A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

Ming Zhang*, Raffaele Ferrari, Maria Carmela Tartaglia, Julia Keith, Ezequiel I. Surace, Uri Wolf, Christine Sato, Mark Grinberg, Yan Liang, Zhengrui Xi, Kyle Dupont, Philip McGoldrick, Anna Weichert, Paul M. McKeever, Raphael Schneider, Michael D. McCorkindale, Claudia Manzoni, Rosa Rademakers, Neill R. Graff-Radford, Dennis W. Dickson & 60 others Joseph E. Parisi, Bradley F. Boeve, Ronald C. Petersen, Bruce L. Miller, William W. Seeley, John C. Van Swieten, Jeroen Van Rooij, Yolande Pijnenburg, Julie Van Der Zee, Christine Van Broeckhoven, Isabelle Le Ber, Vivianna Van Deerlin, Eun Ran Suh, Jonathan D. Rohrer, Simon Mead, Caroline Graff, Linn Öijerstedt, Stuart Pickering-Brown, Sara Rollinson, Giacomina Rossi, Fabrizio Tagliavini, William S. Brooks, Carol Dobson-Stone, Glenda M. Halliday, John R. Hodges, Olivier Piguet, Giuliano Binetti, Luisa Benussi, Roberta Ghidoni, Benedetta Nacmias, Sandro Sorbi, Amalia C. Bruni, Daniela Galimberti, Elio Scarpini, Innocenzo Rainero, Elisa Rubino, Jordi Clarimon, Alberto Lleó, Agustin Ruiz, Isabel Hernández, Pau Pastor, Monica Diez-Fairen, Barbara Borroni, Florence Pasquier, Vincent Deramecourt, Thibaud Lebouvier, Robert Perneczky, Janine Diehl-Schmid, Jordan Henry Grafman, Edward D. Huey, Richard Mayeux, Michael A. Nalls, Dena Hernandez, Andrew Singleton, Parastoo Momeni, Zhen Zeng, John Hardy, Janice Robertson, Lorne Zinman, Ekaterina Rogaeva

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The G 4 C 2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Original languageEnglish (US)
Pages (from-to)2895-2907
Number of pages13
JournalBrain
Volume141
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Age of Onset
DNA Methylation
HLA-DRB1 Chains
Alleles
Single Nucleotide Polymorphism
Genotype
Overlapping Genes
Frontotemporal Dementia
Untranslated RNA
Genome-Wide Association Study
Linkage Disequilibrium
Amyotrophic Lateral Sclerosis
Genetic Association Studies
Microglia
Frontal Lobe
Epigenomics
Meta-Analysis
Autopsy
Phenotype
Gene Expression

Keywords

  • C9orf72
  • age of onset
  • amyotrophic lateral sclerosis
  • frontotemporal dementia
  • genetic association

