On 21 November, Yuriko Katsumata and colleagues published a paper in the Journal of Neuropathology and Experimental Neurology identifying a novel link between theMUC6genetic locus and late-onset Alzheimer’s disease (LOAD). Although twin studies indicate that approximately 79% of LOAD risk is due to genetic factors, common genetic risk factors such asAPOE4can only account for 20-50% of LOAD diagnoses. The ‘missing heritability’ suggests that many genetic risk factors have yet to be identified. This may in part be due to limitations with the technical approach used to identify genetic risk factors: genome-wide association studies (GWAS) use stringent statistical cut-offs that exclude risk genes with modest effects, and may also ignore genomic regions containing repeated DNA sequences.
Katsumata and colleagues therefore turned to the Alzheimer’s Disease Sequencing Project whole-exome sequencing dataset (ADSP-WES). Whole-exome sequencing (WES) more accurately genotypes rare variants and genetic insertion/deletions, overcoming some of the issues encountered with GWAS studies. First, the researchers analysed WES data from 5,412 participants with AD and 4,889 healthy individuals. Mucin 6 (MUC6), a gene which includes a region with repeated sequences, had the strongest association with LOAD status in this dataset. Next, they showed that Tau pathology in the brains of 173 autopsied individuals with LOAD was positively associated with the number ofMUC6sequence repeats identified by WES. Further studies are now required to establish whether this genetic association with LOAD is causal and, if so, what the underlying biological mechanism might be.
Link to article: https://academic.oup.com/jnen/advance-article/doi/10.1093/jnen/nlz116/5631811
