Negative results
No association of CpG SNP rs9357140 with onset age in Belgian C9orf72 repeat expansion carriers
Cemile Koço glu a
,b
,1 , Helena Gossye a
,b
,c
,d
,e
,1 , Lubina Dillen a
,b ,
Sara Van Mossevelde a
,b
,c
,e , Jan L. De Bleecker f , Rik Vandenberghe g
,h ,
Peter P. De Deyn b
,e , Kristel Sleegers a
,b , Patrick Cras b
,c , Sebastiaan Engelborghs b
,d , Christine Van Broeckhoven a
,b
,*, Julie van der Zee a
,b
,**, on behalf of the BELNEU Consortium 2
aNeurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium
bLaboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
cDepartment of Neurology, Antwerp University Hospital, Antwerp, Belgium
dDepartment of Neurology and Center for Neurosciences, UZ Brussel and Vrije Universiteit Brussel, Brussels, Belgium
eDepartment of Neurology and Memory Clinic, Hospital Network Antwerp, Antwerp, Belgium
fDepartment of Neurology, Ghent University Hospital, Ghent, Belgium
gDepartment of Neurology, University Hospitals Leuven, Leuven, Belgium
hDepartment of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium
a r t i c l e i n f o
Article history:
Received 12 June 2020
Received in revised form 18 July 2020 Accepted 23 July 2020
Available online 15 August 2020
Keywords:
Frontotemporal dementia FTD
Amyotrophic lateral sclerosis ALS
C9orf72 Modifier
a b s t r a c t
We investigated the impact of the recently described chromosome 6 open reading frame 10 (C6orf10)/
LOC101929163locus as age-at-onset modifier in an extended cohort of Belgian chromosome 9 open reading frame 72 (C9orf72)G4C2 repeat expansion carriers. We genotyped the tagging CpG single- nucleotide polymorphism rs9357140 in 224 confirmed C9orf72repeat expansion carriers, 102 index cases and 122 relatives, and tested association with onset age. TheC9orf72repeat expansion cohort consisted of 131 symptomatic carriers, that is, 78 with dementia only, 13 with frontotemporal dementia (FTD)eamyotrophic lateral sclerosis (ALS), and 40 ALS only, and 93 presymptomatic carriers. Cox pro- portional hazard regression analysis failed to identify significant association (adjusted hazard ratio¼ 1.15,p¼0.3). We further extended our analysis to a Belgian cohort of unrelated, mutation-negative FTD index patients (n¼230), but also found no association (adjusted hazard ratio¼0.96,p¼0.3). Overall, our findings suggest that in the Belgian cohort, the C6orf10/LOC101929163locus cannot explain the marked variability in age at onset, and other genetic or environmental modifiers must drive the clinical heterogeneity observed amongC9orf72repeat expansion carriers.
Ó2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Chromosome 9 open reading frame 72 (C9orf72)-associated frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and FTD plus ALS patients are characterized by striking variability in disease presentation, with an unusually wide range in age at onset (27
e83 years) (Mahoney et al., 2012; Van Mossevelde et al., 2017).
This clinical heterogeneity suggests the presence of genetic or environmental modi
fiers. Earlier studies investigated the effect of genetic variation in TMEM106B (transmembrane protein 106B), an FTD risk factor, on disease presentation in C9orf72 repeat expansion carriers. They found a protective effect of the homozygous minor allele of rs1990622 in FTD but not in ALS cohorts. (Gallagher et al., 2014; Van Blitterswijk et al., 2014). In addition, repeat size and
*Corresponding author at: Neurodegenerative Brain Diseases Group VIB Center for Molecular Neurology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Tel.:þ32 3 265 1101; fax:þ32 3 265 8410.
**Corresponding author at: Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Tel.:þ32 3 265 1032; fax:þ32 3 265 8410.
E-mail addresses: christine.vanbroeckhoven@uantwerpen.vib.be (C. Van Broeckhoven),julie.vanderzee@uantwerpen.vib.be(J. van der Zee).
1 The sharedfirst authors contributed equally to the research of this paper.
2 The following neurologists of the BELNEU Consortium have contributed to the clinical and pathological phenotyping and follow-up of the Belgian patients and families: Johan Goeman, Roeland Crols (Hospital Network Antwerp (ZNA) Mid- delheim and Hoge Beuken, Antwerp); Rudy Mercelis, Peter De Jonghe, Jonathan Baets (Antwerp University Hospital, Edegem); Anne Sieben, Tim Van Langenhove (University Hospital Ghent, Ghent); Adrian Ivanoiu (Saint-Luc University Hospital, Brussels); Olivier Deryck (General Hospital Sint-Jan Brugge, Bruges); Philippe Pals (General Hospital Sint-Maarten, Mechelen).
