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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