Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions

L.M. Reus*, I.E. Jansen, M.O. Mol, F. van Ruissen, J. van Rooij, N.M. van Schoor, N. Tesi, M.J.T. Reinders, M.A. Huisman, H. Holstege, P.J. Visser, S.C.M. de Boer, M. Hulsman, S. Ahmad, N. Amin, A.G. Uitterlinden, A. Ikram, C.M. van Duijn, H. Seelaar, I.H.G.B. RamakersF.R.J. Verhey, A. van der Lugt, J.A.H.R. Claassen, G.J. Biessels, P.P. De Deyn, P. Scheltens, W.M. van der Flier, J.C. van Swieten, Y.A.L. Pijnenburg, S.J. van der Lee

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 x 10(-9), rs117204439: OR = 4.9, P = 6.0 x 10(-9)) and replication analysis (P < 1.1 x 10(-3)). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 G(4)C(2) repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (similar to 22% versus similar to 2%; P = 7.70 x 10(-58)). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 x 10(-260)). In conclusion, the identified risk haplotype, which is carried by similar to 4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G(4)C(2). These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.
Original languageEnglish
Article number451
Number of pages8
JournalTranslational Psychiatry
Issue number1
Publication statusPublished - 2 Sept 2021


  • UNC13A
  • LOCI
  • TAU

Cite this