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Fine-scale linkage disequilibrium mapping of age-related macular degeneration in the complement factor H gene region

Sarah Ennis¹, Srini Goverdhan², Angela Cree², Josephine Hoh⁴, Andrew Collins¹ and Andrew Lotery³

¹ Genetic Epidemiology and Bioinformatics Group, Human Genetics Division (MP 808), Southampton General Hospital, Southampton, UK
² Clinical Neurosciences Division (MP 806), Southampton General Hospital, Southampton, UK
³ Southampton Eye Unit, Southampton General Hospital, Southampton, UK
⁴ Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, USA

Correspondence to:
Correspondence to:
A Lotery
Clinical Neurosciences, Mailpoint 806, Southampton General Hospital, Southampton SO16 6YD, UK; a.j.lotery{at}soton.ac.uk

Aim: To present results from a nested association study of the complement factor H (CFH) gene region using a novel methodology that uses a high-resolution genetic linkage disequilibrium map to estimate a point location for a causal mutation.

Method: Age-related macular degeneration (AMD) case–control data from a genomewide single-nucleotide polymorphism (SNP) panel were used to identify the target interval to be genotyped at higher density in a second independent panel. The pattern of linkage disequilibrium (LD) and segmental duplications across this region are described in detail.

Result: Data were consistent with other studies in that strong association between the Y402H variant and AMD is observed. However, composite likelihood analysis, which combines association data from all SNPs in the region, and uses genetic locations on a high-resolution LD map, gave a point location for a causal variant between exons 1 and 2 of the CFH gene.

Conclusion: The findings are consistent with evidence that, in addition to the widely described Y402H variant, there is at least one and, most probably, several other mutations in the CFH gene which determine disease manifestation in AMD. A genetic model in which multiple mutations contribute to a varying degree to disease aetiology has been previously well described in ophthalmic genetics, and is typified by the COL2A1 and ABCA4 genes.

Abbreviations: AMD, age-related macular degeneration; CEU, Caucasian; CFH, complement factor H; HapMap, haplotype map of the human genome; LD, linkage disequilibrium; LDU, linkage disequilibrium unit; SNP, single-nucleotide polymorphism

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