Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers

Annelot M Dekker; Meinie Seelen; Perry T C van Doormaal; Wouter van Rheenen; Reinoud J P Bothof; Tim van Riessen; William J Brands; Anneke J van der Kooi; Marianne de Visser; Nicol C Voermans; R Jeroen Pasterkamp; Jan H Veldink; Leonard H van den Berg; Michael A van Es

doi:10.1016/j.neurobiolaging.2015.12.012

Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers

Annelot M Dekker, Meinie Seelen, Perry T C van Doormaal, Wouter van Rheenen, Reinoud J P Bothof, Tim van Riessen, William J Brands, Anneke J van der Kooi, Marianne de Visser, Nicol C Voermans, R Jeroen Pasterkamp, Jan H Veldink, Leonard H van den Berg, Michael A van Es

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

Abstract

Sporadic amyotrophic lateral sclerosis (ALS) is considered to be a complex disease with multiple genetic risk factors contributing to the pathogenesis. Identification of genetic risk factors that co-occur frequently could provide relevant insight into underlying mechanisms of motor neuron degeneration. To dissect the genetic architecture of sporadic ALS, we undertook a large sequencing study in 755 apparently sporadic ALS cases and 959 controls, analyzing 10 ALS genes: SOD1, C9orf72, TARDBP, FUS, ANG, CHMP2B, ATXN2, NIPA1, SMN1, and UNC13A. We observed sporadic cases with multiple genetic risk variants in 4.1% compared with 1.3% in controls. The overall difference was not in excess of what is to be expected by chance (binomial test, p = 0.59). We did, however, observe a higher frequency than expected of C9orf72 repeat carriers with co-occurring susceptibility variants (ATXN2, NIPA1, and SMN1; p = 0.001), which is mainly because of the co-occurrence of NIPA1 repeats in 15% of C9orf72 repeat carriers (p = 0.006).

Original language	English
Journal	Neurobiology of Aging
DOIs	https://doi.org/10.1016/j.neurobiolaging.2015.12.012
Publication status	Published - 29 Dec 2015

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Dekker, A. M., Seelen, M., van Doormaal, P. T. C., van Rheenen, W., Bothof, R. J. P., van Riessen, T., Brands, W. J., van der Kooi, A. J., de Visser, M., Voermans, N. C., Pasterkamp, R. J., Veldink, J. H., van den Berg, L. H., & van Es, M. A. (2015). Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers. Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2015.12.012

@article{8c50994bd60c482bafa4f622248208bc,

title = "Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers",

abstract = "Sporadic amyotrophic lateral sclerosis (ALS) is considered to be a complex disease with multiple genetic risk factors contributing to the pathogenesis. Identification of genetic risk factors that co-occur frequently could provide relevant insight into underlying mechanisms of motor neuron degeneration. To dissect the genetic architecture of sporadic ALS, we undertook a large sequencing study in 755 apparently sporadic ALS cases and 959 controls, analyzing 10 ALS genes: SOD1, C9orf72, TARDBP, FUS, ANG, CHMP2B, ATXN2, NIPA1, SMN1, and UNC13A. We observed sporadic cases with multiple genetic risk variants in 4.1% compared with 1.3% in controls. The overall difference was not in excess of what is to be expected by chance (binomial test, p = 0.59). We did, however, observe a higher frequency than expected of C9orf72 repeat carriers with co-occurring susceptibility variants (ATXN2, NIPA1, and SMN1; p = 0.001), which is mainly because of the co-occurrence of NIPA1 repeats in 15% of C9orf72 repeat carriers (p = 0.006).",

author = "Dekker, {Annelot M} and Meinie Seelen and {van Doormaal}, {Perry T C} and {van Rheenen}, Wouter and Bothof, {Reinoud J P} and {van Riessen}, Tim and Brands, {William J} and {van der Kooi}, {Anneke J} and {de Visser}, Marianne and Voermans, {Nicol C} and Pasterkamp, {R Jeroen} and Veldink, {Jan H} and {van den Berg}, {Leonard H} and {van Es}, {Michael A}",

year = "2015",

month = dec,

day = "29",

doi = "10.1016/j.neurobiolaging.2015.12.012",

language = "English",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier",

}

Dekker, AM, Seelen, M, van Doormaal, PTC, van Rheenen, W, Bothof, RJP, van Riessen, T, Brands, WJ, van der Kooi, AJ, de Visser, M, Voermans, NC, Pasterkamp, RJ , Veldink, JH , van den Berg, LH & van Es, MA 2015, 'Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers', Neurobiology of Aging. https://doi.org/10.1016/j.neurobiolaging.2015.12.012

TY - JOUR

T1 - Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers

AU - Dekker, Annelot M

AU - Seelen, Meinie

AU - van Doormaal, Perry T C

AU - van Rheenen, Wouter

AU - Bothof, Reinoud J P

AU - van Riessen, Tim

AU - Brands, William J

AU - van der Kooi, Anneke J

AU - de Visser, Marianne

AU - Voermans, Nicol C

AU - Pasterkamp, R Jeroen

AU - Veldink, Jan H

AU - van den Berg, Leonard H

AU - van Es, Michael A

PY - 2015/12/29

Y1 - 2015/12/29

N2 - Sporadic amyotrophic lateral sclerosis (ALS) is considered to be a complex disease with multiple genetic risk factors contributing to the pathogenesis. Identification of genetic risk factors that co-occur frequently could provide relevant insight into underlying mechanisms of motor neuron degeneration. To dissect the genetic architecture of sporadic ALS, we undertook a large sequencing study in 755 apparently sporadic ALS cases and 959 controls, analyzing 10 ALS genes: SOD1, C9orf72, TARDBP, FUS, ANG, CHMP2B, ATXN2, NIPA1, SMN1, and UNC13A. We observed sporadic cases with multiple genetic risk variants in 4.1% compared with 1.3% in controls. The overall difference was not in excess of what is to be expected by chance (binomial test, p = 0.59). We did, however, observe a higher frequency than expected of C9orf72 repeat carriers with co-occurring susceptibility variants (ATXN2, NIPA1, and SMN1; p = 0.001), which is mainly because of the co-occurrence of NIPA1 repeats in 15% of C9orf72 repeat carriers (p = 0.006).

AB - Sporadic amyotrophic lateral sclerosis (ALS) is considered to be a complex disease with multiple genetic risk factors contributing to the pathogenesis. Identification of genetic risk factors that co-occur frequently could provide relevant insight into underlying mechanisms of motor neuron degeneration. To dissect the genetic architecture of sporadic ALS, we undertook a large sequencing study in 755 apparently sporadic ALS cases and 959 controls, analyzing 10 ALS genes: SOD1, C9orf72, TARDBP, FUS, ANG, CHMP2B, ATXN2, NIPA1, SMN1, and UNC13A. We observed sporadic cases with multiple genetic risk variants in 4.1% compared with 1.3% in controls. The overall difference was not in excess of what is to be expected by chance (binomial test, p = 0.59). We did, however, observe a higher frequency than expected of C9orf72 repeat carriers with co-occurring susceptibility variants (ATXN2, NIPA1, and SMN1; p = 0.001), which is mainly because of the co-occurrence of NIPA1 repeats in 15% of C9orf72 repeat carriers (p = 0.006).

U2 - 10.1016/j.neurobiolaging.2015.12.012

DO - 10.1016/j.neurobiolaging.2015.12.012

M3 - Article

C2 - 26777436

SN - 0197-4580

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers

Abstract

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