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Valentina Cipriani,
Hin-Tak Leung,
Vincent Plagnol,
Catey Bunce,
Jane C Khan,
Humma Shahid,
Anthony T Moore,
Simon P Harding,
Paul N Bishop,
Caroline Hayward, [......],
Eric H Souied,
José-Alain Sahel,
Thierry Léveillard,
Angela J Cree,
Jane Gibson,
Sarah Ennis,
Andrew J Lotery,
Alan F Wright,
David G Clayton, John R W Yates
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ABSTRACT: Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.
Human Molecular Genetics 06/2012; 21(18):4138-50. · 7.64 Impact Factor
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Valentina Cipriani,
Baljinder K Matharu,
Jane C Khan,
Humma Shahid,
Chloe M Stanton,
Caroline Hayward,
Alan F Wright,
Catey Bunce,
David G Clayton,
Anthony T Moore, John R W Yates
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ABSTRACT: Age-related macular degeneration (AMD) is the commonest cause of blindness in Western populations. Risk is influenced by age, genetic and environmental factors. Complement activation appears to be important in the pathogenesis and associations have been found between AMD and genetic variations in complement regulators such as complement factor H. We therefore investigated other complement regulators for association with AMD.
We carried out a case-control study to test for association between AMD and single nucleotide polymorphisms (SNPs) spanning the genes encoding complement factor P (CFP, properdin), CD46 (membrane cofactor protein, MCP), CD55 (decay accelerating factor, DAF) and CD59 (protectin). All cases and controls were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status.
20 SNPs were genotyped in 446 cases and 262 controls. For two SNPs with p-values approaching significance additional subjects were genotyped to increase the numbers to 622 cases and 359 controls. There was no evidence of association between AMD and any of the SNPs typed in CFP, CD46, CD55 or CD59.
In a case-control sample that has shown the well established associations between AMD and variants in CFH, CFB and C3 there was absence of association with SNPs in CFP, CD46, CD55 and CD59. This suggests that these are not important susceptibility genes for AMD.
Immunobiology 02/2012; 217(2):158-61. · 3.20 Impact Factor
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Acta ophthalmologica 11/2011; 89(7):e603-4. · 2.44 Impact Factor
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Gareth J McKay,
Chris C Patterson,
Usha Chakravarthy,
Shilpa Dasari,
Caroline C Klaver,
Johannes R Vingerling,
Lintje Ho,
Paulus T V M de Jong,
Astrid E Fletcher,
Ian S Young, [......],
Atsuhiro Kanda,
Wei Chen,
Goncalo R Abecasis,
Alan F Wright,
Caroline Hayward,
Paul N Baird,
Robyn H Guymer,
John Attia,
Ammarin Thakkinstian,
Giuliana Silvestri
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ABSTRACT: Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10(-11) ) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10(-15) ) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10(-5) ) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.
Human Mutation 08/2011; 32(12):1407-16. · 5.69 Impact Factor
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ABSTRACT: Family history is considered a risk factor for age-related macular degeneration (AMD). With the advent of effective therapy for the disease, the importance of family history merits further investigation. This study quantifies the risk associated with family history, first, by a case-control study of reported family history and, second, by examining the siblings of AMD cases.
The authors recruited cases with advanced AMD, spouses and siblings. All subjects were carefully phenotyped. Clinical findings in the siblings were compared with spouses. Information about family history was collected. The ORs for reported family history of AMD were calculated. Analyses were adjusted for age, smoking and genotype.
495 AMD cases, 259 spouses and 171 siblings were recruited. The OR for AMD was 27.8 (CI 3.8 to 203.0; p=0.001) with a reported family history of an affected parent and 12.0 (CI 3.7 to 38.6; p<0.0001) with a history of an affected sibling. ORs adjusted for age and smoking were higher. Examination of siblings confirmed their increased risk with 23% affected by AMD and an OR of 10.8 (4.5 to 25.8; p<0.0001). Adjusting for age increased the OR to 16.1 (6.2 to 41.8).
The risk of AMD is greatly increased by having an affected first-degree relative. Those at risk need to be made aware of this and AMD patients should advise siblings and children to seek prompt ophthalmological advice if they develop visual symptoms of distortion or reduced vision.
