Nguyen L, Ajredini R, Guo S, Romano LE, Tomas RF, Bell LR, Ranum PT, Zu T, Bañez Coronel M, Kelley CP, Redding-Ochoa J, Nizamis E, Melloni A, Connors TR, Gaona A, Thangaraju K, Pletnikova O, Clark HB, Davidson BL, Yachnis AT, Golde TE, Lou X, Wang ET, Renton AE, Goate A, Valdmanis PN, Prokop S, Troncoso JC, Hyman BT, Ranum LP. CASP8 intronic expansion identified by poly-glycine-arginine pathology increases Alzheimer's disease risk. Proc Natl Acad Sci U S A. 2025 Feb 18;122(7):e2416885122. Epub 2025 Feb 12 PubMed.
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Institute of Neurology, UCL
To some extent, repeat expansions have been the dark matter of human disease. They are generally missed by SNP arrays and by short-read sequencing technologies and it is only with long-read sequencing we can see them and also appreciate their high mutation rates and perhaps appreciate also their roles as risk loci. What is not yet clear is what pathologies they are associated with: Is it plaque and tangle disease or (like C9orf72 and PGRN genes) is it more with TDP-43 pathology?
View all comments by John HardyVrije Universiteit Amsterdam
This study examined the relationship between short tandem repeat (STR) expansions, a frequently overlooked type of genetic variation, and the risk of AD. While one STR was significantly associated with AD risk, its association could be almost fully accounted for by the APOE-e4 genotype. This lack of single STR association is likely explained by a lack of power due to small sample size (~ 1,500 cases and 1,500 controls).
However, aggregating all STRs into a burden test yielded exciting results. Individuals with more than 30 STR expansions had more than a three-fold risk of AD. An odds ratio of this magnitude is similar to that of the largest genetic effect for late-onset AD, namely APOE4. Current odds-ratio GWAS estimates of this locus range between 2-5. Reassuringly, and in contrast to the single STR association, the authors show this STR burden effect is independent of APOE4.
It remains unclear how well common-variant, SNP-based GWASs tag STR expansions. If SNPs tag STR expansions well, then they would be unable to explain much of the missing heritability, which is part of the study's motivation. To address this, an analysis that adjusts the STR burden effect for a polygenic risk score (PRS), or an analysis that includes both scores, should be performed.
Nevertheless, this is an important study examining the association of non-SNP genetic variation with AD risk. In the future, such studies may combine several types of genetic variation (SNPs, copy number variations, STRs) across the full frequency spectrum.
View all comments by Emil UffelmannMake a Comment
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