C9orf72 and UNC13A are shared risk loci for ALS and FTD: 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 Meininger; Aleksey 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

doi:10.1002/ana.24198

C9orf72 and UNC13A are shared risk loci for ALS and FTD: 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

UMC University Medical Center Utrecht

Research output: Contribution to journal › Article › peer-review

79 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 GWAS data of 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) at C9orf72 on chromosome 9p21.2 (lowest p=2.6×10(-12) ) and one 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 at 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.

Original language	English
Pages (from-to)	120-133
Number of pages	14
Journal	Annals of Neurology
Volume	76
Issue number	1
Early online date	16 Jun 2014
DOIs	https://doi.org/10.1002/ana.24198
Publication status	Published - Jul 2014

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Diekstra, F. P., Van Deerlin, V. M., van Swieten, J. C., Al-Chalabi, A., Ludolph, A. C., Weishaupt, J. H., Hardiman, O., Landers, J. E., Brown, R. H., van Es, M. A., Pasterkamp, R. J., Koppers, M., Andersen, P. M., Estrada, K., Rivadeneira, F., Hofman, A., Uitterlinden, A. G., van Damme, P., Melki, J., ... Veldink, J. H. (2014). C9orf72 and UNC13A are shared risk loci for ALS and FTD: A genome-wide meta-analysis. Annals of Neurology, 76(1), 120-133. https://doi.org/10.1002/ana.24198

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title = "C9orf72 and UNC13A are shared risk loci for ALS and FTD: A genome-wide meta-analysis",

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 GWAS data of 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) at C9orf72 on chromosome 9p21.2 (lowest p=2.6×10(-12) ) and one 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 at 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.",

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}",

year = "2014",

month = jul,

doi = "10.1002/ana.24198",

language = "English",

volume = "76",

pages = "120--133",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

number = "1",

}

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 ALS and FTD: A genome-wide meta-analysis', Annals of Neurology, vol. 76, no. 1, pp. 120-133. https://doi.org/10.1002/ana.24198

TY - JOUR

T1 - C9orf72 and UNC13A are shared risk loci for ALS and FTD

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 - 2014/7

Y1 - 2014/7

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 GWAS data of 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) at C9orf72 on chromosome 9p21.2 (lowest p=2.6×10(-12) ) and one 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 at 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.

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 GWAS data of 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) at C9orf72 on chromosome 9p21.2 (lowest p=2.6×10(-12) ) and one 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 at 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.

U2 - 10.1002/ana.24198

DO - 10.1002/ana.24198

M3 - Article

C2 - 24931836

SN - 0364-5134

VL - 76

SP - 120

EP - 133

JO - Annals of Neurology

JF - Annals of Neurology

IS - 1

ER -

C9orf72 and UNC13A are shared risk loci for ALS and FTD: A genome-wide meta-analysis

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