Large AD Genetic Association Study Announced

The Wellcome Trust announced this week that it will fund what it describes as the largest ever Alzheimer’s gene study. Financed to the tune of £1.3 million (about $2.6 million) and headed by Julie Williams at Cardiff University, Wales, the study will carry out genome-wide genetic association scanning of approximately 14,000 DNA samples from healthy controls and AD patients. The analysis is expected to identify common genetic variants that increase the risk of developing Alzheimer disease. “The genotyping has already gotten underway and we expect the first results in the summer of 2008,” Williams said in an interview with ARF.

“This study is much larger than any similar study of AD to date and is definitely overdue,” Alison Goate, Washington University, St. Louis, told ARF via e-mail. Williams will initially screen 5,000 samples from the U.K.—3,000 from late-onset AD patients and the remainder from age-matched controls—using an Illumina DNA chip designed to detect over 550,000 tag SNPs identified by the human HapMap project (for more on the HapMap project, see ARF related news story). “This particular platform is estimated to cover about 92 percent of variation in human genes,” said Williams. Williams has outsourced the genotyping to a team at the Wellcome Trust Sanger Institute, U.K., led by Panos Deloukas. The Williams lab will then carry out the analysis.

Williams emphasized that the 5,000 subject samples were collected specifically with research in mind and were rigorously screened, giving a positive predictive value of over 92 percent for AD diagnosis. This was confirmed by postmortem analysis on some of the subjects. In addition, all of the initial 5,000 samples are from Caucasians in the U.K. who have U.K. or European grandparents, ensuring that the sample set is relatively homogenous when compared to some smaller studies, which drew from people with different backgrounds. Williams said that some of the current samples have been used previously for pooled genotype studies, but not individual genotype studies. “This is the first full genotyping study that will be done on these samples,” she said.

Williams also has access to a further 5,000 Caucasians drawn from the British 1958 Birth Cohort, a set of samples collected from people who were born in the same week in 1958. And following the initial phase, the findings will be further tested using a different set of samples from 5,000 screened individuals in the U.S.—approximately half with AD and the remainder controls. Goate will collaborate on this part of the study.

This appears to be one of the largest genetic association studies undertaken for Alzheimer disease. “In terms of power in one study, this is the largest I know of,” said Williams. She noted that there have been other genetic association studies, including one currently underway in an Icelandic population that uses approximately 700 AD cases and 20,000 controls. “Although there are more people in that study, the power is much lower than ours because we use 3,000 cases. You don’t really get an advantage in genotyping by increasing the number of controls,” she said.

“This study is comparable in scale to some of the successful genome-wide association studies published for other common diseases, such as type 2 diabetes, earlier this year. I am optimistic that such a large study will identify new genetic risk factors for AD,” said Goate.—Tom Fagan.

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References

News Citations

  1. Charting Genetic Diversity—First Haplotype Map Appears

External Citations

  1. Wellcome Trust
  2. British 1958 Birth Cohort

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