A chromosome 6 locus variant may tie genetics with an important biological pathway in dementia.
TORONTO—A statistically significant association between a genetic variant involved in folate pathways and late-onset Alzheimer’s disease has been found, according to results from a genome-wide association study (GWAS) reported at the 62nd Annual Meeting of the American Academy of Neurology.
In a trial of 2,269 patients with late-onset Alzheimer’s disease and 3,107 controls, Margaret Pericak-Vance, PhD, and colleagues identified a variation in a gene on chromosome 6 encoding the methylenetetrahydrofolate dehydrogenase 1-like protein (MTHFD1L), which may as much as double a person’ risk of disease. Dr. Pericak-Vance, the study’s principal investigator, is the Dr. John T. Macdonald Professor of Human Genomics and Director of the John P. Hussman Institute for Human Genomics (HIHG) at the University of Miami Miller School of Medicine.
According to the investigators, the association with MTHFD1L is noteworthy, because the gene is known to be involved in mitochondrial tetrahydrofolate synthesis and may play a role in the generation of methionine from homocysteine. It may also influence other homocysteine-related pathways, a key finding since high homocysteine levels are a known risk factor for the disease.
The gene variant, which may contribute up to 5% of the overall risk of the disease, is an interesting finding among a spate of recent discoveries in Alzheimer’s disease genetics, including the identification of candidate genes CLU and PICALM, because the biological connection between homocysteine levels and dementia still remains unclear, noted Dr. Pericak-Vance.
“There has been significant literature in the past decade about the potential role of homocysteine in dementia,” she explained. “We now have a gene that may tie genetics to the biology—and that is very exciting.”
Identified and Replicated
The study combined data on 483,399 single nucleotide polymorphisms (SNPs) from an earlier GWAS of 492 subjects with late-onset Alzheimer’s disease and 496 controls and an additional 439 cases and 608 controls to strengthen statistical power to detect true genetic associations. The results were then replicated in an additional 1,338 cases and 2,003 controls. The study cohort comprised Caucasians mostly from the southeastern United States.
“As expected, these analyses unequivocally confirmed APOE’s risk effect,” the researchers reported. “Additionally, the SNP rs11754661 at 151.2Mb of chromosome 6q25.1 in the gene MTHFD1L was significantly associated with late-onset Alzheimer’s disease. Subsequent genotyping of SNPs in high LD with rs11754661 in this case-control set identified statistically significant associations in multiple SNPs, reducing the likelihood of association due to genotyping error.”
Significant Risk, But Rare
Odds of an individual with the MTHFD1L variant developing late-onset Alzheimer’s disease are 2-to-1. Although the gene variant met genome-wide statistical significance, which is the bar researchers use in this type of study, the gene occurs only in a very small percentage of people.
“The variant itself is not very frequent. It’s present in maybe 5% of the population,” said lead author Adam Naj, PhD, also of HIHG. “In our study it was present in about 7% of individuals, but it is more common in those with the disease than in those without. In our study, it was about 9% in cases and 5% in controls.”
However, the researchers noted that their study population has a large subset of individuals of Askenazi Jewish descent, which may have skewed the results to include a greater percentage of individuals with the variant gene, even with steps taken to minimize the effects of combining subsets.
“I think in our study, we are looking at an overestimate, and as we do more studies it may be found to have a more modest effect,” Dr. Pericak-Vance said.
Tying Genetics to Biology
Typically in genetic studies, researchers find genetic variants through epidemiologic studies and then try to determine what role they play in the disease. This study is different in that researchers found a gene with a known function that may tie into dementia, but need to further determine how that function affects the disease. Although the practical applications of this study are still in the future, the researchers hope that in time, genetic findings such as MTHFD1L may play a role in disease diagnosis and pharmaceutical development.
“[This finding] may reinforce that homocysteine levels do play a role in Alzheimer’s disease, although follow-up work is needed to determine if this variation is in any way associated with variations in homocysteine levels,” Dr. Naj pointed out. “Additional confirmation studies need to be done to come up with a more accurate estimate of risk from this variant and then functional genomic studies to see how this variant may change the role of this gene in the folate pathways.”