A repeat expansion in GOLGA8A is a major risk factor for atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions.
De Coster W., Van den Broeck M., Baker M., Ghayal NB., Wynants S., Batzler A., Pottier C., Alidadiani S., Küçükali F., Jenkins GD., Policarpo R., van Blitterswijk M., DeJesus-Hernandez M., Soto-Beasley AI., Faura J., Coopman E., Hutten S., Mol MO., Wallon D., Sieben A., Finger EC., Murray ME., Forrest SL., Tartaglia MC., Troakes C., van Rooij JGJ., Nguyen AT., Reichard RR., Woodman NL., Nana AL., Weintraub S., Gefen T., De Vil B., Bodi I., Lopez OL., Boluda S., Belliard S., Lebert F., Marguet F., Mao Q., Mesulam MM., Boxer AL., Vandenbulcke M., Suh E., Schaeverbeke J., Lambert J-C., Scholz SW., Dalgard CL., Traynor BJ., Gibbs RJ., Schellenberg GD., Dormann D., Joris G., De Pooter T., De Rijk P., D'Hert S., Van Dongen J., van der Zee J., Strazisar M., Gearing M., Kukar T., Flanagan M., Engelborghs S., Ghetti B., Newell KL., King A., Roeber S., Rosen HJ., Spina S., Cras P., Ertekin-Taner N., Wszolek ZK., Uitti RJ., Cheshire WP., Singer W., Herms J., Josephs KA., Whitwell JL., Petersen RC., Pasquier F., Nicolas G., Castellani R., Glass J., Miller BL., Kovacs GG., Rissman RA., Hiniker A., Deramecourt V., Ang L-C., Lee-Way J., Van Deerlin VM., Dugger BN., Thal DR., Grinberg LT., Cruchaga C., Arzberger T., Munoz DG., Keith J., Zinman L., Rogaeva E., Lee EB., Haggarty SJ., Ansorge O., Husain M., Halliday GM., Al-Sarraj S., Ross OA., Sleegers K., Vandenberghe R., Boeve BF., Graff-Radford NR., Kofler J., White CL., Lashley T., Neumann M., Biernacka JM., Seeley WW., Seelaar H., van Swieten JC., Rohrer JD., Dickson DW., Mackenzie IRA., Rademakers R.
Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is neuropathologically characterized by aggregation of the FET family of proteins and clinically manifests as sporadic young-onset frontotemporal dementia. Here we describe a major risk locus on chr15q14 identified through a genome-wide association study in 59 pathologically confirmed aFTLD-U cases and 3,153 controls (lead single nucleotide polymorphism rs549846383, P = 5.85 × 10-21, odds ratio 26.7). When combined with data from 28 additional aFTLD-U cases, 3,712 controls and 3,215 individuals with other neurodegenerative diseases and by leveraging in-house and public long-read genome sequencing data from 1,715 individuals, we identified a tandem repeat expansion on the associated haplotypes in an intron of GOLGA8A. We found variation in repeat length, motif length, and motif sequence, with long CT-dimer expansions strongly associated with aFTLD-U. Although the functional consequence of this repeat remains unknown, its presence in nearly 60% of aFTLD-U cases points to a fundamental role in disease pathogenesis.