Melbourne School of Population and Global Health - Research Publications

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    Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer
    Tomlinson, IPM ; Carvajal-Carmona, LG ; Dobbins, SE ; Tenesa, A ; Jones, AM ; Howarth, K ; Palles, C ; Broderick, P ; Jaeger, EEM ; Farrington, S ; Lewis, A ; Prendergast, JGD ; Pittman, AM ; Theodoratou, E ; Olver, B ; Walker, M ; Penegar, S ; Barclay, E ; Whiffin, N ; Martin, L ; Ballereau, S ; Lloyd, A ; Gorman, M ; Lubbe, S ; Howie, B ; Marchini, J ; Ruiz-Ponte, C ; Fernandez-Rozadilla, C ; Castells, A ; Carracedo, A ; Castellvi-Bel, S ; Duggan, D ; Conti, D ; Cazier, J-B ; Campbell, H ; Sieber, O ; Lipton, L ; Gibbs, P ; Martin, NG ; Montgomery, GW ; Young, J ; Baird, PN ; Gallinger, S ; Newcomb, P ; Hopper, J ; Jenkins, MA ; Aaltonen, LA ; Kerr, DJ ; Cheadle, J ; Pharoah, P ; Casey, G ; Houlston, RS ; Dunlop, MG ; Gibson, G (PUBLIC LIBRARY SCIENCE, 2011-06)
    Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.
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    Can genetic associations change with age? CFH and age-related macular degeneration
    Adams, MKM ; Simpson, JA ; Richardson, AJ ; Guymer, RH ; Williamson, E ; Cantsilieris, S ; English, DR ; Aung, KZ ; Makeyeva, GA ; Giles, GG ; Hopper, J ; Robman, LD ; Baird, PN (OXFORD UNIV PRESS, 2012-12-01)
    Genetic variation in the gene encoding complement factor H (CFH) on chromosome 1q31 has repeatedly been associated with an increased risk of age-related macular degeneration (AMD); however, previous studies have had inadequate numbers of participants across a sufficiently wide age range to determine whether the association varies by age. We conducted a genetic case-control study using data from 2294 cases and 2294 controls selected from the Melbourne Collaborative Cohort Study, matched on age, sex and region of origin. Four consistently replicated CFH single-nucleotide polymorphisms (SNPs) were genotyped: rs1061170 (Y402H), rs2274700, rs393955 and rs800292; their relationship with AMD prevalence was determined across the age range 48-86. A difference in genotype frequencies was seen across age groups, where the low-risk homozygote prevalence rose with each increasing age group. Associations with early AMD were strongly modified by age for three of the four SNPs (interaction P-value: 0.01-0.00003). An inverse association between the high-risk homozygote for each SNP and early AMD was observed in the younger age groups [odds ratios (OR) range 0.37-0.48 for age <55], reversing to a positive association with increasing age (OR 1.87-2.8 for age >75). The direction of associations for this gene change was from inverse to risk with increasing age. These findings have important implications for predictive models for AMD and potentially other age-related diseases which extrapolate risks from older cohorts, as they assume homogeneity of association by age, which might not exist.
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    20/20-Alcohol and Age-related Macular Degeneration: The Melbourne Collaborative Cohort Study
    Adams, MKM ; Chong, EW ; Williamson, E ; Aung, KZ ; Makeyeva, GA ; Giles, GG ; English, DR ; Hopper, J ; Guymer, RH ; Baird, PN ; Robman, LD ; Simpson, JA (OXFORD UNIV PRESS INC, 2012-08-15)
    Little evidence exists regarding associations between age-related macular degeneration (AMD) and moderate alcohol consumption, patterns of consumption, or different types of alcoholic beverage. The authors examined associations between AMD prevalence and alcohol intake using 20,963 participants from the Melbourne Collaborative Cohort Study aged 40-69 years at baseline (1990-1994). Participants' alcohol consumption was determined from a structured interview at baseline. At follow-up from 2003 to 2007, digital macula photographs of both eyes were taken and evaluated for early and late AMD signs. Drinking more than 20 g of alcohol per day was associated with an approximate 20% increase in the odds of early AMD (odds ratio = 1.21, 95% confidence interval: 1.06, 1.38; P = 0.004) when compared with those who reported no alcohol intake at baseline, having adjusted for sex, age, smoking, country of birth, education, physical activity, and energy from food. This positive association was apparent for wine, beer, and spirits. The estimates were similar for both sexes. The odds ratio for those drinking more than 20 g of alcohol per day for late AMD was 1.44 (95% confidence interval: 0.85, 2.45; P = 0.17). These results show a modest association between alcohol consumption and increased AMD risk.