Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration.

Using a large sample of cases and controls from a single center, we show that a T-->C substitution in exon 9 (Y402H) of the complement factor H gene is strongly associated with susceptibility to age-related macular degeneration, the most common cause of blindness in the elderly. Frequency of the C allele was 0.61 in cases, versus 0.34 in age-matched controls (P<1x10(-24)). Genotype frequencies also differ markedly between cases and controls (chi2=112.68 [2 degrees of freedom]; P<1x10(-24)). A multiplicative model fits the data well, and we estimate the population frequency of the high-risk C allele to be 0.39 (95% confidence interval 0.36-0.42) and the genotype relative risk to be 2.44 (95% confidence interval 2.08-2.83) for TC heterozygotes and 5.93 (95% confidence interval 4.33-8.02) for CC homozygotes.

[1]  Jacqueline K. Wittke-Thompson,et al.  Rational inferences about departures from Hardy-Weinberg equilibrium. , 2005, American journal of human genetics.

[2]  J. Haines,et al.  A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy , 2002, Ophthalmic genetics.

[3]  J. Haines,et al.  Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. , 2004, American journal of human genetics.

[4]  V. Sheffield,et al.  Molecular genetics of age-related macular degeneration. , 2001, Human molecular genetics.

[5]  L. V. Johnson,et al.  Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. , 2001, Experimental eye research.

[6]  J. Ott,et al.  Complement Factor H Polymorphism in Age-Related Macular Degeneration , 2005, Science.

[7]  Association Between C-Reactive Protein and Age-Related Macular Degeneration , 2004 .

[8]  M. Smith-Wheelock,et al.  Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. , 2004, Investigative ophthalmology & visual science.

[9]  J Blangero,et al.  Large upward bias in estimation of locus-specific effects from genomewide scans. , 2001, American journal of human genetics.

[10]  D. Weeks,et al.  A full genome scan for age-related maculopathy. , 2000, Human molecular genetics.

[11]  Robert W. Massof,et al.  Racial variations in causes of vision loss in nursing homes: The Salisbury Eye Evaluation in Nursing Home Groups (SEEING) Study. , 2004, Archives of ophthalmology.

[12]  M. Klein,et al.  Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. , 2003, Human molecular genetics.

[13]  R. Allikmets,et al.  Evaluation of the ARMD1 locus on 1q25–31 in patients with age-related maculopathy: genetic variation in laminin genes and in exon 104 of HEMICENTIN-1 , 2004, Ophthalmic genetics.

[14]  Silke Schmidt,et al.  Ordered subset linkage analysis supports a susceptibility locus for age-related macular degeneration on chromosome 16p12 , 2004, BMC Genetics.

[15]  Y. Arsenijévic,et al.  Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Gilbert,et al.  Complement Factor H Variant Increases the Risk of Age-Related Macular Degeneration , 2005, Science.

[17]  E. Lander,et al.  Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease , 2003, Nature Genetics.

[18]  V. Sheffield,et al.  Missense variations in the fibulin 5 gene and age-related macular degeneration. , 2004, The New England journal of medicine.

[19]  T. Matise,et al.  Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. , 1998, Archives of ophthalmology.

[20]  G. Abecasis,et al.  Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. , 2005, Human molecular genetics.

[21]  Robert F. Mullins,et al.  An Integrated Hypothesis That Considers Drusen as Biomarkers of Immune-Mediated Processes at the RPE-Bruch's Membrane Interface in Aging and Age-Related Macular Degeneration , 2001, Progress in Retinal and Eye Research.

[22]  G. Abecasis,et al.  Age-Related Macular Degeneration: A High-Resolution Genome Scan for Susceptibility Loci in a Population Enriched for Late-Stage Disease , 2004 .

[23]  N. Risch.  Linkage strategies for genetically complex traits. I. Multilocus models. , 1990, American journal of human genetics.

[24]  Robyn H Guymer,et al.  The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. , 2004, Investigative ophthalmology & visual science.

[25]  A. Hofman,et al.  Genetic association of apolipoprotein E with age-related macular degeneration. , 1998, American journal of human genetics.

[26]  S. Russell,et al.  Drusen associated with aging and age‐related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  S. Santangelo,et al.  A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions. , 2003, American journal of human genetics.

[28]  T. Matise,et al.  Age-related macular degeneration--a genome scan in extended families. , 2003, American journal of human genetics.

[29]  P. Jong.  Prevalence of age-related macular degeneration in the United States. , 2004 .

[30]  S. Ranganathan,et al.  A common site within factor H SCR 7 responsible for binding heparin, C‐reactive protein and streptococcal M protein , 2003 .

[31]  Thomas E. Nichols,et al.  Linkage Disequilibrium: Ancient History Drives the New Genetics , 2005, Human Heredity.

[32]  Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. , 2004, American journal of human genetics.

[33]  V. Sheffield,et al.  A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy , 1999, Nature Genetics.

[34]  Michael Boehnke,et al.  Joint modeling of linkage and association: identifying SNPs responsible for a linkage signal. , 2005, American journal of human genetics.