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Zhang, M., Ferrari, R., Tartaglia, M. C., Keith, J., Surace, E. I., Wolf, U., ... Rogaeva, E. (2018). A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers. Brain, 141(10), 2895-2907. https://doi.org/10.1093/brain/awy238
Zhang, Ming ; Ferrari, Raffaele ; Tartaglia, Maria Carmela ; Keith, Julia ; Surace, Ezequiel I. ; Wolf, Uri ; Sato, Christine ; Grinberg, Mark ; Liang, Yan ; Xi, Zhengrui ; Dupont, Kyle ; McGoldrick, Philip ; Weichert, Anna ; McKeever, Paul M. ; Schneider, Raphael ; McCorkindale, Michael D. ; Manzoni, Claudia ; Rademakers, Rosa ; Graff-Radford, Neill R. ; Dickson, Dennis W. ; Parisi, Joseph E. ; Boeve, Bradley F. ; Petersen, Ronald C. ; Miller, Bruce L. ; Seeley, William W. ; Van Swieten, John C. ; Van Rooij, Jeroen ; Pijnenburg, Yolande ; Van Der Zee, Julie ; Van Broeckhoven, Christine ; Le Ber, Isabelle ; Van Deerlin, Vivianna ; Suh, Eun Ran ; Rohrer, Jonathan D. ; Mead, Simon ; Graff, Caroline ; Öijerstedt, Linn ; Pickering-Brown, Stuart ; Rollinson, Sara ; Rossi, Giacomina ; Tagliavini, Fabrizio ; Brooks, William S. ; Dobson-Stone, Carol ; Halliday, Glenda M. ; Hodges, John R. ; Piguet, Olivier ; Binetti, Giuliano ; Benussi, Luisa ; Ghidoni, Roberta ; Nacmias, Benedetta ; Sorbi, Sandro ; Bruni, Amalia C. ; Galimberti, Daniela ; Scarpini, Elio ; Rainero, Innocenzo ; Rubino, Elisa ; Clarimon, Jordi ; Lleó, Alberto ; Ruiz, Agustin ; Hernández, Isabel ; Pastor, Pau ; Diez-Fairen, Monica ; Borroni, Barbara ; Pasquier, Florence ; Deramecourt, Vincent ; Lebouvier, Thibaud ; Perneczky, Robert ; Diehl-Schmid, Janine ; Grafman, Jordan Henry ; Huey, Edward D. ; Mayeux, Richard ; Nalls, Michael A. ; Hernandez, Dena ; Singleton, Andrew ; Momeni, Parastoo ; Zeng, Zhen ; Hardy, John ; Robertson, Janice ; Zinman, Lorne ; Rogaeva, Ekaterina. / A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers. In: Brain. 2018 ; Vol. 141, No. 10. pp. 2895-2907.
@article{608259c9dfbb482d99161012214a998f,
title = "A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers",
abstract = "The G 4 C 2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30{\%} (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.",
keywords = "C9orf72, age of onset, amyotrophic lateral sclerosis, frontotemporal dementia, genetic association",
author = "Ming Zhang and Raffaele Ferrari and Tartaglia, {Maria Carmela} and Julia Keith and Surace, {Ezequiel I.} and Uri Wolf and Christine Sato and Mark Grinberg and Yan Liang and Zhengrui Xi and Kyle Dupont and Philip McGoldrick and Anna Weichert and McKeever, {Paul M.} and Raphael Schneider and McCorkindale, {Michael D.} and Claudia Manzoni and Rosa Rademakers and Graff-Radford, {Neill R.} and Dickson, {Dennis W.} and Parisi, {Joseph E.} and Boeve, {Bradley F.} and Petersen, {Ronald C.} and Miller, {Bruce L.} and Seeley, {William W.} and {Van Swieten}, {John C.} and {Van Rooij}, Jeroen and Yolande Pijnenburg and {Van Der Zee}, Julie and {Van Broeckhoven}, Christine and {Le Ber}, Isabelle and {Van Deerlin}, Vivianna and Suh, {Eun Ran} and Rohrer, {Jonathan D.} and Simon Mead and Caroline Graff and Linn {\"O}ijerstedt and Stuart Pickering-Brown and Sara Rollinson and Giacomina Rossi and Fabrizio Tagliavini and Brooks, {William S.} and Carol Dobson-Stone and Halliday, {Glenda M.} and Hodges, {John R.} and Olivier Piguet and Giuliano Binetti and Luisa Benussi and Roberta Ghidoni and Benedetta Nacmias and Sandro Sorbi and Bruni, {Amalia C.} and Daniela Galimberti and Elio Scarpini and Innocenzo Rainero and Elisa Rubino and Jordi Clarimon and Alberto Lle{\'o} and Agustin Ruiz and Isabel Hern{\'a}ndez and Pau Pastor and Monica Diez-Fairen and Barbara Borroni and Florence Pasquier and Vincent Deramecourt and Thibaud Lebouvier and Robert Perneczky and Janine Diehl-Schmid and Grafman, {Jordan Henry} and Huey, {Edward D.} and Richard Mayeux and Nalls, {Michael A.} and Dena Hernandez and Andrew Singleton and Parastoo Momeni and Zhen Zeng and John Hardy and Janice Robertson and Lorne Zinman and Ekaterina Rogaeva",
year = "2018",
month = "10",
day = "1",
doi = "10.1093/brain/awy238",
language = "English (US)",
volume = "141",
pages = "2895--2907",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "10",

