Tandem repeat expansions in DAPK1, ANK3, and RPL14 are associated with diverse neurodegenerative diseases

Tandem repeat expansions, a known cause of more than 50 neurological conditions, are screened here at biobank scale across 6,539 short tandem repeat loci from short-read sequencing data.

Tandem repeat expansions cause more than 50 neurological conditions, yet their contribution to neurodegenerative disease risk at population scale remains incompletely characterised. The authors performed a repeat expansion association study across 6,539 short tandem repeat loci in 276,411 UK Biobank and 44,370 All of Us participants, using two composite neurodegenerative phenotypes to increase power and capture pleiotropic effects. Meta-analysis across the two cohorts recovered associations at eight established pathogenic loci — C9orf72, DMPK, HTT, ATXN2, ATXN3, CACNA1A, CNBP and PPP2R2B — from short-read sequencing data, validating the approach at biobank scale. Three additional candidate loci emerged: an intronic AATAA expansion in DAPK1 (q = 0.0045), with fine-mapping and conditional analysis supporting the repeat as the likely underlying variant; an intronic ATTTT expansion in ANK3 (q = 0.034), observed exclusively in individuals of African and Latino/admixed American ancestry; and an exonic polyalanine expansion in RPL14 (q = 0.039), where longer alleles were consistently associated with reduced RPL14 expression across independent datasets.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The positive control is convincing: recovering C9orf72, HTT or ATXN2 from short-read data at biobank scale validates the calling pipeline before any new signal is even examined. That is not enough to make DAPK1, ANK3 or RPL14 diagnostic loci, as the composite phenotypes dilute clinical specificity and the preprint provides neither long-read confirmation nor family segregation. The most instructive result is methodological: the ANK3 signal appears only in individuals of African and Latino/admixed American ancestry, a concrete illustration of what European cohorts cannot see.

Analysis by Dr Thibaut Benquey