Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
Jakobsdottir J., van der Lee SJ., Bis JC., Chouraki V., Li-Kroeger D., Yamamoto S., Grove ML., Naj A., Vronskaya M., Salazar JL., DeStefano AL., Brody JA., Smith AV., Amin N., Sims R., Ibrahim-Verbaas CA., Choi S-H., Satizabal CL., Lopez OL., Beiser A., Ikram MA., Garcia ME., Hayward C., Varga TV., Ripatti S., Franks PW., Hallmans G., Rolandsson O., Jansson J-H., Porteous DJ., Salomaa V., Eiriksdottir G., Rice KM., Bellen HJ., Levy D., Uitterlinden AG., Emilsson V., Rotter JI., Aspelund T., Cohorts for Heart and Aging Research in Genomic Epidemiology consortium None., Alzheimer’s Disease Genetic Consortium None., Genetic and Environmental Risk in Alzheimer’s Disease consortium None., O'Donnell CJ., Fitzpatrick AL., Launer LJ., Hofman A., Wang L-S., Williams J., Schellenberg GD., Boerwinkle E., Psaty BM., Seshadri S., Shulman JM., Gudnason V., van Duijn CM.
We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.