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New Susceptibility Genes Uncovered for AD Lzheimer Disease (Ad) Is a Highly 9.00 Rs11136000 Rs1048699 Chr1 Heritable Neurological Disorder

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New Susceptibility Genes Uncovered for AD Lzheimer Disease (Ad) Is a Highly 9.00 Rs11136000 Rs1048699 Chr1 Heritable Neurological Disorder RESEARCH HIGHLIGHTS ALZHEIMER DISEASE New susceptibility genes uncovered for AD lzheimer disease (AD) is a highly 9.00 rs11136000 rs1048699 Chr1 heritable neurological disorder. 8.50 (CLU) (APOE locus) Chr2 Chr3 8.00 Nevertheless, the genetics underlying rs3851179 Chr4 A 7.50 (PICALM) late-onset AD, which accounts for most Chr5 7.00 Chr6 cases of AD, are poorly understood and 6.50 Chr7 seemingly complex. For many years, 6.00 Chr8 5.50 Chr9 Chr10 the only well-established genetic risk P 5.00 10 Chr11 factor for late-onset cases has been the 4.50 Chr12 apolipoprotein E (APOE) ε4 allele. Now, –log 4.00 Chr13 3.50 Chr14 two large-scale genome wide association 3.00 Chr15 studies, both published in Nature Genetics, 2.50 Chr16 Chr17 2.00 together report three new susceptibility Chr18 1.50 Chr19 genes for AD—CLU, CR1 and PICALM. 1.00 Chr20 Genome-wide association studies 0.50 Chr21 Chr22 examine single nucleotide polymorphisms 0.00 (SNPs) in DNA samples from many Figure 1 | Scatter plot of the data from the genome-wide association study by Williams and individuals to discover genetic variants that colleagues. The single nucleotide polymorphisms reaching genome-wide significance lie above are associated with disease. Such studies have the red line. Abbreviation: Chr, chromosome. Permission obtained from Nature Publishing Group © Harold, D. et al. Nat. Genet. 41, 1088–1093 (2009). been successful in identifying risk alleles for several genetically complex disorders, including Parkinson disease and diabetes. chromosome 11 in the vicinity of PICALM. Many researchers believe that an Several genome-wide association The associations for both these SNPs increase in the level of the 42-amino-acid studies have been conducted for AD, yet were confirmed in an independent group form of the amyloid β (Aβ) peptide—the no susceptibility genes have been firmly comprising ~2,000 patients with AD and a principal component of the neuritic established aside from APOE. The lack of similar number of aged-matched controls. plaques observed in AD—is a central event further associations might be attributable Meanwhile, investigators based mainly in in the pathogenesis of AD. The findings to limitations in study design, rather than France were conducting a similarly scaled, from several studies, most notably from the absence of other genetic risk factors. yet independent, two-stage genome-wide those using mouse models of AD, suggest “The eight studies for AD that have been association study for AD. The study, led that allelic variation at CLU, CR1 or published were too small to identify effect by Philippe Amouyel (Insitut Pasteur de APOE might affect the deposition and/or sizes of the magnitude likely to be conferred Lille), assessed 537,029 SNPs in 2,032 clearance of Aβ. PICALM encodes a protein by most susceptibility genes,” explains Julie French cases of AD and 12,062 controls. involved in clathrin-mediated endocytosis, Williams of Cardiff University, principal SNPs corresponding to two loci, APOE and and genetic variation at this locus might investigator of one of the new studies. “To CLU, reached genome-wide significance, also influence Aβ biology. Alternatively, a detect such associations, we sought to while several other SNPs approached this PICALM risk allele might exert its effect on conduct a large, powerful study.” threshold. Results from the replication synaptic transmission, a process that seems Williams and colleagues set up a two- phase of the study, conducted in 3,978 to be impaired in the early stages of AD. stage genome-wide association study, patients with AD and 3,297 controls from Both groups of researchers are looking to involving >19,000 participants from four European countries, confirmed the identify other susceptibility genes for AD, across Europe and the US. The researchers associations shown by APOE and CLU, and through involvement in further genome- assessed 529,205 autosomal SNPs for uncovered a further susceptibility gene, wide association studies and by combining association in 3,941 individuals with CR1, on chromosome 1. existing data. Amouyel’s group also intends AD and 7,848 controls. Of the six SNPs Cross-examination of the data from to study how CLU and CR1 variants might that reached genome-wide significance both studies revealed that suggestive affect disease progression. (Figure 1), four were related to the APOE evidence existed in the Williams-led Darran Yates locus, confirming the association of study for an association of CR1 with AD, Original articles Harold, D. et al. Genome-wide association this gene with AD. The two other SNPs while the results from French-based study identifies variants at CLU and PICALM associated with corresponded to two novel associations. investigation supported an association Alzheimer’s disease. Nat. Genet. 41, 1088–1093 (2009). One of the SNPs was located on for PICALM and the disease. “This Lambert, J. C. et al. Genome-wide association study chromosome 8 within an intron of CLU, significantly reinforced the validity of our identifies variants at CLU and CR1 associated with whereas the other SNP was found on findings,” notes Amouyel. Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009). NATURE REVIEWS | NEUROLOGY VOLUME 5 | NOVEMBER 2009 | 575 © 2009 Macmillan Publishers Limited. All rights reserved.
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