Contents lists available atScienceDirect
Neurobiology of Aging
j o u r n a l h o me p a g e : w w w . e l s e v i e r . c o m / l o ca t e / n e u a g i n g
0197-4580/Ó2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.neurobiolaging.2020.07.021
Neurobiology of Aging 97 (2021) 145.e1e145.e4
hypermethylation of the C9orf72 G
4C
2repeat were shown to correlate with age at onset (Gijselinck et al., 2016).
A genomewide DNA methylation study in carriers of a C9orf72 repeat expansion identi
fied a CpG locus associated with age at onset on chr6p21.32 and mapping to 2 overlapping genes, LOC101929163 and chromosome 6 open reading frame 10 (C6orf10), tagged by the top-signi
ficant single-nucleotide polymorphism (SNP) rs9357140 (Zhang et al., 2018). The authors demonstrated that in C9orf72 repeat expansion carriers, the rs9357140 minor A allele was reproducibly associated with a later onset age and delayed median disease onset with 6 years in homozygous A/A- allele carriers. The age-modifying effect of rs9357140 was much smaller in an international cohort of C9orf72-negative patients with FTD, FTD-ALS, and ALS. The rs9357140 A-allele was associated with reduced expression of the LOC101929163 and
flanking HLA-DRB1 (major histocompatibility complex, class II, DR beta 1) genes in speci
fic brain regions, including ALS brain frontal cortex.
In our study, we evaluated the impact of rs9357140 on age at onset in an extended cohort of Belgian C9orf72 repeat expansion carriers.
2. Materials and methods
Patients were recruited in the framework of the Belgian Neurology Consortium across Flanders-Belgium (Van Mossevelde et al., 2017). The rs9357140 SNP was genotyped in index cases (n
¼102) and their relatives (n
¼122) carrying a C9orf72 repeat expansion, referred to as the C9orf72 carriers cohort (n
¼224), comprising both patients (n
¼131: 78 dementia-only, 13 FTD-ALS, 40 ALS-only patients) and presymptomatic carriers (n
¼93). In addition, we genotyped an FTD cohort of unrelated, mutation- negative patients (n
¼230: 222 FTD, 8 FTD-ALS) for rs9357140.
We tested association of rs9357140 with onset age by mixed effects Cox proportional hazard regression analysis using the coxme package, adjusting for gender and disease phenotype and censoring age of last follow-up for asymptomatic carriers (R survival and survminer packages). To account for the degree of kinship in the C9orf72 carriers cohort, we created a kinship matrix (R kinship2
package), and included this in the Cox mixed effects model. Asso- ciation tests were performed under an additive model, comparing the 3 genotypic groups (A/A versus A/G versus G/G), and under a recessive model comparing homozygous minor allele A/A carriers to heterozygous and homozygous of the major allele (A/A versus G/
A
þG/G).
Detailed methodology, cohort description, and ethical clearance are available in the Supplementary Material.
3. Results
3.1. C9orf72 carriers cohort
In the cohort of 224 C9orf72 repeat expansion carriers, disease onset in carriers of the A/A genotype (minor A allele) was earlier than for the G/A- and G/G-genotype carriers: 56 years for A/A (95%
con
fidence interval [CI]: 54
e69), 62 years for G/A (95% CI: 58
e65), and 61 years for G/G (95% CI: 55
e66) (Fig. 1A, Supplementary Fig. 1).
Cox proportional hazard regression analysis on ages at onset, strati
fied by rs9357140 genotype, showed that this difference was not signi
ficantly different: p
¼0.30, hazard ratio (HR)
¼1.15 (95%
CI: 0.87
e1.51). We repeated the same analysis by grouping G/A- and G/G-genotype carriers together to assess the effect of homozygous A/A carriers in a recessive model. The median age at onset for G/A
þG/G carriers was 61 years (95% CI: 60
e64) which was not signi
fi- cant: p
¼0.36, HR
¼1.24 (95% CI: 0.87
e1.51) (Fig. 1B). To exclude possible familial confounders due to shared environmental expo- sure or lifestyle, we additionally performed a subgroup analysis on the unrelated C9orf72 index cases only (n
¼102). Also here we did not observe an association (Supplementary Fig. 2).
3.2. FTD cohort
We used the same analysis for the 230 unrelated, mutation- negative patients of the FTD cohort. The median age at onset of the A/A genotype carriers was approximately 3 years later compared with the G/G carriers: 67 years for A/A carriers (95% CI:
65
e69), 64.5 years for G/A carriers (95% CI: 62
e65) and 64 years for
Fig. 1.Kaplan-Meier cumulative incidence plot of disease onset inC9orf72carriers cohort (n¼224) stratified by rs9357140 genotypes. (A) Additive model: A/A versus G/A versus G/
G; (B) recessive model: A/A versus G/AþG/G.
C. Koçoglu et al. / Neurobiology of Aging 97 (2021) 145.e1e145.e4 145.e2
G/G carriers (95% CI: 62
e67) (Supplementary Figure 1, 2). Cox proportional hazard regression analysis showed that also this dif- ference was not signi
ficant, both under an additive model: adjusted p
¼0.3, HR
¼0.96 (95% CI: 0.81
e1.13) and a recessive model:
65 years for G/A
þG/G carriers (95% CI: 63
e66), p
¼0.60, HR
¼0.98 (95% CI: 0.82
e1.18) (Supplementary Fig. 3A and B).
