A meta-analysis of four large Alzheimer’s genome-wide association studies has doubled the number of genetic loci strongly linked to the disease. The findings were previously reported at the Alzheimer’s Association International Conference, held July 13–18 in Boston (see ARF related news story), and are now formally published in the October 27 Nature Genetics. Hundreds of researchers in the International Genomics of Alzheimer’s Project (IGAP) collaborated on the study, which turned up 11 new loci associated with AD risk. The study also confirmed nine previous GWAS hits, failing to replicate only CD33 among the AlzGene Top Results.

Although the GWAS results pinpoint regions of the genome associated with AD, researchers still need to identify the genetic variants in those regions that actually cause disease. Candidate genes near the susceptibility loci participate in many pathways previously implicated in Alzheimer’s, including cholesterol metabolism, intracellular trafficking, and immunity. The findings may help point to new therapeutic targets, said author Julie Williams at Cardiff University, U.K.

GWAS typically find common variants with small effects. The new loci contribute slightly less risk than previous GWAS hits BIN1, CLU, and PICALM. For those genes, the percentage of disease in the population estimated to be due to each runs between 5 and 8 percent. For the new genes, the population-attributable fractions are mostly between 2 and 5 percent. To find rare variants with larger effects, like the recently identified one in the immune receptor TREM2 (see ARF related news story), researchers need to look at families with earlier-onset sporadic AD, Williams said.—Madolyn Bowman Rogers.
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References

News Citations

  1. Pooled GWAS Reveals New Alzheimer’s Genes and Pathways
  2. Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk

Paper Citations

  1. . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013 Dec;45(12):1452-8. PubMed.

External Citations

  1. CD33
  2. AlzGene Top Results

Further Reading

News

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  3. AD GWAS in African Americans Confirms, Reshuffles AlzGene List
  4. Protective Microglial Gene Variant Promotes Phagocytosis
  5. RNA Sequencing Helps Identify Functional Variants from GWAS
  6. Vienna: New Genes, Anyone? ICAD Saves Best for Last
  7. Vienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits
  8. LOADing Up—Largest GWAS to Date Confirms Two, Adds Two Risk Genes
  9. Repeat Offenders—CLU, CR1, PICALM Hold Up in Association Studies
  10. Barcelona: What Lies Beyond Genomewide Association Studies?
  11. Large Genetic Analysis Pays Off With New AD Risk Genes
  12. AlzGene Reorg—"Top Results" Reduced to Elite Few
  13. Late- and Early-Onset AD—Not So Distant at Genetic Level
  14. GWAS and Anatomy—Pooled Data Finger Genes Driving Brain Size, IQ
  15. GWAS Mega-Meta Yields More Risk Genes, BIN1 Binds Tau?
  16. ENCODE Turns Human Genome From Sequence to Machine
  17. Newly Mapped DNA Elements Help Interpret GWAS
  18. Genetics Project Update: Over 1,000 Genomes and Counting
  19. Getting a CLU—Does Genetic Risk Factor Mediate Aβ Toxicity?
  20. First Plaque-Based GWAS Revives Enzyme Link