Large-Scale Whole-Genome Sequencing of Three Diverse Asian Populations in Singapore.

Underrepresentation of Asian genomes has hindered population and medical genetics research on Asians, leading to population disparities in precision medicine. By whole-genome sequencing of 4,810 Singapore Chinese, Malays, and Indians, we found 98.3 million SNPs and small insertions or deletions, over half of which are novel. Population structure analysis demonstrated great representation of Asian genetic diversity by three ethnicities in Singapore and revealed a Malay-related novel ancestry component. Furthermore, demographic inference suggested that Malays split from Chinese ∼24,800 years ago and experienced significant admixture with East Asians ∼1,700 years ago, coinciding with the Austronesian expansion. Additionally, we identified 20 candidate loci for natural selection, 14 of which harbored robust associations with complex traits and diseases. Finally, we show that our data can substantially improve genotype imputation in diverse Asian and Oceanian populations. These results highlight the value of our data as a resource to empower human genetics discovery across broad geographic regions.

Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations.

Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10-16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10-11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.

Multicenter study on the genetics of glomerular diseases among southeast and south Asians: Deciphering Diversities - Renal Asian Genetics Network (DRAGoN).

Multinational studies have reported monogenic etiologies in 25%-30% of children with steroid-resistant nephrotic syndrome. Such large studies are lacking in Asia. We established Deciphering Diversities: Renal Asian Genetics Network (DRAGoN) and aimed to describe the genetic and clinical spectrums in Asians. We prospectively studied a cohort of 183 probands with suspected genetic glomerulopathies from South and Southeast Asia, of whom 17% had positive family history. Using multi-gene panel sequencing, we detected pathogenic variants in 26 (14%) probands, of whom one-third had COL4A4 or COL4A5 variants (n = 9, 5%). Of those with COL4A5 defects, only 25% had features suggestive of Alport syndrome. Besides traditional predictors for genetic disease (positive family history and extrarenal malformations), we identified novel predictors, namely older age (6.2 vs. 2.4 years; p = 0.001), hematuria (OR 5.6; 95% CI 2.1-14.8; p < 0.001), and proteinuria in the absence of nephrotic syndrome (OR 4.6; 95% CI 1.8-11.8; p = 0.001) at first manifestation. Among patients who first presented with proteinuria without nephrotic syndrome, the genetic diagnostic rates were >60% when a second risk factor (positive family history or extrarenal manifestation) co-existed. The genetic spectrum of glomerulopathies appears different in Asia. Collagen IV genes may be included in sequencing panels even when suggestive clinical features are absent.

High-Resolution Digital Phenotypes From Consumer Wearables and Their Applications in Machine Learning of Cardiometabolic Risk Markers: Cohort Study.

BACKGROUND: Consumer-grade wearable devices enable detailed recordings of heart rate and step counts in free-living conditions. Recent studies have shown that summary statistics from these wearable recordings have potential uses for longitudinal monitoring of health and disease states. However, the relationship between higher resolution physiological dynamics from wearables and known markers of health and disease remains largely uncharacterized. OBJECTIVE: We aimed to derive high-resolution digital phenotypes from observational wearable recordings and to examine their associations with modifiable and inherent markers of cardiometabolic disease risk. METHODS: We introduced a principled framework to extract interpretable high-resolution phenotypes from wearable data recorded in free-living conditions. The proposed framework standardizes the handling of data irregularities; encodes contextual information regarding the underlying physiological state at any given time; and generates a set of 66 minimally redundant features across active, sedentary, and sleep states. We applied our approach to a multimodal data set, from the SingHEART study (NCT02791152), which comprises heart rate and step count time series from wearables, clinical screening profiles, and whole genome sequences from 692 healthy volunteers. We used machine learning to model nonlinear relationships between the high-resolution phenotypes on the one hand and clinical or genomic risk markers for blood pressure, lipid, weight and sugar abnormalities on the other. For each risk type, we performed model comparisons based on Brier scores to assess the predictive value of high-resolution features over and beyond typical baselines. We also qualitatively characterized the wearable phenotypes for participants who had actualized clinical events. RESULTS: We found that the high-resolution features have higher predictive value than typical baselines for clinical markers of cardiometabolic disease risk: the best models based on high-resolution features had 17.9% and 7.36% improvement in Brier score over baselines based on age and gender and resting heart rate, respectively (P<.001 in each case). Furthermore, heart rate dynamics from different activity states contain distinct information (maximum absolute correlation coefficient of 0.15). Heart rate dynamics in sedentary states are most predictive of lipid abnormalities and obesity, whereas patterns in active states are most predictive of blood pressure abnormalities (P<.001). Moreover, in comparison with standard measures, higher resolution patterns in wearable heart rate recordings are better able to represent subtle physiological dynamics related to genomic risk for cardiometabolic disease (improvement of 11.9%-22.0% in Brier scores; P<.001). Finally, illustrative case studies reveal connections between these high-resolution phenotypes and actualized clinical events, even for borderline profiles lacking apparent cardiometabolic risk markers. CONCLUSIONS: High-resolution digital phenotypes recorded by consumer wearables in free-living states have the potential to enhance the prediction of cardiometabolic disease risk and could enable more proactive and personalized health management.