4. Discussion
We analyzed the association between CpG SNP rs9357140 and age at onset to investigate if it could explain the striking range in onset age in our cohort of Belgian C9orf72 repeat expansion carriers (n
¼224, average onset: 56.5 10.2 years, range 18
e80 years) and FTD cohort (n
¼230, average onset: 64.5 10.3 years, range 29
e88 years). While Zhang et al reported reproducible association for rs9357140 under an additive model, with every A allele reducing hazard by 57% (Zhang et al., 2018), we did not observe such a trend in our C9orf72 carriers cohort, nor under a recessive model. By contrast, we observed the earliest age at onset in C9orf72 repeat expansion carriers with an A/A genotype (Fig. 1). Although our cohort of 224 con
firmed C9orf72 repeat expansion carriers could be underpowered to show association, its size is larger than the dis- covery set (n
¼144) and the replication set (n
¼187) of the original study (Zhang et al., 2018). Furthermore, in our study, we selected carriers from the geographical region of Flanders in Belgium, which maximizes the homogeneity of the study cohort and increases ge- netic power to detect association. An important limitation in our study and the original study when looking for disease modi
fiers in C9orf72-related FTD and ALS is that we did not account for repeat size and degree of DNA methylation in our analyses of the carriers (Gijselinck et al., 2016). We previously showed that in the Belgian C9orf72 repeat expansion carriers, repeat size and methylation of the upstream CpG island of the G
4C
2repeat are correlated and both alter age at onset (Gijselinck et al., 2016), pointing toward genetic/
epigenetic modulation of gene expression. A major factor deter- mining disease onset in the C9of72 phenotype spectrum is the clinical presentation of the patient, with ALS and FTD-ALS patients having an earlier age at onset than FTD patients (Moore et al., 2020).
In our study cohorts, the patients were mostly FTD patients. This is in sharp contrast to the original study, where the discovery group consisted of 70% ALS patients carrying a C9orf72 repeat expansion, which may have in
fluenced the outcomes. Nevertheless, in the Belgian cohort, onset ages between FTD, ALS, and FTD-ALS phenotypic groups were largely comparable (Supplementary Table 2).
In conclusion, our observations in an extended cohort of Belgian C9orf72 repeat expansion carriers and FTD patients indicate that methylation status at CpG SNP rs9357140 alone is not suf
ficient to predict age at onset in asymptomatic C9orf72 carriers.
Disclosure statement
The authors report no disclosures with respect to the data pre- sented in this article.
CRediT authorship contribution statement
Cemile Koço glu: Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing - original draft, Writing - review & editing. Helena Gossye: Data curation, Formal analysis, Investigation, Methodology, Resources, Validation, Visualization, Writing - original draft, Writing - review & editing.
Lubina Dillen: Data curation, Formal analysis, Methodology, Re- sources, Validation. Sara Van Mossevelde: Conceptualization, Data curation, Investigation, Methodology, Resources, Writing - review &
editing. Jan L. De Bleecker: Resources, Writing - review & editing.
Rik Vandenberghe: Resources, Writing - review & editing. Peter P.
De Deyn: Resources, Supervision, Writing - review & editing.
Kristel Sleegers: Conceptualization, Methodology, Writing - review
& editing. Patrick Cras: Resources, Supervision, Funding acquisi- tion, Writing - review & editing. Sebastiaan Engelborghs: Re- sources, Supervision, Funding acquisition, Writing - review &
editing. Christine Van Broeckhoven: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing. Julie van der Zee: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing.
Acknowledgements
The authors thank the members of the Belgian Neurology (BELNEU) Consortium. The following neurologists of the BELNEU Consortium have contributed to the clinical and pathological phe- notyping and follow-up of the Belgian patients and families: Johan Goeman, Roeland Crols (Hospital Network Antwerp (ZNA) Mid- delheim and Hoge Beuken, Antwerp); Rudy Mercelis, Peter De Jonghe, Jonathan Baets (Antwerp University Hospital, Edegem);
Anne Sieben, Tim Van Langenhove (University Hospital Ghent, Ghent); Adrian Ivanoiu (Saint-Luc University Hospital, Brussels);
Olivier Deryck (General Hospital Sint-Jan Brugge, Bruges); Philippe Pals (General Hospital Sint-Maarten, Mechelen).
The authors further thank the personnel of the Neuromics Support Facility of the VIB-UAntwerp Center for Molecular Neurology for their expert support.
Funding: The research was in part funded by the Flemish gov- ernment initiated Impulse Program on Networks for Dementia Research (VIND) (to C.V.B.) and the Methusalem excellence pro- gram (to C.V.B.).
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.neurobiolaging.2020.07.021
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