The British journal of ophthalmology 08/2011; 96(3):427-31. · 2.92 Impact Factor
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Chloe M Stanton, John R W Yates,
Anneke I den Hollander,
Johanna M Seddon,
Anand Swaroop,
Dwight Stambolian,
Sascha Fauser,
Carel Hoyng,
Yi Yu,
Kanda Atsuhiro,
Kari Branham,
Mohammad Othman,
Wei Chen,
Elod Kortvely,
Kevin Chalmers,
Caroline Hayward,
Anthony T Moore,
Baljean Dhillon,
Marius Ueffing,
Alan F Wright
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ABSTRACT: To examine the role of complement factor D (CFD) in age-related macular degeneration (AMD) by analysis of genetic association, copy number variation, and plasma CFD concentrations.
Single nucleotide polymorphisms (SNPs) in the CFD gene were genotyped and the results analyzed by binary logistic regression. CFD gene copy number was analyzed by gene copy number assay. Plasma CFD was measured by an enzyme-linked immunosorbent assay.
Genetic association was found between CFD gene SNP rs3826945 and AMD (odds ratio 1.44; P = 0.028) in a small discovery case-control series (462 cases and 325 controls) and replicated in a combined cohorts meta-analysis of 4765 cases and 2693 controls, with an odds ratio of 1.11 (P = 0.032), with the association almost confined to females. Copy number variation in the CFD gene was identified in 13 out of 640 samples examined but there was no difference in frequency between AMD cases (1.3%) and controls (2.7%). Plasma CFD concentration was measured in 751 AMD cases and 474 controls and found to be elevated in AMD cases (P = 0.00025). The odds ratio for those in the highest versus lowest quartile for plasma CFD was 1.81. The difference in plasma CFD was again almost confined to females.
CFD regulates activation of the alternative complement pathway, which is implicated in AMD pathogenesis. The authors found evidence for genetic association between a CFD gene SNP and AMD and a significant increase in plasma CFD concentration in AMD cases compared with controls, consistent with a role for CFD in AMD pathogenesis.
Investigative ophthalmology & visual science 01/2011; 52(12):8828-34. · 3.43 Impact Factor
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ABSTRACT: We have developed the Early Childhood Epilepsy Severity Scale (E-Chess) to quantify the severity of epilepsy in infants and young children with tuberous sclerosis as an aid to the evaluation of treatment efficacy and the investigation of the influence of epilepsy severity on development.
Twenty infants aged 11-36 months with a diagnosis of tuberous sclerosis participated in the study. From the literature, six potential measures of epilepsy severity were identified: time period over which seizures occurred; seizure frequency; number of seizure types; occurrence and duration of status epilepticus; number of anticonvulsant medications used; response to treatment. The variables were given a score, usually from 0 to 3, a higher score indicating greater severity. For each child, these variables were scored over consecutive 1 year time periods by three independent raters. We employed restricted and nonrestricted factor analytic models to identify the latent structure of the six items.
The six severity items had a unidimensional structure. All severity indicators loaded highly on the latent epilepsy severity factor (>0.77), with the exception of the status indicator which had a poor loading (<0.40) and was excluded from further analyses. Goodness of fit indices were all well within the acceptable criteria for model fit. The E-Chess score at 12 months was significantly predictive of scores at 24 and 36 months.
A single continuous latent variable accounts for the variation in five of the six epilepsy severity indicators under study. These form the Early Childhood Epilepsy Severity Scale. The predictive validity of the E-Chess was satisfactory. The E-Chess provides an epilepsy severity score that can be easily used to assess epilepsy severity in tuberous sclerosis and would merit evaluation in other early onset childhood epilepsies.
Epilepsy Research 05/2008; 79(2-3):139-45. · 2.29 Impact Factor
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ABSTRACT: X-linked ichthyosis (XLI) (steroid sulfatase deficiency) is caused by deletions or point mutations of the steroid sulfatase (STS) gene on chromosome Xp22.32. Deletions of this region can be associated with cognitive behavioural difficulties including autism. Animal work suggests the STS gene may be involved in attentional processes. We have therefore undertaken a systematic study of autism and attention deficit hyperactivity disorder (ADHD) in boys with XLI.
Cases of XLI were recruited from families originally ascertained when pregnancies with STS deficiency were identified through a routine maternal screening programme. Boys with XLI were assessed for ADHD and autism using standardised questionnaires and interviews. Deletions of the STS gene were identified and characterised by analysis of genomic DNA and/or fluorescent in situ hybridisation.
25 boys with XLI were assessed for autism and ADHD. 40% fulfilled DSM-IV criteria for a diagnosis of ADHD, 80% of which were inattentive subtype. ADHD diagnoses were present in those with both deletions and presumed point mutations of STS. Additionally, five boys, from three unrelated families, fulfilled criteria for an autistic spectrum disorder or related language/communication difficulty, and all had an unusually large deletion of the STS gene with loss of the neuroligin 4 (NLGN4) gene. None of the boys with the typical deletion or presumed point mutations of STS demonstrated autistic difficulties.
