations with typical neovascular AMD (tAMD). We aim to examine the extent to which common genetic variants are shared between these two subtypes. We performed the meta-analysi...
Disturbance in lipid metabolism has been suggested as a major pathogenic factor for age-related macular degeneration (AMD). Conventional lipid measures have been inconsistently associated with AMD. Other factors which can alter lipid metabolism include lipoprotein phenotype and genetic mutations. We performed a case-control study to examine the ass...
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and a...
To examine the association of systemic, ocular and genetic risk factors in neovascular age-related macular degeneration (nAMD) in a large cohort of Asian patients, and to further compare risk factors between those with typical AMD and polypoidal choroidal vasculoapthy (PCV) subtypes. We recruited 456 cases and 1,824 controls matched for age, gender...
Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase 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...
Purpose:
Genetic association studies to date have not identified any robust risk loci for diabetic retinopathy (DR). We hypothesized that individuals with more diabetes genetic risk alleles have a higher risk of developing DR.
Design:
Case-control genetic association study.
Participants:
We evaluated the aggregate effects of multiple type 2 di...
Previous studies have identified many genetic loci for refractive error and myopia. We aimed to investigate the effect of these loci on ocular biometry as a function of age in children, adolescents, and adults. The study population consisted of three age groups identified from the international CREAM consortium: 5,490 individuals aged <10 years; 5,...
Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 ch...
Abstract
Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated i...
Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on r...
Supplementary Figures 1-5, Supplementary Tables 1-10, Supplementary Notes 1-2 and Supplementary References
We examined the joint effects of intraocular pressure (IOP) and myopia on the risk of primary open angle glaucoma (POAG) in a multi-ethnic Asian population. A total of 9,422 participants (18,469 eyes) in the Singapore Epidemiology of Eye Diseases Study were included. Of them, 213 subjects (273 eyes) had POAG. All participants underwent standardised...
To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged < 25 years (4 cohorts, N = 5,640); and...
Corneal curvature (CC) measures the steepness of the cornea and is an important parameter for clinically diseases such as
astigmatism and myopia. Despite the high heritability of CC, only two associated genes have been discovered to date. We performed
a three-stage genome-wide association study meta-analysis in 12 660 Asian individuals. Our Stage 1...
Refractive error is a complex ocular trait governed by both genetic and environmental factors and possibly their interplay.
Thus far, data on the interaction between genetic variants and environmental risk factors for refractive errors are largely
lacking. By using findings from recent genome-wide association studies, we investigated whether the ma...
Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for...
Our study aims to explore the heritability of retinal vascular caliber among Singapore Chinese families.
In the Strabismus, Amblyopia and Refractive Error Study in Singaporean Chinese Preschoolers (STARS) Family study conducted from 2008 to 2010, a total of 727 participants (304 parent-child pairs, 83 sibling pairs and 87 spouse pairs) were include...
Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loc...
Purpose:
To examine the extent to which the two major determinants of refractive error, corneal curvature and axial length, are scaled relative to one another by shared genetic variants, along with their relationship to the genetic scaling of height.
Methods:
Corneal curvature, axial length, and height were measured in unrelated 14- to 17-year-o...
Quantile-Quantile (Q-Q) plots of P-values for association between all SNPs and AL in the individual cohort (A) SCES, (B) SCORM, (C) SiMES, and combined meta-analysis of the discovery cohorts (D) SCES+SCORM+SiMES.
(PDF)
Characteristics of high myopia cases and controls in three Singapore cohorts.
(DOCX)
Association between genetic variants at chromosome 1q41 and high myopia in the meta-analysis of five cohorts.
(DOCX)
Principal Component Analysis (PCA) of discovery cohorts SCES, SCORM and SiMES with respect to the four population panels in phase 2 of the HapMap samples (CEU - European, YRI – African, CHB – Chinese, JPT – Japanese) (A), and with respect to two reference population panels CHB and JPT (B–D). (A) Principal components 1 versus 2; the principal compon...
Association between genetic variants at chromosome 1q41 and spherical equivalent (SE) in the meta-analysis of three Asian cohorts.
(DOCX)
Definitions and numbers of high-myopia cases and controls used in the main and supplementary association analyses for high myopia.
(DOCX)
Gene accession number in the nucleotide sequence database (NCBI), and qRT-PCR primer sequences in mice genome.
