Trawling for AD Genes Nets New SNPs on Chromosomes X and 12

In the genetics of late-onset Alzheimer disease, ApoE is the big fish, accounting for much of a person’s risk of developing the condition. But there are plenty of little fish in the sea, too, and scientists are casting genomewide nets to catch those other AD genes. This month two groups report genomewide association screens (GWAS) that picked up single nucleotide polymorphisms (SNPs), on chromosomes 12 and X, that increase risk of AD.

First author Gary Beecham, working with principal investigator Margaret Pericak-Vance at the Miami Institute for Human Genomics in Florida, analyzed approximately 530,000 SNPs in nearly 1,000 people to fish out the chromosome 12 connection. The work is published in the January issue of the American Journal of Human Genetics.

Writing in Nature Genetics, in a paper posted online today, first author Minerva Carrasquillo and principal investigator Steven Younkin at the Mayo Clinic in Jacksonville, Florida, netted the first sex-linked gene associated with AD. They analyzed more than 300,000 SNPs in more than 2,000 individual genomes. Dennis Dickson, also at the Florida clinic, and Neill Graff-Radford, Ronald Petersen, and statistician Shane Pankratz, all of the Mayo Clinic in Rochester, Minnesota, also contributed to the research.

The beautiful thing about these studies is they’re unbiased; you don’t pick the genes in advance, said Rudy Tanzi of Harvard Medical School in Boston, Massachusetts, who was not involved with either paper. Combining the results of the current research with data from previous and future GWAS, scientists hope to assemble a picture of genetic risk for AD. The geneticists then hand that information off to the molecular and cellular biologists, who can sort through the chemical pathways and eventually develop treatments, Tanzi said.

Beecham’s screen had several hits, although the chromosome 12 SNP was the only one (besides ApoE) to pass the most stringent statistical tests. The 12q13 locus is not in a known gene, and resides in a poorly characterized genetic neighborhood, Beecham said. The hypothetical gene FAM113B, a vitamin D receptor gene (VDR), and the code for the adhesion molecule AMIGO 2, are found nearby. VDR has been linked to memory performance, making it an appealing candidate gene for AD risk (Przybelski et al., 2007). Loci on chromosomes 1, 4, 6, and 19 also associated with AD risk, although none reached statistical significance in the current study.

In Carrasquillo’s study, the X-linked gene was the strongest of several potential new SNPs. The hit at locus Xq21.3 is in the protocadherin 11 gene (PCD11X), and analysis confirmed that PCD11X is almost certainly the gene with the AD risk variant, Younkin said. Not much is known about the gene. It is part of a family of cell-surface receptors, some of which may be metabolized by presenilins, Younkin said. It is not clear yet where in the gene the mutation that enhances Alzheimer risk resides.

The PCD11X AD risk variant is quite common. Among the control group of women without AD, 21 percent were homozygous for the relevant SNP; that number rose to 28 percent in women with AD. According to the study, homozygotes have a 1.75-fold risk of developing AD, compared to people who don’t carry the variant. Female hemizygotes and male hemizygotes have a 1.2-fold risk, the study found. The data do not necessarily imply, Younkin said, that women have a higher risk for AD than do men. That analysis was not part of the study.

Both groups plan further analysis to determine if SNPs that reached near-significance are truly involved in AD risk, and to further study the genes they have already identified. But the real value of GWAS is in comparing data between groups. What we’re going to do next is watch with bated breath as others look at our variant, Younkin said. Meta-analyses, such as AlzGene, bring all the data together to clarify results.

That means a new published paper is nearly as big a deal for other researchers as for authors. I got so excited when I saw [Pericak-Vance’s] paper come out, Tanzi said. He was particularly intrigued by an SNP hit, not quite statistically significant in Beecham’s analysis, in a part of chromosome 18 fingered in other GWAS. We already had a group meeting and said, we need to intensify our efforts on this gene on chromosome 18, he said.

As more and more labs cast their nets, the SNP haul will only increase. The nice thing is that we’re working together, Tanzi says. As enough people do these experiments and compare data, the list of the bona fide genes will emerge.

Beecham GW, Martin ER, Li Y-J, Slifer MA, Gilbert JR, Haines JL, Pericak-Vance MA. Genomewide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet 2009 Jan;84(1):35-43. Abstract

Carrasquillo MM, Zou F, Pankratz VS, Wilcox SL, Ma L, Walker LP, Younkin SG, Younkin CS, Younkin LH, Bisceglio GD, Ertekin-Taner N, Crook JE, Dickson DW, Petersen RC, Graff-Radford NR, Younkin SG. Genetic variation in PDCH11X is associated with susceptibility to late-onset Alzheimer’s disease. Nat Genet 2009 AOP 11 Jan 2009 doi:10.1038/ng.305.

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