STS deficiency may be a risk factor for ADHD with predominantly inattentive symptoms. Boys with XLI and large deletions encompassing STS and NLGN4 are at increased risk of developing autism and related disorders.
Journal of Medical Genetics 05/2008; 45(8):519-24. · 6.36 Impact Factor
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ABSTRACT: Intellectual disability (ID) is highly prevalent in tuberous sclerosis (TS). Putative neurobiological risk factors include indices of cortical tuber (CT) load and epilepsy. We have used univariate and multivariate analyses, including both CT and epilepsy measures as predictors, in an attempt to clarify the pattern of cross-sectional associations between these variables and ID in TS.
Forty-eight children, adolescents and young adults with TS were identified through regional specialist clinics. All subjects underwent thorough history taking and examination, and had brain magnetic resonance imaging (MRI) scans. The number and regional distribution of CTs was recorded. Subjects were assigned to one of nine ordered intellectual quotient (IQ) categories (range 130) using age-appropriate tests of intelligence.
On univariate analyses, ID was significantly associated with both a history of infantile spasm (IS) (Z=-2.49, p=0.01) and total CT count (Spearman's rho=-0.30, p=0.04). When controlling for total CT count, the presence of CTs in frontal (regression coefficient=-2.43, p=0.02) and temporal (regression coefficient=-1.60, p=0.02) lobes was significantly associated with ID. In multivariate analyses the association between IS and ID was rendered insignificant by the inclusion of the presence of CTs in temporal and frontal lobes, both of which remained associated (p=0.05 and p=0.06 respectively) with ID.
The presence of CTs in specific brain regions as opposed to a history of IS was associated with ID in TS. The significance of these findings is discussed in relation to previous work in TS, and the neural basis of intelligence.
Psychological Medicine 10/2007; 37(9):1293-304. · 6.16 Impact Factor
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John R W Yates,
Tiina Sepp,
Baljinder K Matharu,
Jane C Khan,
Deborah A Thurlby,
Humma Shahid,
David G Clayton,
Caroline Hayward,
Joanne Morgan,
Alan F Wright,
Ana Maria Armbrecht,
Baljean Dhillon,
Ian J Deary,
Elizabeth Redmond,
Alan C Bird,
Anthony T Moore
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ABSTRACT: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis.
We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls.
The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9x10(-5)) and the Scottish group (244 cases and 351 controls, P=5.0x10(-5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%.
Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease.
New England Journal of Medicine 09/2007; 357(6):553-61. · 53.30 Impact Factor
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John R W Yates
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ABSTRACT: Tuberous sclerosis is a serious inherited disease which poses major challenges for affected families and those caring for them. Identification of the genes causing the condition and study of their protein products has shed light on the pathogenesis of the disease and provided valuable new information about signalling pathways regulating protein synthesis and cell growth. There is now the exciting possibility of drug therapy for some of the manifestations of the disease.
European Journal of HumanGenetics 11/2006; 14(10):1065-73. · 4.40 Impact Factor
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ABSTRACT: The complement factor H (CFH) gene polymorphism Y402H (1277T-->C) has been associated with susceptibility to age-related macular degeneration (AMD). The purpose of this study was to confirm this association in a U.K. population, to determine whether the association holds for both geographic atrophy (GA) and choroidal neovascularization (CNV), and to investigate interactions with smoking.
A case-control study was undertaken in 443 cases of AMD, with 262 spouses as control subjects. All subjects completed a health and lifestyle questionnaire, had an ophthalmic assessment with fundus photography, and were genotyped.
The frequencies of the C allele and CC genotype were significantly higher in cases than in controls. In comparison to the TT genotype, the odds ratios for AMD associated with the CT and CC genotypes were 3.1 (CI 2.0-4.6) and 6.3 (CI 3.8-10.4), respectively. The results were similar in subgroup analyses confined to cases with GA or CNV. The findings were also similar for subgroup analyses restricted to subjects who had never smoked, moderate smokers, or heavier smokers (>20 pack years of smoking). Heavier smokers with the CC genotype may be particularly at risk. The frequency of the CC genotype did not differ significantly between cases with and without a family history of AMD. There was no evidence that genotype had any influence on age at onset of disease.
The CFH Y402H variant is strongly associated with both GA and CNV in the U.K. population. This association is similar in smokers and nonsmokers. Heavier smokers with the CC genotype may be at particular risk.
