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

Lianne M. Reus*, Iris E. Jansen, Merel O. Mol, Fred van Ruissen, Jeroen van Rooij, Natasja M. van Schoor, Niccolò Tesi, Marcel J.T. Reinders, Martijn A. Huisman, Henne Holstege, Pieter Jelle Visser, Sterre C.M. de Boer, Marc Hulsman, Shahzad Ahmad, Najaf Amin, Andre G. Uitterlinden, Arfan Ikram, Cornelia M. van Duijn, Harro Seelaar, Inez H.G.B. RamakersFrans R.J. Verhey, Aad van der Lugt, Jurgen A.H.R. Claassen, Geert Jan Biessels, Peter Paul De Deyn, Philip Scheltens, Wiesje M. van der Flier, John C. van Swieten, Yolande A.L. Pijnenburg, Sven J. van der Lee

*Corresponding author for this work

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Abstract

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 × 10−9, rs117204439: OR = 4.9, P = 6.0 × 10−9) and replication analysis (P < 1.1 × 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 G4C2 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 (~22% versus ~2%; P = 7.70 × 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 × 10−260). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G4C2. 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
JournalTranslational Psychiatry
Volume11
Issue number1
DOIs
Publication statusPublished - 2 Sept 2021

Bibliographical note

Funding Information:
Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. This research is supported by ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case–control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). The Longitudinal Aging Study Amsterdam is supported by a grant from the Netherlands Ministry of Health Welfare and Sports, Directorate of Long-Term Care. The work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007 to 2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/ initiatives/parelsnoer). The 100-plus study work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814), and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). The European Medical Information Frame-work for AD (EMIF-AD) PreclinAD study and EMIF 90+ study have been funded by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement #115372. We thank and acknowledge the International FTD-Genomics Consortium (IFGC). We thank Eleonora Maria Vromen from Amsterdam UMC, Alzheimer Center for proofreading our manuscript.

Funding Information:
YALP received a personal fellowship from the Dutch brain foundation. All other authors report no disclosures or conflicts of interest.

Publisher Copyright:
© 2021, The Author(s).

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