Beyond fitness tracking: The use of consumer-grade wearable data from normal volunteers in cardiovascular and lipidomics research.

The use of consumer-grade wearables for purposes beyond fitness tracking has not been comprehensively explored. We generated and analyzed multidimensional data from 233 normal volunteers, integrating wearable data, lifestyle questionnaires, cardiac imaging, sphingolipid profiling, and multiple clinical-grade cardiovascular and metabolic disease markers. We show that subjects can be stratified into distinct clusters based on daily activity patterns and that these clusters are marked by distinct demographic and behavioral patterns. While resting heart rates (RHRs) performed better than step counts in being associated with cardiovascular and metabolic disease markers, step counts identified relationships between physical activity and cardiac remodeling, suggesting that wearable data may play a role in reducing overdiagnosis of cardiac hypertrophy or dilatation in active individuals. Wearable-derived activity levels can be used to identify known and novel activity-modulated sphingolipids that are in turn associated with insulin sensitivity. Our findings demonstrate the potential for wearables in biomedical research and personalized health.

Variation in Genome-Wide NF-κB RELA Binding Sites upon Microbial Stimuli and Identification of a Virus Response Profile.

NF-κB transcription factors are master regulators of the innate immune response. Activated downstream of pathogen recognition receptors, they regulate the expression of genes to help fight infections as well as recruit the adaptive immune system. NF-κB responds to a wide variety of signals, but the processes by which stimulus specificity is attained remain unclear. In this article, we characterized the response of one NF-κB member, RELA, to four stimuli mimicking infection in human nasopharyngeal epithelial cells. Comparing genome-wide RELA binding, we observed stimulus-specific sites, although most sites overlapped across stimuli. Specifically, the response to poly I:C (mimicking viral dsRNA and signaling through TLR3) induced a distinct RELA profile, binding in the vicinity of antiviral genes and correlating with corresponding gene expression. This group of binding sites was also enriched in IFN regulatory factor motifs and showed overlapping with IFN regulatory factor binding sites. A novel NF-κB target, OASL, was further validated and showed TLR3-specific activation. This work showed that some RELA DNA binding sites varied in activation response following different stimulations and that interaction with more specialized factors could help achieve this stimulus-specific activity. Our data provide a genomic view of regulated host response to different pathogen stimuli.

Personalized genome sequencing coupled with iPSC technology identifies GTDC1 as a gene involved in neurodevelopmental disorders.

The cellular and molecular mechanisms underlying neurodevelopmental conditions such as autism spectrum disorders have been studied intensively for decades. The ability to generate patient-specific induced pluripotent stem cells (iPSCs) now offers a novel strategy for modelling human diseases. Recent studies have reported the derivation of iPSCs from patients with neurological disorders. The key challenge remains the demonstration of disease-related phenotypes and the ability to model the disease. Here we report a case study with signs of neurodevelopmental disorders (NDDs) harbouring chromosomal rearrangements that were sequenced using long-insert DNA paired-end tag (DNA-PET) sequencing approach. We identified the disruption of a specific gene, GTDC1. By deriving iPSCs from this patient and differentiating them into neural progenitor cells (NPCs) and neurons we dissected the disease process at the cellular level and observed defects in both NPCs and neuronal cells. We also showed that disruption of GTDC1 expression in wild type human NPCs and neurons showed a similar phenotype as patient's iPSCs. Finally, we utilized a zebrafish model to demonstrate a role for GTDC1 in the development of the central nervous system. Our findings highlight the importance of combining sequencing technologies with the iPSC technology for NDDs modelling that could be applied for personalized medicine.

Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders.

PURPOSE: Genomic studies have demonstrated the necessity of ethnicity-specific population data to ascertain variant pathogenicity for disease diagnosis and treatment. This study examined the carrier prevalence of treatable inherited disorders (TIDs), where early diagnosis of at-risk offspring can significantly improve clinical outcomes. METHODS: Existing exome/ genome sequencing data of 831 Singaporeans were aggregated and examined for disease causing variants in 104 genes associated with 80 TIDs. RESULTS: Among the 831 Singaporean participants, genomic variant filtering and analysis identified 1 in 18 individuals (6%) to be carriers amongst one of 13 TIDs. Citrin deficiency and Wilson disease had the highest carrier frequency of 1 in 41, and 1 in 103 individuals, respectively. The pathogenic variants associated with citrin deficiency were 24 times more prevalent in our local cohorts when compared to Western cohorts. CONCLUSION: This study demonstrates the value of a population specific genomic database to determine true disease prevalence and has enabled the discovery of carrier frequencies of treatable genetic conditions specific to South East Asian populations, which are currently underestimated in existing data sources. This study framework can be adapted to other population groups and expanded to multiple genetic conditions to inform health policies directing precision medicine.

ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder.

PURPOSE: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. METHODS: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. RESULTS: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. CONCLUSION: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

Harnessing technology and molecular analysis to understand the development of cardiovascular diseases in Asia: a prospective cohort study (SingHEART).

BACKGROUND: Cardiovascular disease (CVD) imposes much mortality and morbidity worldwide. The use of "deep learning", advancements in genomics, metabolomics, proteomics and devices like wearables have the potential to unearth new insights in the field of cardiology. Currently, in Asia, there are no studies that combine the use of conventional clinical information with these advanced technologies. We aim to harness these new technologies to understand the development of cardiovascular disease in Asia. METHODS: Singapore is a multi-ethnic country in Asia with well-represented diverse ethnicities including Chinese, Malays and Indians. The SingHEART study is the first technology driven multi-ethnic prospective population-based study of healthy Asians. Healthy male and female subjects aged 21-69 years old without any prior cardiovascular disease or diabetes mellitus will be recruited from the general population. All subjects are consented to undergo a detailed on-line questionnaire, basic blood investigations, resting and continuous electrocardiogram and blood pressure monitoring, activity and sleep tracking, calcium score, cardiac magnetic resonance imaging, whole genome sequencing and lipidomic analysis. Outcomes studied will include mortality and cause of mortality, myocardial infarction, stroke, malignancy, heart failure, and the development of co-morbidities. DISCUSSION: An initial target of 2500 patients has been set. From October 2015 to May 2017, an initial 683 subjects have been recruited and have completed the initial work-up the SingHEART project is the first contemporary population-based study in Asia that will include whole genome sequencing and deep phenotyping: including advanced imaging and wearable data, to better understand the development of cardiovascular disease across different ethnic groups in Asia.

Changes in H3K27ac following lipopolysaccharide stimulation of nasopharyngeal epithelial cells.

BACKGROUND: The epithelium is the first line of defense against pathogens. Notably the epithelial cells lining the respiratory track are crucial in sensing airborne microbes and mounting an effective immune response via the expression of target genes such as cytokines and chemokines. Gene expression regulation following microbial recognition is partly regulated by chromatin re-organization and has been described in immune cells but data from epithelial cells is not as detailed. Here, we report genome-wide changes of the H3K27ac mark, characteristic of activated enhancers and promoters, after stimulation of nasopharyngeal epithelial cells with the bacterial endotoxin Lipopolysaccharide (LPS). RESULTS: In this study, we have identified 626 regions where the H3K27ac mark showed reproducible increase following LPS induction in epithelial cells. This indicated that sensing of LPS led to opening of the chromatin in our system. Moreover, this phenomenon seemed to happen extensively at enhancers regions and we could observe instances of Super-enhancer formation. As expected, LPS-increased H3K27ac regions were found in the vicinity of genes relevant for LPS response and these changes correlated with up-regulation of their expression. In addition, we found the induction of H3K27ac mark to overlap with the binding of one of the NF-kB members and key regulator of the innate immune response, RELA, following LPS sensing. Indeed, inhibiting the NF-kB pathway abolished the deposition of H3K27ac at the TNF locus, a target of RELA, suggesting that these two phenomena are associated. CONCLUSIONS: Enhancers' selection and activation following microbial or inflammatory stimuli has been described previously and shown to be mediated via the NF-kB pathway. Here, we demonstrate that this is also likely to occur in the case of LPS-sensing by nasopharyngeal epithelial cells as well. In addition to validating previous findings, we generated a valuable data set relevant to the host immune response to epithelial cell colonizing or infecting pathogens.

