The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies(GWASs) were mostly based on European d...The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies(GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent(SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou(631 <-6.00 D and 574 > 0.00 D) and Wenzhou(593 <-6.00 D and54 >-1.75 D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci, which show genome-wide significant associations with SE, including 1 q25.2 FAM163 A, 10 p11.22 NRP1/PRAD3, and 10 p11.21 ANKRD30 A/MTRNR2 L7, together explaining 3.34% of SE variance. 10 p11.21 is successfully replicated.The allele frequencies of all three loci show significant differences between major continental groups(P < 0.001). The SE reducing(more myopic) allele of rs10913877(1 q25.2 FAM163 A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans(EAS = 0.60,EUR = 0.20, and AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5, and ARPP19. These results provide new insights into myopia pathogenesis and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.展开更多
Background:Keratoconus(KC)is a common corneal condition with an unknown gender predominance.Although numerous studies have investigated the genetic component of KC,no specific genes have yet been attributed to the con...Background:Keratoconus(KC)is a common corneal condition with an unknown gender predominance.Although numerous studies have investigated the genetic component of KC,no specific genes have yet been attributed to the condition.We recently reported posterior segment changes occurring in the eyes of KC patients.However,it is not clear whether these changes are part of KC pathogenesis or reflect changes in anatomical features of the eye manifested by changes at the cornea.Given retinal changes represent the main characteristics observed in agerelated macular degeneration(AMD)and that pleiotropy has been demonstrated between different eye diseases,we wished to assess if known AMD associated genes were also associated with KC.Methods:A total of 248 KC subjects and 366 non-KC(control)subjects were recruited from public and private clinics in Melbourne for this analysis.Nineteen single nucleotide polymorphisms(SNPs)previously associated with AMD,including rs10490924(ARMS2/HTRA1),rs10737680(CFH),rs13278062(TNFRSF10A),rs1864163(CETP),rs2230199(C3),rs3130783(IER3/DDR1),rs334353(TGFBR1),rs3812111(COL10A1),rs429608(C2/CFB),rs4420638(APOE),rs4698775(CFI),rs5749482(TIMP3),rs6795735(ADAMTS9),rs8017304(RAD51B),rs8135665(SLC16A8),rs920915(LIPC),rs943080(VEGFA),rs9542236(B3GALTL)and rs13081855(COL8A1/FILIP1L),were genotyped in this cohort.Logistic regression was applied to evaluate the association between these SNPs and KC on both genders together,as well as each gender separately.Linear regression was also applied to assess the association between SNPs and corneal curvature.Bonferroni correction was applied to adjust for multiple testing.Results:Genotyping data were available for 18 SNPs.The SNP,rs6795735(ADAMTS9)was significantly associated with KC(p=3.5×10−4)when both genders were assessed,whereas rs5749482(TIMP3)was only associated in males(p=7.7×10−4)following Bonferroni multiple correction.However,when the covariates of age and gender were included,the associations became non-significant.In addition,none of the SNPs appeared significant for corneal curvature.Conclusions:Our study suggested a potential association of rs6795735 in the ADAMTS9 gene and rs5749482 in the TIMP3 gene in KC and that different associations may be gender specific.Overall,SNPs initially identified as associated with AMD following multiple correction may be further impacted by other factors such as age or gender and further studies are needed to resolve this issue.展开更多
基金supported by the Strategic Priority Research Program of Chinese Academy of Sciences (XDB38010400)National Key R&D Program of China (2018YFC0116500)+4 种基金Science and Technology Service Network Initiative of Chinese Academy of Sciences (KFJSTS-ZDTP-079)Science and Technology Planning Project of Guangdong Province (2013B20400003)the Fundamental Research Funds of the State Key Laboratory of Ophthalmologythe Open Project of Key Laboratory of Genomic and Precision Medicine of the CASsupported by the China Scholarship Council (CSC) and China Postdoctoral Science Foundation (2019TQ0365)。
文摘The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies(GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent(SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou(631 <-6.00 D and 574 > 0.00 D) and Wenzhou(593 <-6.00 D and54 >-1.75 D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci, which show genome-wide significant associations with SE, including 1 q25.2 FAM163 A, 10 p11.22 NRP1/PRAD3, and 10 p11.21 ANKRD30 A/MTRNR2 L7, together explaining 3.34% of SE variance. 10 p11.21 is successfully replicated.The allele frequencies of all three loci show significant differences between major continental groups(P < 0.001). The SE reducing(more myopic) allele of rs10913877(1 q25.2 FAM163 A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans(EAS = 0.60,EUR = 0.20, and AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5, and ARPP19. These results provide new insights into myopia pathogenesis and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.
基金supported by the Australian National Health and Medical Research Council(NHMRC)project grant GNT1104700Senior Research Fellowship(1138585 to PN Baird)+1 种基金the Angior Family Foundation and a Lions Eye Foundation Fellowship(SS)The Centre for Eye Research Australia(CERA)receives Operational Infrastructure Support from the Victorian Government.
文摘Background:Keratoconus(KC)is a common corneal condition with an unknown gender predominance.Although numerous studies have investigated the genetic component of KC,no specific genes have yet been attributed to the condition.We recently reported posterior segment changes occurring in the eyes of KC patients.However,it is not clear whether these changes are part of KC pathogenesis or reflect changes in anatomical features of the eye manifested by changes at the cornea.Given retinal changes represent the main characteristics observed in agerelated macular degeneration(AMD)and that pleiotropy has been demonstrated between different eye diseases,we wished to assess if known AMD associated genes were also associated with KC.Methods:A total of 248 KC subjects and 366 non-KC(control)subjects were recruited from public and private clinics in Melbourne for this analysis.Nineteen single nucleotide polymorphisms(SNPs)previously associated with AMD,including rs10490924(ARMS2/HTRA1),rs10737680(CFH),rs13278062(TNFRSF10A),rs1864163(CETP),rs2230199(C3),rs3130783(IER3/DDR1),rs334353(TGFBR1),rs3812111(COL10A1),rs429608(C2/CFB),rs4420638(APOE),rs4698775(CFI),rs5749482(TIMP3),rs6795735(ADAMTS9),rs8017304(RAD51B),rs8135665(SLC16A8),rs920915(LIPC),rs943080(VEGFA),rs9542236(B3GALTL)and rs13081855(COL8A1/FILIP1L),were genotyped in this cohort.Logistic regression was applied to evaluate the association between these SNPs and KC on both genders together,as well as each gender separately.Linear regression was also applied to assess the association between SNPs and corneal curvature.Bonferroni correction was applied to adjust for multiple testing.Results:Genotyping data were available for 18 SNPs.The SNP,rs6795735(ADAMTS9)was significantly associated with KC(p=3.5×10−4)when both genders were assessed,whereas rs5749482(TIMP3)was only associated in males(p=7.7×10−4)following Bonferroni multiple correction.However,when the covariates of age and gender were included,the associations became non-significant.In addition,none of the SNPs appeared significant for corneal curvature.Conclusions:Our study suggested a potential association of rs6795735 in the ADAMTS9 gene and rs5749482 in the TIMP3 gene in KC and that different associations may be gender specific.Overall,SNPs initially identified as associated with AMD following multiple correction may be further impacted by other factors such as age or gender and further studies are needed to resolve this issue.
