Christopher J Hammond

Publications (60) View all

• Article: Copy number variation at chromosome 5q21.2 is associated with intra-ocular pressure.

  Abhishek Nag, Cristina Venturini, Pirro G Hysi, Matthew Arno, Estibaliz Aldecoa-Otalora Astarloa, Stuart Macgregor, Alex W Hewitt, Terri L Young, Paul Mitchell, Ananth C Viswanathan, David A Mackey, Christopher J Hammond
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  ABSTRACT: PURPOSE. GLAUCOMA IS A MAJOR CAUSE OF BLINDNESS IN THE WORLD. RECENT GENOME-WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED COMMON GENETIC VARIANTS FOR GLAUCOMA, BUT STILL A SIGNIFICANT HERITABILITY GAP REMAINS. WE HYPOTHESIZED THAT COPY NUMBER VARIANTS (CNVS) MIGHT INFLUENCE PART OF THE SUSCEPTIBILITY TO GLAUCOMA OR ITS RELATED QUANTITATIVE ENDOPHENOTYPES. METHODS. THIS STUDY EXAMINED THE ASSOCIATION BETWEEN CNVS AND INTRA-OCULAR PRESSURE (IOP), THE MAJOR MODIFIABLE RISK FACTOR FOR PRIMARY OPEN ANGLE GLAUCOMA (POAG), IN THREE POPULATION PANELS OF EUROPEAN ANCESTRY: TwinsUK cohort (N=1047), Australian Twin Eye Study (N=561) and Wellcome Trust Case-Control Consortium 2 (WTCCC2) / Blue Mountains Eye Study (BMES) (N=1660). We also used PCR-based assays to investigate a locus of interest that we found associated with IOP, in a POAG case-control panel of European ancestry from London, UK. RESULTS. WE IDENTIFIED ASSOCIATIONS BETWEEN IOP AND TWO CNV REGIONS IN THE TWINSUK COHORT: 5q21.2 (p=0.003) overlapping the gene RAB9BP1 and 12p13.3 (p=0.03) overlapping the genes SLC2A14 and SLC2A3. The Australian Twin Eye Study and BMES both replicated the 5q21.2 CNV association and direction of effect (p=0.001 and p=0.02 respectively). A meta-analysis across all the cohorts showed that presence of a copy number change at this locus increased IOP by 1.56 mmHg (p=1.24 x 10-6). In the case-control study, the 5q21.2 CNV locus did not show association with high pressure (≥21 mmHg) POAG cases. Conclusions. The 5q21.2 CNV locus could represent a novel locus controlling IOP. Interestingly, this IOP locus is located in close vicinity to the previously widely replicated GLC1G linkage locus for glaucoma, for which subsequent studies have not reached consensus on the causal gene.
  Investigative ophthalmology & visual science 04/2013; · 3.43 Impact Factor
• Article: Investigation of Genetic Variation in Scavenger Receptor Class B, Member 1 (SCARB1) and Association with Serum Carotenoids.

  Gareth J McKay, Edward Loane, John M Nolan, Christopher C Patterson, Kristin J Meyers, Julie A Mares, Ekaterina Yonova-Doing, Christopher J Hammond, Stephen Beatty, Giuliana Silvestri
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  ABSTRACT: OBJECTIVE: To investigate association of scavenger receptor class B, member 1 (SCARB1) genetic variants with serum carotenoid levels of lutein (L) and zeaxanthin (Z) and macular pigment optical density (MPOD). DESIGN: A cross-sectional study of healthy adults aged 20 to 70. PARTICIPANTS: We recruited 302 participants after local advertisement. METHODS: We measured MPOD by customized heterochromatic flicker photometry. Fasting blood samples were taken for serum L and Z measurement by high-performance liquid chromatography and lipoprotein analysis by spectrophotometric assay. Forty-seven single nucleotide polymorphisms (SNPs) across SCARB1 were genotyped using Sequenom technology. Association analyses were performed using PLINK to compare allele and haplotype means, with adjustment for potential confounding and correction for multiple comparisons by permutation testing. Replication analysis was performed in the TwinsUK and Carotenoids in Age-Related Eye Disease Study (CAREDS) cohorts. MAIN OUTCOME MEASURES: Odds ratios for MPOD area, serum L and Z concentrations associated with genetic variations in SCARB1 and interactions between SCARB1 and gender. RESULTS: After multiple regression analysis with adjustment for age, body mass index, gender, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, smoking, and dietary L and Z levels, 5 SNPs were significantly associated with serum L concentration and 1 SNP with MPOD (P<0.01). Only the association between rs11057841 and serum L withstood correction for multiple comparisons by permutation testing (P<0.01) and replicated in the TwinsUK cohort (P = 0.014). Independent replication was also observed in the CAREDS cohort with rs10846744 (P = 2×10(-4)), an SNP in high linkage disequilibrium with rs11057841 (r(2) = 0.93). No interactions by gender were found. Haplotype analysis revealed no stronger association than obtained with single SNP analyses. CONCLUSIONS: Our study has identified association between rs11057841 and serum L concentration (24% increase per T allele) in healthy subjects, independent of potential confounding factors. Our data supports further evaluation of the role for SCARB1 in the transport of macular pigment and the possible modulation of age-related macular degeneration risk through combating the effects of oxidative stress within the retina. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references.
  Ophthalmology 04/2013; · 5.45 Impact Factor
• Article: Age of myopia onset in a British population-based twin cohort.

