I'm dreaming of a white (matter) Christmas

In the almost 20 years since the discovery of the ApoE4 allele’s association with increased risk for late-onset Alzheimer’s disease, not a single additional SNP was discovered with a comparably strong effect … until this year. And the SNP discovered has interesting implications not only for Alzheimer’s but for how it bolsters a theory about diseases in general.

Publishing back to back in the November issue of NEJM (PMID 23150908, PMID 23150934), both the deCODE and Alzheimer Genetic Analysis Group teams found that a single copy of rs75932628(T), a SNP in the TREM2 gene, increases risk for Alzheimer’s about three-fold. This is comparable to the increased risk associated with an APOE4 allele. But it has a frequency of under 1%, too low to have been used or detected in most genome wide association (GWAS) studies, unlike the APOE4 allele’s frequency of about 15%.

The TREM2 gene encodes a protein known as “triggering receptor expressed on myeloid cells 2”, involved in microglial activity and inflammation. The rs75932638(T) allele somehow leads to reduced TREM2 activity, apparently reducing the microglial-cell based removal of beta amyloid. In addition to the quest for drugs that will reduce amyloid deposition directly, there’s now likely to be more support for drugs stimulating TREM2 activity as well as other molecules of the inflammatory cascade with roles in amyloid clearance (PMID:23237888).

It also turns out that homozygous recessive loss-of-function mutations in TREM2 have previously been associated with Nasu-Hakola disease, a very rare disorder involving early-onset dementia and bone fractures. The addition of another example where inheriting two loss-of-function mutations leads to a severe, early-onset disease, while inheriting only one leads to the late-onset of an apparently different disease, was noted by both sets of authors. It may well be that inheriting single loss-of-function SNPs will be the most common underlying risk factors for late-onset diseases (PMID 20813421).

Exome and genome sequencing are proving effective at uncovering these moderate risk, low frequency variants. In 2013 (and beyond) we hope to see more studies of late-onset diseases in the heterozygous relatives of children diagnosed with loss-of-function homozygous recessive diseases.