Expression predictions inform molecular interpretation of Alzheimer's disease risk loci

Abstract

Sequence models predict the molecular effects of genetic variation, yet their contribution to interpreting Alzheimers disease (AD) association signals remains uncertain. Here we analysed AlphaGenome Atlas predictions for 111,446 common variants across 75 regions from a European-ancestry genome-wide association study (GWAS) of AD and related dementias. Predicted expression effects modestly tracked association within loci (mean partial Spearman {rho} = 0.018, P = 0.003) and were higher in variants with the highest posterior inclusion probability than in correlated variants outside credible sets (mean difference, 0.044 percentile units; P = 0.005). This relationship remained after adjustment for genic position ({rho} = 0.011, P = 0.026). Predicted splicing effects also tracked association, but this relationship was attenuated after the adjustment. Expression and splicing scores were associated with the corresponding Genotype-Tissue Expression (GTEx) quantitative trait locus (QTL) status, although these analyses did not establish colocalization or agreement in allelic direction. Across 50 loci with multiple fine-mapping candidates, predicted cellular labels were no more concentrated than in position-matched comparisons, and expression direction profiles showed no detectable excess concordance with lead variants. These findings support expression predictions as complementary evidence for interpreting AD risk variants, while showing that the assignment of cellular context must account for fine-mapping uncertainty.