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. Ramakers; F.R.J. Verhey; A. van der Lugt; J.A.H.R. Claassen; G. Jan 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

doi:10.1038/s41398-021-01577-3

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. Jan 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

Research output: Contribution to Journal › Article › Academic › peer-review

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 language	English
Article number	451
Pages (from-to)	1-8
Number of pages	8
Journal	Translational Psychiatry
Volume	11
DOIs	https://doi.org/10.1038/s41398-021-01577-3
Publication status	Published - 2 Sept 2021

Bibliographical note

Funding

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\u2013control 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. YALP received a personal fellowship from the Dutch brain foundation. All other authors report no disclosures or conflicts of interest.

Funders	Funder number
ABOARD
Dutch Federation of University Medical Centers
Dutch Brain Foundation
Edwin Bouw Fonds and Gieskes-Strijbisfonds
European Medical Information Frame-work
Netherlands Ministry of Health Welfare and Sports, Directorate of Long-Term Care
Stichting Diorapthe, horstingstuit foundation	733050814
Stichting VUmc Fonds
Topsector Life Sciences & Health	20106
Health~Holland
ZonMw	733051061
ZonMw
Stichting Dioraphte
Innovative Medicines Initiative	115372
Innovative Medicines Initiative
Alzheimer Nederland	WE09.2014-03
Alzheimer Nederland

Keywords

C9orf72 Protein/genetics
DNA Repeat Expansion/genetics
Frontotemporal Dementia/genetics
Genome-Wide Association Study
Haplotypes
Humans

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41398-021-01577-3

Persistent URL (handle)

Persistent link

Longitudinal Aging Study Amsterdam
Huisman, M. (Creator), van Tilburg, T. (Creator), Broese Van Groenou, M. (Creator), Suanet, B. (Creator), Visser, M. (Creator), Kok, A. A. L. (Creator), Hoogendijk, E. O. (Creator), Deeg, D. (Creator), Schaap, L. (Creator), Beekman, A. F. T. (Creator) & van Schoor, N. M. (Creator), Amsterdam UMC, 1992
http://www.lasa-vu.nl
Dataset / Software: Dataset

Cite this

Reus, L. M., Jansen, I. E., Mol, M. O., van Ruissen, F., van Rooij, J., van Schoor, N. M., Tesi, N., Reinders, M. J. T., Huisman, M. A., Holstege, H., Visser, P. J., de Boer, S. C. M., Hulsman, M., Ahmad, S., Amin, N., Uitterlinden, A. G., Ikram, A., van Duijn, C. M., Seelaar, H., ... van der Lee, S. J. (2021). Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions. Translational Psychiatry, 11, 1-8. Article 451. https://doi.org/10.1038/s41398-021-01577-3

@article{21ed2bb599bd4142aa17beecb7e7490b,

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

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.",

keywords = "C9orf72 Protein/genetics, DNA Repeat Expansion/genetics, Frontotemporal Dementia/genetics, Genome-Wide Association Study, Haplotypes, Humans",

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

note = "{\textcopyright} 2021. The Author(s).",

year = "2021",

month = sep,

day = "2",

doi = "10.1038/s41398-021-01577-3",

language = "English",

volume = "11",

pages = "1--8",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

}

Reus, LM, Jansen, IE, Mol, MO, van Ruissen, F, van Rooij, J, van Schoor, NM, Tesi, N, Reinders, MJT, Huisman, MA, Holstege, H, Visser, PJ, de Boer, SCM, Hulsman, M, Ahmad, S, Amin, N, Uitterlinden, AG, Ikram, A, van Duijn, CM, Seelaar, H, Ramakers, IHGB, Verhey, FRJ, van der Lugt, A, Claassen, JAHR, Jan Biessels, G, De Deyn, PP, Scheltens, P, van der Flier, WM, van Swieten, JC, Pijnenburg, YAL & van der Lee, SJ 2021, 'Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions', Translational Psychiatry, vol. 11, 451, pp. 1-8. https://doi.org/10.1038/s41398-021-01577-3

TY - JOUR

T1 - Genome-wide association study of frontotemporal dementia identifies a C9ORF72 haplotype with a median of 12-G4C2 repeats that predisposes to pathological repeat expansions

AU - Reus, L.M.

AU - Jansen, I.E.

AU - Mol, M.O.

AU - van Ruissen, F.

AU - van Rooij, J.

AU - van Schoor, N.M.

AU - Tesi, N.

AU - Reinders, M.J.T.

AU - Huisman, M.A.

AU - Holstege, H.

AU - Visser, P.J.

AU - de Boer, S.C.M.

AU - Hulsman, M.

AU - Ahmad, S.

AU - Amin, N.

AU - Uitterlinden, A.G.

AU - Ikram, A.

AU - van Duijn, C.M.

AU - Seelaar, H.

AU - Ramakers, I.H.G.B.

AU - Verhey, F.R.J.

AU - van der Lugt, A.

AU - Claassen, J.A.H.R.

AU - Jan Biessels, G.

AU - De Deyn, P.P.

AU - Scheltens, P.

AU - van der Flier, W.M.

AU - van Swieten, J.C.

AU - Pijnenburg, Y.A.L.

AU - van der Lee, S.J.

PY - 2021/9/2

Y1 - 2021/9/2

N2 - 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.

AB - 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.

KW - C9orf72 Protein/genetics

KW - DNA Repeat Expansion/genetics

KW - Frontotemporal Dementia/genetics

KW - Genome-Wide Association Study

KW - Haplotypes

KW - Humans

U2 - 10.1038/s41398-021-01577-3

DO - 10.1038/s41398-021-01577-3

M3 - Article

C2 - 34475377

SN - 2158-3188

VL - 11

SP - 1

EP - 8

JO - Translational Psychiatry

JF - Translational Psychiatry

M1 - 451

ER -

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Persistent URL (handle)

Fingerprint

Datasets

Longitudinal Aging Study Amsterdam

Cite this