C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: A genome-wide meta-analysis

Frank P. Diekstra, Vivianna M. Van Deerlin, John C. Van Swieten, Ammar Al-Chalabi, Albert C. Ludolph, Jochen H. Weishaupt, Orla Hardiman, John E. Landers, Robert H. Brown, Michael A. Van Es, R. Jeroen Pasterkamp, Max Koppers, Peter M. Andersen, Karol Estrada, Fernando Rivadeneira, Albert Hofman, André G. Uitterlinden, Philip Van Damme, Judith Melki, Vincent MeiningerAleksey Shatunov, Christopher E. Shaw, P. Nigel Leigh, Pamela J. Shaw, Karen E. Morrison, Isabella Fogh, Adriano Chiò, Bryan J. Traynor, David Czell, Markus Weber, Peter Heutink, Paul I W De Bakker, Vincenzo Silani, Wim Robberecht, Leonard H. Van Den Berg, Jan H. Veldink

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Objective Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10-12) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10-11) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10-7) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10-7). Interpretation We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP. Ann Neurol 2014;76:120-133

Original languageEnglish
Pages (from-to)120-133
Number of pages14
JournalAnnals of Neurology
Volume76
Issue number1
DOIs
Publication statusPublished - 2014

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Meta-Analysis
Genome
Frontotemporal Dementia
Chromosomes
Single Nucleotide Polymorphism
Genotype
Frontotemporal Dementia With Motor Neuron Disease
Genome-Wide Association Study
Amyotrophic Lateral Sclerosis
Sample Size
Neurotransmitter Agents
Joints
Pathology
Weights and Measures

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Diekstra, F. P., Van Deerlin, V. M., Van Swieten, J. C., Al-Chalabi, A., Ludolph, A. C., Weishaupt, J. H., ... Veldink, J. H. (2014). C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: A genome-wide meta-analysis. Annals of Neurology, 76(1), 120-133. https://doi.org/10.1002/ana.24198

C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia : A genome-wide meta-analysis. / Diekstra, Frank P.; Van Deerlin, Vivianna M.; Van Swieten, John C.; Al-Chalabi, Ammar; Ludolph, Albert C.; Weishaupt, Jochen H.; Hardiman, Orla; Landers, John E.; Brown, Robert H.; Van Es, Michael A.; Pasterkamp, R. Jeroen; Koppers, Max; Andersen, Peter M.; Estrada, Karol; Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, André G.; Van Damme, Philip; Melki, Judith; Meininger, Vincent; Shatunov, Aleksey; Shaw, Christopher E.; Leigh, P. Nigel; Shaw, Pamela J.; Morrison, Karen E.; Fogh, Isabella; Chiò, Adriano; Traynor, Bryan J.; Czell, David; Weber, Markus; Heutink, Peter; De Bakker, Paul I W; Silani, Vincenzo; Robberecht, Wim; Van Den Berg, Leonard H.; Veldink, Jan H.

In: Annals of Neurology, Vol. 76, No. 1, 2014, p. 120-133.