(DOCX)
Principal Component Analysis (PCA) was performed in SiMES to assess the extent of population structure. Each figure represents a bivariate plot of two principal components from the PCA of genetic diversity within SiMES on the thinned set of 83,585 SNPs (r2<0.2). The first 5 principal components were used as covariates to account for population stru...
Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci a...
As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay a...
Principal component analysis (PCA) was performed in SiMES to assess the extent of population structure. Each figure represents a bivariate plot of two principal components from the PCA analysis of genetic diversity within SiMES. (A) 1st eigenvector against 2nd eigenvector, (B) 2nd eigenvector against 3rd eigenvector, (C) 3rd eigenvector against 4th...
Principal component analysis (PCA) of discovery cohort SP2 and SiMES with respect to the population panels in phase 2 of the HapMap samples (CEU - European, YRI – African, CHB – Chinese, JPT – Japanese). (A) 1st eigenvector against 2nd eigenvector, (B) 2nd eigenvector against 3rd eigenvector.
(TIF)
Principal component analysis (PCA) was performed in SINDI to assess the extent of population structure. Each figure represents a bivariate plot of two principal components from the PCA analysis of genetic diversity within SINDI. (A) 1st eigenvector against 2nd eigenvector, (B) 2nd eigenvector against 3rd eigenvector, (C) 3rd eigenvector against 4th...
Corneal astigmatism refers to refractive abnormalities and irregularities in the curvature of the cornea, and this interferes with light being accurately focused at a single point in the eye. This ametropic condition is highly prevalent, influences visual acuity, and is a highly heritable trait. There is currently a paucity of research in the genet...
Statistics is an integral part of research in ophthalmology. The application of appropriate statistical strategies allows clinicians to realize the full potential in analyzing data from paired ocular measurements, longitudinal design, and genome-wide association study (GWAS). The increasing popularity of longitudinal follow-up in either clinical or...
Corneal curvature (CC) is a key determinant of major eye diseases, such as keratoconus, myopia and corneal astigmatism. No
prior studies have discovered the genes for CC. Here we report the findings from four genome-wide association studies of CC
in 10 008 samples from three population groups in Singapore. Our discovery phase surveyed 2867 Chinese...
To determine susceptibility genes for high myopia in Singaporean Chinese.
A meta-analysis of 2 genome-wide association (GWA) datasets in Chinese and a follow-up replication cohort in Japanese.
Two independent datasets of Singaporean Chinese individuals aged 10 to 12 years (Singapore Cohort Study of the Risk factors for Myopia [SCORM]: cases = 65, c...
Zha et al¹ identified a new marker within TGFB1 that proved to be more informative in predicting the risk of high myopia in individuals of Chinese descent over and above the previously reported rs1800470.² We provide evidence in another Chinese population in support of the observations by Zha and colleagues. We show new data linking TGFB1 rs4803455...
To assess if natural genetic variation in hepatocyte growth factor (HGF) is associated with altered retinal vessel diameter.
Two-stage cohort study.
Discovery set (set 1, n = 682 children) and confirmatory set (set 2, n = 1293 adults).
Children in the discovery set were genotyped for a panel of genetic markers within HGF. Markers that were found to...
Genome wide association (GWA) studies have become a powerful approach for identifying genetic loci or susceptibility genes for common complex diseases.While the number of susceptibility loci identified by GWA studies is increasing, GWA studies for myopia are lagging behind many complex diseases. However, it is expected that more GWA studies related...
A secondary analysis of the Dialysis Clinical Outcomes Revisited (DCOR) trial suggested that sevelamer reduced hospitalizations relative to calcium-based phosphate binders. However, whether changed medical costs associated with reduced hospitalizations or other medical services offset the higher cost of sevelamer is unclear. This DCOR secondary ana...
To determine the testability of several vision and refraction tests in preschool-aged children.
Population-based study of Chinese preschool-aged children in Singapore.
One thousand five hundred and forty-two Singaporean Chinese children aged 6 to 72 months were recruited through door-to-door screening of government-subsidized apartments in Singapor...
Myopia development is characterised by an increased axial eye length. Therefore, identifying factors that influence eye size may provide new insights into the aetiology of myopia. In humans, axial length is positively correlated to height and weight, and in mice, eye weight is positively correlated with body weight. The purpose of this study was to...
