Genomic Dragnet Finds Clues to Likely Suspects in Alzheimer’s

First Family-Based Study of its Kind Taps Large NIMH Sample

November 6, 2008 • Science Update

Gene Chip

In the first study of its kind, researchers have pinpointed four genes likely associated with risk for the most common, late-onset form of Alzheimer’s disease, including a very strong candidate on chromosome 14. NIMH grantee Rudolph Tanzi, Ph.D., of Massachusetts General Hospital and Harvard University, and colleagues report on their findings in the November issue of the American Journal of Human Genetics.

Background

Until now, only one gene variant, ApoE-4, has been implicated in such late-onset Alzheimer’s disease. Its involvement was also confirmed in the new study. Yet this variant, and three others implicated in early-onset Alzheimer’s, account for only 30% of the genetic risk for the disorder, which is up to 80 percent heritable. To find clues to other susceptibility genes, the researchers performed the first Alzheimer’s disease family-based genome-wide association study . They used about half a million markers to search samples from 410 families in the largest uniformly-assessed group of Alzheimer’s pedigrees to date, the NIMH Genetics Initiative sample.

Results of This Study

The study turned up four new suspect genomic locations which were further tested in three additional independent samples totaling nearly 900 affected families. A still unknown gene traced to a location on chromosome 14 emerged as the strongest candidate. The three weaker association signals were in known genes previously linked to response to bacterial infections, communications between neurons, and another neurodegenerative disorder called spinocerebellar ataxia 1 .

Like Alzheimer’s-affected families with ApoE-4, those that harbored the chromosome 14 hotspot tended to have affected members who developed symptoms under age 65 – called “early/mixed onset.” This had been hinted at in earlier studies by Tanzi and colleagues. One of the weaker signals also was associated with this somewhat younger age of onset. The findings, based on analysis of 5,476 samples overall, apply only to Caucasian families.

Significance

While the researchers don’t yet know the identity of the suspected gene variant on Chromosome 14 or what its function might be, the evidence “strongly implies” that it increases Alzheimer’s susceptibility. By suggesting possible connections to specific functions or other disease processes, the three other genes that significantly increase risk help to focus the search for causes of the disorder.

What’s Next?

The researchers recommend follow-up studies in additional independent samples and efforts to link the suspect genomic locations to specific functions.

Reference

Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, Divito J, Ionita I, Jiang H, Laird N, Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE.  Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOE. Am J Hum Genet. 2008 Oct 29. [Epub ahead of print] PMID: 18976728