Research output: Contribution to journalArticle

Diekstra, FP, Van Deerlin, VM, Van Swieten, JC, Al-Chalabi, A, Ludolph, AC, Weishaupt, JH, Hardiman, O, Landers, JE, Brown, RH, Van Es, MA, Pasterkamp, RJ, Koppers, M, Andersen, PM, Estrada, K, Rivadeneira, F, Hofman, A, Uitterlinden, AG, Van Damme, P, Melki, J, Meininger, V, Shatunov, A, Shaw, CE, Leigh, PN, Shaw, PJ, Morrison, KE, Fogh, I, Chiò, A, Traynor, BJ, Czell, D, Weber, M, Heutink, P, De Bakker, PIW, Silani, V, Robberecht, W, Van Den Berg, LH & Veldink, JH 2014, 'C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: A genome-wide meta-analysis', Annals of Neurology, vol. 76, no. 1, pp. 120-133. https://doi.org/10.1002/ana.24198
Diekstra, Frank P. ; Van Deerlin, Vivianna M. ; Van Swieten, John C. ; Al-Chalabi, Ammar ; Ludolph, Albert C. ; Weishaupt, Jochen H. ; Hardiman, Orla ; Landers, John E. ; Brown, Robert H. ; Van Es, Michael A. ; Pasterkamp, R. Jeroen ; Koppers, Max ; Andersen, Peter M. ; Estrada, Karol ; Rivadeneira, Fernando ; Hofman, Albert ; Uitterlinden, André G. ; Van Damme, Philip ; Melki, Judith ; Meininger, Vincent ; Shatunov, Aleksey ; Shaw, Christopher E. ; Leigh, P. Nigel ; Shaw, Pamela J. ; Morrison, Karen E. ; Fogh, Isabella ; Chiò, Adriano ; Traynor, Bryan J. ; Czell, David ; Weber, Markus ; Heutink, Peter ; De Bakker, Paul I W ; Silani, Vincenzo ; Robberecht, Wim ; Van Den Berg, Leonard H. ; Veldink, Jan H. / C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia : A genome-wide meta-analysis. In: Annals of Neurology. 2014 ; Vol. 76, No. 1. pp. 120-133.
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abstract = "Objective Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10-12) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10-11) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10-7) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10-7). Interpretation We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP. Ann Neurol 2014;76:120-133",
author = "Diekstra, {Frank P.} and {Van Deerlin}, {Vivianna M.} and {Van Swieten}, {John C.} and Ammar Al-Chalabi and Ludolph, {Albert C.} and Weishaupt, {Jochen H.} and Orla Hardiman and Landers, {John E.} and Brown, {Robert H.} and {Van Es}, {Michael A.} and Pasterkamp, {R. Jeroen} and Max Koppers and Andersen, {Peter M.} and Karol Estrada and Fernando Rivadeneira and Albert Hofman and Uitterlinden, {Andr{\'e} G.} and {Van Damme}, Philip and Judith Melki and Vincent Meininger and Aleksey Shatunov and Shaw, {Christopher E.} and Leigh, {P. Nigel} and Shaw, {Pamela J.} and Morrison, {Karen E.} and Isabella Fogh and Adriano Chi{\`o} and Traynor, {Bryan J.} and David Czell and Markus Weber and Peter Heutink and {De Bakker}, {Paul I W} and Vincenzo Silani and Wim Robberecht and {Van Den Berg}, {Leonard H.} and Veldink, {Jan H.}",
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TY - JOUR

T1 - C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia

T2 - A genome-wide meta-analysis

AU - Diekstra, Frank P.

AU - Van Deerlin, Vivianna M.

AU - Van Swieten, John C.

AU - Al-Chalabi, Ammar

AU - Ludolph, Albert C.

AU - Weishaupt, Jochen H.

AU - Hardiman, Orla

AU - Landers, John E.

AU - Brown, Robert H.

AU - Van Es, Michael A.

AU - Pasterkamp, R. Jeroen

AU - Koppers, Max

AU - Andersen, Peter M.

AU - Estrada, Karol

AU - Rivadeneira, Fernando

AU - Hofman, Albert

AU - Uitterlinden, André G.

AU - Van Damme, Philip

AU - Melki, Judith

AU - Meininger, Vincent

AU - Shatunov, Aleksey

AU - Shaw, Christopher E.

AU - Leigh, P. Nigel

AU - Shaw, Pamela J.

AU - Morrison, Karen E.

AU - Fogh, Isabella

AU - Chiò, Adriano

AU - Traynor, Bryan J.

AU - Czell, David

AU - Weber, Markus

AU - Heutink, Peter

AU - De Bakker, Paul I W

AU - Silani, Vincenzo

AU - Robberecht, Wim

AU - Van Den Berg, Leonard H.

AU - Veldink, Jan H.

PY - 2014

Y1 - 2014

N2 - Objective Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10-12) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10-11) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10-7) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10-7). Interpretation We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP. Ann Neurol 2014;76:120-133

AB - Objective Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10-12) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10-11) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10-7) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10-7). Interpretation We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP. Ann Neurol 2014;76:120-133

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