Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
1.
Nat Genet ; 48(6): 640-7, 2016 06.
Article in English | MEDLINE | ID: mdl-27089177

ABSTRACT

Polypoidal choroidal vasculopathy (PCV), a subtype of 'wet' age-related macular degeneration (AMD), constitutes up to 55% of cases of wet AMD in Asian patients. In contrast to the choroidal neovascularization (CNV) subtype, the genetic risk factors for PCV are relatively unknown. Exome sequencing analysis of a Han Chinese cohort followed by replication in four independent cohorts identified a rare c.986A>G (p.Lys329Arg) variant in the FGD6 gene as significantly associated with PCV (P = 2.19 × 10(-16), odds ratio (OR) = 2.12) but not with CNV (P = 0.26, OR = 1.13). The intracellular localization of FGD6-Arg329 is distinct from that of FGD6-Lys329. In vitro, FGD6 could regulate proangiogenic activity, and oxidized phospholipids increased expression of FGD6. FGD6-Arg329 promoted more abnormal vessel development in the mouse retina than FGD6-Lys329. Collectively, our data suggest that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.


Subject(s)
Guanine Nucleotide Exchange Factors/genetics , Mutation, Missense , Wet Macular Degeneration/genetics , Cells, Cultured , China , Cohort Studies , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Ethnicity , Gene Expression Profiling , Guanine Nucleotide Exchange Factors/metabolism , Humans , Polymorphism, Single Nucleotide , Subcellular Fractions/metabolism
2.
Nat Commun ; 6: 6916, 2015 Apr 23.
Article in English | MEDLINE | ID: mdl-25903422

ABSTRACT

Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.


Subject(s)
Asian People/genetics , Psoriasis/genetics , White People/genetics , Adaptor Proteins, Vesicular Transport/genetics , Case-Control Studies , Core Binding Factor Alpha 2 Subunit/genetics , DEAD-box RNA Helicases/genetics , Genes, MHC Class I/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Interferon-Induced Helicase, IFIH1 , Interleukin-12 Subunit p40/genetics , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics
3.
Genet Epidemiol ; 39(3): 207-16, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25631615

ABSTRACT

Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.


Subject(s)
Genome-Wide Association Study , Glaucoma/genetics , Optic Disk/pathology , Optic Nerve Diseases/genetics , Quantitative Trait Loci/genetics , Asian People/genetics , Glaucoma/ethnology , Glaucoma/pathology , Humans , Optic Nerve Diseases/ethnology , Optic Nerve Diseases/pathology , White People/genetics
4.
Nat Commun ; 5: 4883, 2014 Sep 22.
Article in English | MEDLINE | ID: mdl-25241763

ABSTRACT

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.


Subject(s)
Genome-Wide Association Study , Glaucoma/genetics , Glaucoma/physiopathology , Asian People/genetics , Case-Control Studies , Gene Expression Profiling , Gene Frequency , Genotype , Glaucoma/ethnology , Humans , Optic Disk/pathology , Optic Nerve/pathology , Phenotype , Polymorphism, Single Nucleotide , White People/genetics
5.
Am J Hum Genet ; 92(1): 52-66, 2013 Jan 10.
Article in English | MEDLINE | ID: mdl-23290073

ABSTRACT

Whole-genome sequencing across multiple samples in a population provides an unprecedented opportunity for comprehensively characterizing the polymorphic variants in the population. Although the 1000 Genomes Project (1KGP) has offered brief insights into the value of population-level sequencing, the low coverage has compromised the ability to confidently detect rare and low-frequency variants. In addition, the composition of populations in the 1KGP is not complete, despite the fact that the study design has been extended to more than 2,500 samples from more than 20 population groups. The Malays are one of the Austronesian groups predominantly present in Southeast Asia and Oceania, and the Singapore Sequencing Malay Project (SSMP) aims to perform deep whole-genome sequencing of 100 healthy Malays. By sequencing at a minimum of 30× coverage, we have illustrated the higher sensitivity at detecting low-frequency and rare variants and the ability to investigate the presence of hotspots of functional mutations. Compared to the low-pass sequencing in the 1KGP, the deeper coverage allows more functional variants to be identified for each person. A comparison of the fidelity of genotype imputation of Malays indicated that a population-specific reference panel, such as the SSMP, outperforms a cosmopolitan panel with larger number of individuals for common SNPs. For lower-frequency (<5%) markers, a larger number of individuals might have to be whole-genome sequenced so that the accuracy currently afforded by the 1KGP can be achieved. The SSMP data are expected to be the benchmark for evaluating the value of deep population-level sequencing versus low-pass sequencing, especially in populations that are poorly represented in population-genetics studies.


Subject(s)
Asian People/genetics , Genetic Variation , High-Throughput Nucleotide Sequencing , Genetics, Population , Genome, Human , Humans , Malaysia , Polymorphism, Single Nucleotide , Population Groups/genetics , Singapore
6.
Eur J Hum Genet ; 20(1): 102-10, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21792231

ABSTRACT

Recent reports have identified a north-south cline in genetic variation in East and South-East Asia, but these studies have not formally explored the basis of these clinical differences. Understanding the origins of these variations may provide valuable insights in tracking down the functional variants in genomic regions identified by genetic association studies. Here we investigate the genetic basis of these differences with genome-wide data from the HapMap, the Human Genome Diversity Project and the Singapore Genome Variation Project. We implemented four bioinformatic measures to discover genomic regions that are considerably differentiated either between two Han Chinese populations in the north and south of China, or across 22 populations in East and South-East Asia. These measures prioritized genomic stretches with: (i) regional differences in the allelic spectrum for SNPs common to the two Han Chinese populations; (ii) differential evidence of positive selection between the two populations as quantified by integrated haplotype score (iHS) and cross-population extended haplotype homozygosity (XP-EHH); (iii) significant correlation between allele frequencies and geographical latitudes of the 22 populations. We also explored the extent of linkage disequilibrium variations in these regions, which is important in combining genetic association studies from North and South Chinese. Two of the regions that emerged are found in HLA class I and II, suggesting that the HLA imputation panel from the HapMap may not be directly applicable to every Chinese sample. This has important implications to autoimmune studies that plan to impute the classical HLA alleles to fine map the SNP association signals.


Subject(s)
Genetic Variation , Polymorphism, Single Nucleotide , Selection, Genetic , Altitude , Computational Biology , Ethnicity/genetics , Asia, Eastern/ethnology , Gene Frequency , Genes, MHC Class I , Genetics, Population , Genome, Human , HapMap Project , Haplotypes , Homozygote , Humans , Linkage Disequilibrium
7.
Nat Genet ; 44(2): 178-82, 2011 Dec 25.
Article in English | MEDLINE | ID: mdl-22197929

ABSTRACT

We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10(-11), OR = 1.21; rs4227, P = 4.31 × 10(-10), OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10(-14), OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and α-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10(-20), OR = 1.34; rs1794275, P = 3.43 × 10(-13), OR = 1.30; rs2523946, P = 1.74 × 10(-11), OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10(-11), OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation.


Subject(s)
Asian People/genetics , Genetic Loci , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Glomerulonephritis, IGA/genetics , Asian People/statistics & numerical data , Case-Control Studies , Female , Glomerulonephritis, IGA/diagnosis , Glomerulonephritis, IGA/epidemiology , Humans , Immunoglobulin A/blood , Major Histocompatibility Complex/genetics , Male , Polymorphism, Single Nucleotide , Proteinuria/genetics , Tumor Necrosis Factor Ligand Superfamily Member 13/genetics , alpha-Defensins/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...