}

Zhang, M, Ferrari, R, Tartaglia, MC, Keith, J, Surace, EI, Wolf, U, Sato, C, Grinberg, M, Liang, Y, Xi, Z, Dupont, K, McGoldrick, P, Weichert, A, McKeever, PM, Schneider, R, McCorkindale, MD, Manzoni, C, Rademakers, R, Graff-Radford, NR, Dickson, DW, Parisi, JE, Boeve, BF, Petersen, RC, Miller, BL, Seeley, WW, Van Swieten, JC, Van Rooij, J, Pijnenburg, Y, Van Der Zee, J, Van Broeckhoven, C, Le Ber, I, Van Deerlin, V, Suh, ER, Rohrer, JD, Mead, S, Graff, C, Öijerstedt, L, Pickering-Brown, S, Rollinson, S, Rossi, G, Tagliavini, F, Brooks, WS, Dobson-Stone, C, Halliday, GM, Hodges, JR, Piguet, O, Binetti, G, Benussi, L, Ghidoni, R, Nacmias, B, Sorbi, S, Bruni, AC, Galimberti, D, Scarpini, E, Rainero, I, Rubino, E, Clarimon, J, Lleó, A, Ruiz, A, Hernández, I, Pastor, P, Diez-Fairen, M, Borroni, B, Pasquier, F, Deramecourt, V, Lebouvier, T, Perneczky, R, Diehl-Schmid, J, Grafman, JH, Huey, ED, Mayeux, R, Nalls, MA, Hernandez, D, Singleton, A, Momeni, P, Zeng, Z, Hardy, J, Robertson, J, Zinman, L & Rogaeva, E 2018, 'A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers', Brain, vol. 141, no. 10, pp. 2895-2907. https://doi.org/10.1093/brain/awy238

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers. / Zhang, Ming; Ferrari, Raffaele; Tartaglia, Maria Carmela; Keith, Julia; Surace, Ezequiel I.; Wolf, Uri; Sato, Christine; Grinberg, Mark; Liang, Yan; Xi, Zhengrui; Dupont, Kyle; McGoldrick, Philip; Weichert, Anna; McKeever, Paul M.; Schneider, Raphael; McCorkindale, Michael D.; Manzoni, Claudia; Rademakers, Rosa; Graff-Radford, Neill R.; Dickson, Dennis W.; Parisi, Joseph E.; Boeve, Bradley F.; Petersen, Ronald C.; Miller, Bruce L.; Seeley, William W.; Van Swieten, John C.; Van Rooij, Jeroen; Pijnenburg, Yolande; Van Der Zee, Julie; Van Broeckhoven, Christine; Le Ber, Isabelle; Van Deerlin, Vivianna; Suh, Eun Ran; Rohrer, Jonathan D.; Mead, Simon; Graff, Caroline; Öijerstedt, Linn; Pickering-Brown, Stuart; Rollinson, Sara; Rossi, Giacomina; Tagliavini, Fabrizio; Brooks, William S.; Dobson-Stone, Carol; Halliday, Glenda M.; Hodges, John R.; Piguet, Olivier; Binetti, Giuliano; Benussi, Luisa; Ghidoni, Roberta; Nacmias, Benedetta; Sorbi, Sandro; Bruni, Amalia C.; Galimberti, Daniela; Scarpini, Elio; Rainero, Innocenzo; Rubino, Elisa; Clarimon, Jordi; Lleó, Alberto; Ruiz, Agustin; Hernández, Isabel; Pastor, Pau; Diez-Fairen, Monica; Borroni, Barbara; Pasquier, Florence; Deramecourt, Vincent; Lebouvier, Thibaud; Perneczky, Robert; Diehl-Schmid, Janine; Grafman, Jordan Henry; Huey, Edward D.; Mayeux, Richard; Nalls, Michael A.; Hernandez, Dena; Singleton, Andrew; Momeni, Parastoo; Zeng, Zhen; Hardy, John; Robertson, Janice; Zinman, Lorne; Rogaeva, Ekaterina.

