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 - 2016
Y1 - 2016
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 - https://doi.org/10.1016/j.neurobiolaging.2015.12.012
DO - https://doi.org/10.1016/j.neurobiolaging.2015.12.012
M3 - Article
C2 - 26777436
SN - 0197-4580
VL - 39
SP - 220.e9-220.15
JO - Neurobiology of aging
JF - Neurobiology of aging
ER -