Correction: Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders.

At the time of publication the author Jyn Ling Kuan did not have a master's degree; this has now been amended to BSc. This has now been corrected in the PDF and HTML versions of the article.

An Immunochip-based interaction study of contrasting interaction effects with smoking in ACPA-positive versus ACPA-negative rheumatoid arthritis.

OBJECTIVE: To investigate the gene-environment interaction between smoking and single nucleotide polymorphisms (SNPs), using Immunochip material, on the risk of developing either of two serologically defined subsets of RA. METHODS: Interaction between smoking and 133,648 genetic markers from the Immunochip was examined for two RA subsets, defined by the presence or absence of ACPA. A total of 1590 ACPA-positive and 891 ACPA-negative cases were compared with 1856 controls in the Swedish Epidemiological Investigation of RA (EIRA) case-control study. Logistic regression models were used to determine the presence of interaction. The proportion attributable to interaction was calculated for each smoking-SNP pair. Replication was carried out in an independent dataset from northern Sweden. To further validate and extend the results, interaction analysis was also performed using genome-wide association studies data on EIRA individuals. RESULTS: In ACPA-positive RA, 102 SNPs interacted significantly with smoking, after Bonferroni correction. All 102 SNPs were located in the HLA region, mainly within the HLA class II region, 51 of which were replicated. No additional loci outside chromosome 6 were identified in the genome-wide association studies validation. After adjusting for HLA-DRB1 shared epitope, 15 smoking-SNP pairs remained significant for ACPA-positive RA, with 8 of these replicated (loci: BTNL2, HLA-DRA, HLA-DRB5, HLA-DQA1, HLA-DOB and TAP2). For ACPA-negative RA, no smoking-SNP pairs passed the threshold for significance. CONCLUSION: Our study presents extended gene variation patterns involved in gene-smoking interaction in ACPA-positive, but not ACPA-negative, RA. Notably, variants in HLA-DRB1 and those in additional genes within the MHC class II region, but not in any other gene regions, showed interaction with smoking.

cnvCapSeq: detecting copy number variation in long-range targeted resequencing data.

Targeted resequencing technologies have allowed for efficient and cost-effective detection of genomic variants in specific regions of interest. Although capture sequencing has been primarily used for investigating single nucleotide variants and indels, it has the potential to elucidate a broader spectrum of genetic variation, including copy number variants (CNVs). Various methods exist for detecting CNV in whole-genome and exome sequencing datasets. However, no algorithms have been specifically designed for contiguous target sequencing, despite its increasing importance in clinical and research applications. We have developed cnvCapSeq, a novel method for accurate and sensitive CNV discovery and genotyping in long-range targeted resequencing. cnvCapSeq was benchmarked using a simulated contiguous capture sequencing dataset comprising 21 genomic loci of various lengths. cnvCapSeq was shown to outperform the best existing exome CNV method by a wide margin both in terms of sensitivity (92.0 versus 48.3%) and specificity (99.8 versus 70.5%). We also applied cnvCapSeq to a real capture sequencing cohort comprising a contiguous 358 kb region that contains the Complement Factor H gene cluster. In this dataset, cnvCapSeq identified 41 samples with CNV, including two with duplications, with a genotyping accuracy of 99%, as ascertained by quantitative real-time PCR.

Electrostatic analysis of bacterial expansins.

Expansins are a family of proteins with plant cell wall remodeling-activity, which bind cell wall components through hydrophobic and electrostatic interactions. A shallow area on the surface of the protein serves as the polysaccharide binding site (PBS) and it is composed of conserved residues. However, electric charge differences on the opposite face of the PBS produce basic, neutral, or acidic proteins. An analysis of forty-four bacterial expansins, homologues of BsEXLX1, revealed two main groups defined by: (a) the presence or absence of disulfide bonds; and (b) by the proteins isoelectric point (pI). We determined the location of the residues responsible for the pI on the structure of representative expansins. Our results suggest that the electric charge at the opposite site of the PBS may help in substrate differentiation among expansins from different species; in addition, electrostatic polarization between the front and the back of the molecule could affect expansin activity on cellulose.