In: Brain, Vol. 141, No. 10, 01.10.2018, p. 2895-2907.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers

AU - Zhang, Ming

AU - Ferrari, Raffaele

AU - Tartaglia, Maria Carmela

AU - Keith, Julia

AU - Surace, Ezequiel I.

AU - Wolf, Uri

AU - Sato, Christine

AU - Grinberg, Mark

AU - Liang, Yan

AU - Xi, Zhengrui

AU - Dupont, Kyle

AU - McGoldrick, Philip

AU - Weichert, Anna

AU - McKeever, Paul M.

AU - Schneider, Raphael

AU - McCorkindale, Michael D.

AU - Manzoni, Claudia

AU - Rademakers, Rosa

AU - Graff-Radford, Neill R.

AU - Dickson, Dennis W.

AU - Parisi, Joseph E.

AU - Boeve, Bradley F.

AU - Petersen, Ronald C.

AU - Miller, Bruce L.

AU - Seeley, William W.

AU - Van Swieten, John C.

AU - Van Rooij, Jeroen

AU - Pijnenburg, Yolande

AU - Van Der Zee, Julie

AU - Van Broeckhoven, Christine

AU - Le Ber, Isabelle

AU - Van Deerlin, Vivianna

AU - Suh, Eun Ran

AU - Rohrer, Jonathan D.

AU - Mead, Simon

AU - Graff, Caroline

AU - Öijerstedt, Linn

AU - Pickering-Brown, Stuart

AU - Rollinson, Sara

AU - Rossi, Giacomina

AU - Tagliavini, Fabrizio

AU - Brooks, William S.

AU - Dobson-Stone, Carol

AU - Halliday, Glenda M.

AU - Hodges, John R.

AU - Piguet, Olivier

AU - Binetti, Giuliano

AU - Benussi, Luisa

AU - Ghidoni, Roberta

AU - Nacmias, Benedetta

AU - Sorbi, Sandro

AU - Bruni, Amalia C.

AU - Galimberti, Daniela

AU - Scarpini, Elio

AU - Rainero, Innocenzo

AU - Rubino, Elisa

AU - Clarimon, Jordi

AU - Lleó, Alberto

AU - Ruiz, Agustin

AU - Hernández, Isabel

AU - Pastor, Pau

AU - Diez-Fairen, Monica

AU - Borroni, Barbara

AU - Pasquier, Florence

AU - Deramecourt, Vincent

AU - Lebouvier, Thibaud

AU - Perneczky, Robert

AU - Diehl-Schmid, Janine

AU - Grafman, Jordan Henry

AU - Huey, Edward D.

AU - Mayeux, Richard

AU - Nalls, Michael A.

AU - Hernandez, Dena

AU - Singleton, Andrew

AU - Momeni, Parastoo

AU - Zeng, Zhen

AU - Hardy, John

AU - Robertson, Janice

AU - Zinman, Lorne

AU - Rogaeva, Ekaterina

PY - 2018/10/1

Y1 - 2018/10/1

N2 - The G 4 C 2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

AB - The G 4 C 2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

KW - C9orf72

KW - age of onset

KW - amyotrophic lateral sclerosis

KW - frontotemporal dementia

KW - genetic association

UR - http://www.scopus.com/inward/record.url?scp=85054408708&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054408708&partnerID=8YFLogxK

U2 - 10.1093/brain/awy238

DO - 10.1093/brain/awy238

M3 - Article

VL - 141

SP - 2895

EP - 2907

JO - Brain

JF - Brain

SN - 0006-8950

IS - 10

ER -

Zhang M, Ferrari R, Tartaglia MC, Keith J, Surace EI, Wolf U et al. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers. Brain. 2018 Oct 1;141(10):2895-2907. https://doi.org/10.1093/brain/awy238