Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.
Johanna JakobsdottirSven J Van der LeeJoshua C BisVincent ChourakiDavid Li-KroegerShinya YamamotoMegan L GroveAdam NajMaria VronskayaJose L SalazarAnita L DeStefanoJennifer A BrodyAlbert V SmithNajaf AminRebecca SimsCarla A Ibrahim-VerbaasSeung-Hoan ChoiClaudia L SatizabalOscar L LopezAlexa BeiserM Arfan IkramMelissa E GarciaCaroline HaywardTibor V VargaSamuli RipattiPaul W FranksGöran HallmansOlov RolandssonJan-Håkon JanssonDavid J PorteousVeikko SalomaaGudny EiriksdottirKenneth M RiceHugo J BellenDaniel LevyAndre G UitterlindenValur EmilssonJerome I RotterThor Aspelundnull nullnull nullnull nullChristopher J O'DonnellAnnette L FitzpatrickLenore J LaunerAlbert HofmanLi-San WangJulie WilliamsGerard D SchellenbergEric BoerwinkleBruce M PsatySudha SeshadriJoshua M ShulmanVilmundur GudnasonCornelia M van DuijnPublished in: PLoS genetics (2016)
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.