Impaired development of neural-crest cell-derived organs and intellectual disability caused by MED13L haploinsufficiency.

MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a translocation t(12;19) breakpoint of a patient with Pierre-Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full-length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short-hairpin RNA in ES-derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L-deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.

Cluster analysis and visualisation of electronic health records data to identify undiagnosed patients with rare genetic diseases.

Rare genetic diseases affect 5-8% of the population but are often undiagnosed or misdiagnosed. Electronic health records (EHR) contain large amounts of data, which provide opportunities for analysing and mining. Data mining, in the form of cluster analysis and visualisation, was performed on a database containing deidentified health records of 1.28 million patients across 3 major hospitals in Singapore, in a bid to improve the diagnostic process for patients who are living with an undiagnosed rare disease, specifically focusing on Fabry Disease and Familial Hypercholesterolaemia (FH). On a baseline of 4 patients, we identified 2 additional patients with potential diagnosis of Fabry disease, suggesting a potential 50% increase in diagnosis. Similarly, we identified > 12,000 individuals who fulfil the clinical and laboratory criteria for FH but had not been diagnosed previously. This proof-of-concept study showed that it is possible to perform mining on EHR data albeit with some challenges and limitations.

Disruption of vascular homeostasis in patients with Kawasaki disease: involvement of vascular endothelial growth factor and angiopoietins.

OBJECTIVE: In Kawasaki disease (KD), a pediatric vasculitis of medium-sized arteries, the coronary arteries are most commonly affected. Angiopoietins and vascular endothelial growth factor (VEGF) play an important role in maintaining vascular homeostasis. Recently, we identified ANGPT1 and VEGFA as susceptibility loci for KD. This study was undertaken to fine-map these associations and to gain further insight into their role in this vasculitis of unknown etiology to further the search for improved diagnostic and therapeutic options. METHODS: A total of 292 single-nucleotide polymorphisms (SNPs) located in VEGF and ANGPT and their receptors were genotyped in 574 families, including 462 trios. For replication, 123 cases and 171 controls were genotyped. RESULTS: A significant association with KD susceptibility was observed with 5 SNPs in the ANGPT1 gene (most significantly associated SNP +265037 C>T; Pcombined=2.3×10(-7) ) and 2 SNPs in VEGFA (most significantly associated SNP rs3025039; Pcombined=2.5×10(-4) ). Both ANGPT1 +265037 C>T and VEGFA rs3025039 are located in 3' regulatory regions at putative transcription factor binding sites. We observed significantly down-regulated transcript levels of angiopoietin 1 (Ang-1) in patients with acute KD compared to patients with convalescent KD. In patients with acute KD, high serum protein levels of VEGF and Ang-2 were observed compared to patients with convalescent KD and to both controls with and controls without fever. Immunohistochemistry demonstrated VEGF and angiopoietin expression in the coronary artery wall in autopsy tissue. CONCLUSION: Our data support the hypothesis that dysregulation of VEGF and angiopoietins contributes to the disruption of vascular homeostasis in KD.

Mutations in SEC63 cause autosomal dominant polycystic liver disease.

Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease.

Contribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes.

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 identify twelve loci, of which four are novel ([Formula: see text]). Substantial genetic sharing between PCV and typical nAMD is noted (rg = 0.666), whereas collagen extracellular matrix and fibrosis-related pathways are more pronounced for PCV. Whole-exome sequencing in 259 PCV patients revealed functional rare variants burden in collagen type I alpha 1 chain gene (COL1A1; [Formula: see text]) and potential enrichment of functional rare mutations at AMD-associated loci. At the GATA binding protein 5 (GATA5) locus, the most significant GWAS novel loci, the expressions of genes including laminin subunit alpha 5 (Lama5), mitochondrial ribosome associated GTPase 2 (Mtg2), and collagen type IX alpha 3 chain (Col9A3), are significantly induced during retinal angiogenesis and subretinal fibrosis in murine models. Furthermore, retinoic acid increased the expression of LAMA5 and MTG2 in vitro. Taken together, our data provide insights into the genetic basis of AMD pathogenesis in the Asian population.