Gene variants that double Alzheimer's risk identified

Researchers have identified variations in a gene that double a person's risk of developing Alzheimer's disease later in life.
A team led by researchers at Washington University School of Medicine in St Louis identified the variations, found in a gene never before linked to Alzheimer's.
"We were very excited to be able to identify a gene that contains some of these rare variants," said lead author Carlos Cruchaga, an assistant professor in the Department of Psychiatry.
"And we were surprised to find that the effect of the gene was so large. After adjusting for other factors that can influence risk for the disease, we found that people with certain gene variants were twice as likely as those who didn't have the variants to develop Alzheimer's," Cruchaga said.

As in many genetic studies of Alzheimer's, Cruchaga and his co-investigators analysed DNA from people in families in which multiple members were affected by the disease.
"That allowed us to identify several families affected by the common mutations in genes we already knew about," Cruchaga explained.

"We removed those families from the dataset and focused our efforts on other families that were affected by Alzheimer's disease but did not have any known genetic variants that had been linked to the disease," Cruchaga said.
They sequenced all the protein-coding genes from several individuals in each of the 14 families, using a technique called whole exome sequencing. Some of these family members had an Alzheimer's diagnosis but others did not.

The investigators compared DNA from affected individuals in a family to those in the same family who didn't have the disorder.
Eventually, they identified two families that carried the same variation in the phospholipase-D 3 gene (PLD3). The variation was present in affected family members but not in the elderly family members who did not have Alzheimer's disease.
"We then studied another 11,000 other people with and without the disease and found that a PLD3 gene variant doubled the risk for Alzheimer's disease," said Cruchaga.
"This PLD3 variant, like the recently identified rare variant in the TREM2 gene, appears to confer more risk for Alzheimer's disease than other genes identified by the latest genome-wide association studies," Cruchaga said.

After the initial exome sequencing, researchers used more detailed sequencing to look closely at the PLD3 gene in another 4,000 people of the same age, some of whom had Alzheimer's disease.
This experiment helped them identify additional variants in the gene that increased risk for Alzheimer's, indicating that the PLD3 gene clearly had a role in the development of late-onset Alzheimer's disease.
The study is published in the journal Nature.