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GWAS Reveals New Risk Locus for Late-Onset Alzheimer's

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a paper appearing online last night in PLoS Genetics, American researchers reported that they have tracked a new genetic locus associated with late-onset Alzheimer's disease.

"By applying the new tools of genomics we are now making rapid progress in finding out what genetic changes are involved in Alzheimer disease," co-senior author Jonathan Haines, director of Vanderbilt University's Center for Human Genetics, said in a statement.

Through genome-wide association and validation studies involving nearly 2,300 individuals with late-onset Alzheimer's disease and more than 3,100 healthy controls, the team verified known associations between late-onset Alzheimer's and variants affecting the APOE gene — and turned up previously undetected ties to SNPs on chromosome 6.

These newly detected variants fall in and around a gene called MTHFD1L, the team noted, which may, in turn, affect levels of homocysteine — an amino acid implicated in Alzheimer's and other diseases.

Several past studies have linked late-onset Alzheimer's disease to changes to the APOE gene, the researchers explained. But despite the apparent heritability of the condition, they added, relatively few other variants have been consistently linked to Alzheimer's disease diagnosed in individuals who are 65 years old or older.

In an effort to find additional late-onset Alzheimer's-related variants, the researchers first brought together data at nearly half a million SNPs for 931 individuals with late-onset Alzheimer's disease and 1,104 cognitively healthy controls who had been genotyped using Illumina arrays. The average age for both the cases and controls was roughly 74 years old.

Along with associations between late-onset Alzheimer's and variants in APOE, the team detected a significant association between late-onset Alzheimer's disease and a chromosome 6 SNP in MTHFD1L, a gene coding for an enzyme producing an intermediate in the conversion of homocysteine to methionine.

The group's subsequent analyses turned up additional SNPs in and around MTHFD1L that were in linkage disequilibrium with the original SNP. Meanwhile, a validation study involving 1,338 cases and 2,003 controls confirmed the link between late-Alzheimer's disease and SNPs in the chromosome 6 locus.

As such, the team explained, the findings provide a potential link between genetic risk of Alzheimer's, homocysteine levels, and vascular changes that may contribute to possible Alzheimer's related brain changes, since homocysteine has linked to Alzheimer's disease and neurological conditions as well as heart disease, pre-eclampsia, and complications occurring in diabetes.

"Identifying this gene is important because the gene is known to be involved in influencing the body's levels of homocysteine, and high levels of homocysteine are a strong risk factor for late-onset Alzheimer's disease," co-senior author Margaret Pericak-Vance, director of the University of Miami's John P. Hussman Institute for Human Genomics, said in a statement.

"Since the function of blood vessels in the brain may affect Alzheimer's disease, this finding may also help us understand how homocysteine levels and blood vessel function in the brain affect Alzheimer's disease," she added.

Moreover, since environmental factors and lifestyle also seem to contribute to homocysteine levels, co-senior author Joseph Buxbaum, a genetics, genomics, and neuroscience researcher at Mount Sinai School of Medicine in New York, noted, the current findings might ultimately lead to a better understanding of the genetic and environmental interplay in Alzheimer's.

"We know of environmental and lifestyle factors that can impact homocysteine levels, and it will be important to understand whether variations of the MTHFD1L gene can modulate these effects," Buxbaum said in a statement.

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