  Katie M Williams, Pirro G Hysi, Abhishek Nag, Ekaterina Yonova-Doing, Cristina Venturini, Christopher J Hammond
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  ABSTRACT: PURPOSE: School-age myopia is becoming more common in Asia and North America; data from the United Kingdom has suggested a significant amount of myopia develops after the age of 17 years. Age of spectacle wear has been used as a proxy of myopia severity in a recent large genome-wide association study. The purpose of this study was to examine the age of onset of spectacle wear in a large British twin cohort, to examine the reliability and reproducibility of self-reported age of onset as a proxy measure of myopia severity, and to see if there is evidence in the UK of a rising prevalence of myopia. METHODS: Non-cycloplegic autorefraction was performed on over 6000 subjects from the TwinsUK cohort, a large, well-characterized volunteer cohort of British, predominantly Caucasian female twins, between 1998 and 2010. Questionnaires asking age of first spectacle wear were conducted in 2003 and 2008. Myopia was defined as worse than or equal to -1.00 Dioptres, and adult onset myopia as occurring on or after the age of 17 years. RESULTS: Autorefractive data was available on 6097 participants at a mean age of 53 years. The mean S.E. was -0.36 D (S.D. 2.67, range -25.13 to +9.38). 1705 subjects (28%) were myopic with a mean refractive error of -3.54 (S.D. 2.51, range -25.13 to -1.00) and the median age of first glasses wear was 15 years (mean 18.4 years, S.D. 12.24, range 0-74). Of those who provided an age at which they first wore glasses in both questionnaire sources (n = 628), there was median difference in response of 0 years (S.D. 7.18, mean 0.7, maximum 53). A statistically significant cohort effect for increased myopia prevalence across a range of age groups between 1998-1999 and 2008-2010 was identified, with myopia prevalence increasing from 27% to 34% in those aged 50-54 and from 16% to 32% in those aged 55-59. CONCLUSIONS: Almost half the myopes in this UK-based population wore glasses after the age of 17; further research into adult-onset myopia is required. Although self-reported age of glasses is reproducible and reflects severity, it only explains approximately 15% of the variance of spherical equivalent, so is a rough proxy of refractive error, but still may be useful in large-scale population studies without access to refraction. We have demonstrated a significant cohort effect for increased myopia prevalence in the UK population over a 10-year period.
  Ophthalmic and Physiological Optics 03/2013; · 1.58 Impact Factor
• Article: Association Mapping of the High-grade Myopia MYP3 Locus Reveals Novel Candidates UHRF1BP1L, PTPRR and PPFIA2.

  Felicia Hawthorne, Sheng Feng, Ravikanth Metlapally, Yi-Ju Li, Khanh-Nhat Tran-Viet, Jeremy A Guggenheim, Francois Malecaze, Patrick Calvas, Thomas Rosenberg, David A Mackey, Cristina Venturini, Pirro G Hysi, Christopher J Hammond, Terri L Young
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  ABSTRACT: PURPOSE: Myopia, or nearsightedness, is a common ocular genetic disease for which over 20 candidate genomic loci have been identified. The high-grade myopia locus, MYP3, has been reported on chromosome 12q21-23 by four independent linkage studies. METHODS: We performed a genetic association study of the MYP3 locus in a family based high-grade myopia cohort (N=82) by genotyping 768 SNPs within the linkage region. Qualitative testing for high-grade myopia (sphere ≤-5 D affected, >-0.5 D unaffected) and quantitative testing on the average dioptric sphere were performed. RESULTS: Several genetic markers were nominally significantly associated with high-grade myopia in qualitative testing including rs3803036, a missense mutation in PTPRR (p=9.1X10-4); and rs4764971, an intronic SNP in UHRF1BP1L (p = 6.1X10-4). Quantitative testing determined statistically significant SNPs rs4764971, also found by qualitative testing (p = 3.1x10-6); rs7134216, in the 31 UTR of DEPDC4 (p = 5.4X10-7); and rs17306116, an intronic SNP within PPFIA2 (p < 9X10-4). Independently conducted whole genome expression array analyses, identified Protein tyrosine phosphatase genes PTPRR and PPFIA2, which are in the same gene family, as differentially expressed in normal rapidly growing fetal relative to normal adult ocular tissue (confirmed by RT-qPCR). CONCLUSIONS: In an independent high-grade myopia cohort, an intronic SNP in UHRF1BP1L, rs4764971, was validated for quantitative association, and SNPs within PTPRR (quantitative) and PPFIA2 (qualitative and quantitative) approached significance. Three genes identified by our association study and supported by ocular expression and/or replication, UHRF1BP1L, PTPRR, and PPFIA2, are novel candidates for myopic development within the MYP3 locus that should be further studied.
  Investigative ophthalmology & visual science 02/2013; · 3.43 Impact Factor
• Source

  Available from: Virginie Johanna Maria Verhoeven

  Dataset: Verhoeven 2013 meta-GWAS refractive error and myopia supp

  Virginie J M Verhoeven, Pirro G Hysi, Robert Wojciechowski, Qiao Fan, Jeremy A Guggenheim, René Höhn, Stuart Macgregor, Alex W Hewitt, Abhishek Nag, Ching-Yu Cheng, [......], Konrad Oexle, Norbert Pfeiffer, David A Mackey, Terri L Young, Cornelia M van Duijn, Seang-Mei Saw, Joan E Bailey-Wilson, Dwight Stambolian, Caroline C Klaver, Christopher J Hammond