Last year, four independent research groups reported a linkage between polymorphisms in the complement factor H (CFH) gene to age-related macular degeneration (AMD), the most common cause of blindness in people over 60. One particular SNP, which changed a tyrosine (Y402) to histidine, was strongly associated with disease in all the studies.
The results seemed clear enough, but now a more extensive examination of variability in the region has yielded a different take on the genetics of AMD. In two papers in the August 27 online edition of Nature Genetics, researchers report finding additional CFH sequence variants that are even more strongly associated with the risk of AMD than the Y402H allele. One of the papers, from a group of Boston researchers led by Johanna Seddon at the Massachusetts Eye and Ear Infirmary, also confirms variants in two other genes that act additively with CFH to determine the risk of AMD in individuals.
While not directly relevant to Alzheimer disease, the findings provide a cautionary tale for researchers searching for the genetic risk factors of complex diseases like AD. Determining genetic risk is an exceedingly complicated proposition, the study indicates, and finding all the risk alleles for common diseases will likely involve a thorough analysis of hundreds or thousands of cases.
In the study from the Seddon group, first author Julian Maller worked together with Mark Daly and colleagues at the Broad Institute of Harvard and MIT to survey 1,536 SNPs over three genes in more than 2,000 people (1,238 affected individuals and 934 controls). Unexpectedly, the strongest disease association they found within the CFH gene was not the previously observed Y402H SNP, but an intronic SNP that did not affect protein sequence.
To complicate matters even more, further SNP typing by Seddon and colleagues confirmed a second AMD locus on chromosome 10, and showed that two gene variants there were strongly associated with AMD. They also found two SNPs in a second complement-related locus, this one containing the gene for complement component 1 and complement factor B (C2/CFB). The five SNPs in three genes acted in additive fashion to increase the risk of AMD from less than 1 percent in people with the lowest-risk genotypes at each SNP, to more than 50 percent for those with five risky SNPs. Mixed genotypes of high- and low-risk SNPs displayed intermediate risk, forming a gradient of risk in the population. Finally, the authors estimated that the five common variants explain half the excess risk of AMD in siblings of affected individuals.
In the second paper, from Goncalo Abecasis and Anand Swaroop of the University of Michigan at Ann Arbor, a similarly intensive survey of SNPs in the CFH gene in 762 affected people and 268 controls turned up 20 polymorphisms that showed stronger association than Y402H. In this study, led by first author Mingyao Li, no single SNP accounted for disease susceptibility, but instead they found multiple SNPs making up four common haplotypes, two associated with increased risk, and two that were protective.
In both studies, the CFH variant showing the strongest association was an SNP in a non-coding region, raising questions of what change it would cause in the carrier. One possibility is that the variants affect complement factor H gene expression. Alleles that change a gene’s expression level without altering protein structure have been implicated in several other neurodegenerative diseases, revealing an increasing role for regulatory polymorphisms (see ARF related news story).
“Our results show that dissection of complex disease susceptibility loci will be a challenging process and that identification of strongly associated alleles, even when they are protein coding, should not preclude further detailed genetic analysis,” write Abecasis and Swaroop. They call for careful studies not just of SNP association, but of regional DNA sequence and gene expression patterns to get a full understanding of the contribution of the CFH gene.
Beyond the genetics lesson, could the role of complement in AMD also have something to teach us about AD? Resulting from the loss of retinal ganglion cells required for vision, AMD is a form of neurodegeneration. A role for the complement cascade was not suspected in the disease until the genetic association was made, but since then much work has cemented the idea that the macula is destroyed by complement-stimulated inflammatory and/or angiogenic processes. Complement activation and inflammation occur in AD, possibly because of Aβ production. (For more on the AD-complement angle, see comments below by Ben Barres and Tony Wyss-Coray on the potential roles of complement in AD neuropathology.) Recently, it was found that the characteristic protein deposits (Drusen) that mark AMD contain nonfibrillar amyloid (Luibl et al., 2006), making yet another intriguing link between AMD and AD pathology.—Pat McCaffrey
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