A large genome scan for rare CNVs in amyotrophic lateral sclerosis.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.

DOI: 10.1093/hmg/ddq323

2 Figures and Tables


Citations per Year

1,385 Citations

Semantic Scholar estimates that this publication has 1,385 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Blauw2010ALG, title={A large genome scan for rare CNVs in amyotrophic lateral sclerosis.}, author={Hylke Merijn Blauw and Ammar Al-Chalabi and Peter Munch Andersen and Paul W. J. van Vught and Frank P. Diekstra and Michael A van Es and Christiaan G. J. Saris and Ewout J N Groen and Wouter van Rheenen and Max Koppers and Ruben van't Slot and Eric Strengman and Karol Estrada and Fernando Rivadeneira and Albert Hofman and Andr{\'e} G. Uitterlinden and Lambertus A Kiemeney and Sita H. H. M. Vermeulen and Anna Birve and Stefan Waibel and Thomas Meyer and Simon Cronin and R. McLaughlin and Orla Hardiman and Peter C. Sapp and Martin D Tobin and Louise V Wain and Barbara Tomik and Agnieszka Julia Slowik and Robin Lemmens and Dan Rujescu and Claudia C Schulte and Thomas Gasser and Robert H. Brown and John E Landers and Wim Robberecht and Albert Christian Ludolph and Roel A. Ophoff and Jan Herman Veldink and Leonard H van den Berg}, journal={Human molecular genetics}, year={2010}, volume={19 20}, pages={4091-9} }