Investigative Ophthalmology & Visual Science 02/2006; 47(2):536-40. · 3.60 Impact Factor
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ABSTRACT: A pair of monozygotic male twins with tuberous sclerosis (TS) were followed between 18 months and 3 years of age. Twin A with 25 large cortical tubers and hence extensive brain involvement was moderately mentally retarded and met criteria for autism. The other twin had more (n = 31) but smaller tubers. He was not mentally retarded and did not meet criteria for autism. This study provides evidence that nongenetic factors such as extent of brain abnormality and not just number of cortical tubers are important in determining phenotypic variability in TS. The findings also raise questions about the mechanisms giving rise to autism in TS.
Neurology 04/2004; 62(5):795-8. · 8.31 Impact Factor
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ABSTRACT: Many mRNAs carrying mutations that are predicted to encode a truncated protein are subject to a mechanism known as nonsense-mediated mRNA decay (NMD), which results in reduced levels of mutant transcript. Tuberous sclerosis (TSC), an autosomal dominant neurocutaneous disorder with mutations in either of two genes, TSC1 or TSC2, requires comprehensive screening of both genes for molecular diagnosis. Virtually all TSC1 mutations are predicted to truncate the protein product. Coding and newly identified 3' untranslated region polymorphisms in TSC1 were used to develop a transcript imbalance assay to investigate TSC1 transcript levels in patients. This approach allowed the correct identification of six out of seven TSC1 patients tested blind from a panel of TSC1 and TSC2 patients, with no false positives. The extent of NMD in TSC1 was found to correlate with each individual mutation regardless of intra-familial variation in clinical features and with no strong evidence for positional bias. NMD in TSC1 was more pronounced in cultured cells than in RNA prepared directly from peripheral lymphocytes (in which novel splicing of exon 5 was observed). The advent of a dense SNP map of transcribed regions of the genome may allow a similar transcript imbalance assay in the assessment of candidate genes for diseases whose causes are still unknown.
Human Genetics 01/2003; 111(6):555-65. · 5.07 Impact Factor
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ABSTRACT: Tuberous sclerosis (TSC) is an autosomal dominant condition characterised by tumour-like malformations (hamartomas) in the brain and other organs. A proportion of hamartomas from patients with TSC show loss of heterozygosity (LOH) for DNA markers in the region of either the TSCI gene on chromosome 9834 or the TSC2 gene on 16p13.3. This implies that these lesions are clonal. We have studied X-chromosome inactivation, as a marker of clonality, in 13 hamartomas from females with TSC. The hamartomas comprised five renal angiomyolipomas, three fibromas and seven other lesions. In previous studies, four of the lesions showed LOH. A polymerase chain reaction assay was used to analyse differential methylation of anHpalI restriction site adjacent to the androgen-receptor triplet-repeat polymorphism on Xg11-12. In 12 of the lesions, there was a skewed inactivation pattern with one X chromosome being fully methylated and the other unmethylated. Normal tissue showed a random pattern of inactivation. These data confirm that most TSC hamartomas are clonal in origin. This is an intriguing finding, since these lesions are composed of more than one cell type.
Human Genetics 01/1996; 97(2):240-243. · 5.07 Impact Factor
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ABSTRACT: The term Charles Bonnet syndrome (CBS) is used to describe visual hallucinations resulting from ocular pathology. As part of a larger case-control study we assessed factors which may predispose to this phenomenon in Age-related macular degeneration (AMD).
Three-hundred and sixty cases of late AMD underwent a detailed questionnaire about visual symptoms experienced. Potential ocular and environmental risk factors were compared in two groups; those experiencing symptoms of CBS (n = 97) and those not experiencing CBS symptoms (n = 263).
Twenty-seven percent experienced CBS. Poor visual acuity was the only factor associated with the development of these images in AMD with an odds ratio of 3.50 (95% CI 1.64-7.48, p = 0.001) for those with best binocular visual acuity worse than 6/36. In those who experienced CBS, the images tended to be straight ahead (84.5%), colored (72.2%), have moving parts (62.9%), and occur on average once per day (34%). The most common visual image was of people (19.6%) followed by geometric patterns (15.8%). The majority (71.1%) felt the experience to be neither pleasant nor unpleasant. In 41% images were present throughout the course of their disease. There was no association between visual acuity and complexity of images.
The prevalence of CBS in late AMD is high, the main risk factor being poor better eye visual acuity. The most commonly experienced hallucinations were of people. Although most patients were unperturbed by the images, reassurance of their benign nature was welcomed. Practitioners should be aware that resolution of symptoms over time does not always occur.
Ophthalmic epidemiology 15(3):202-8. · 1.93 Impact Factor
