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

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

Human molecular genetics (2010-08-06)

Hylke M Blauw, Ammar Al-Chalabi, Peter M Andersen, Paul W J van Vught, Frank P Diekstra, Michael A van Es, Christiaan G J Saris, Ewout J N Groen, Wouter van Rheenen, Max Koppers, Ruben Van't Slot, Eric Strengman, Karol Estrada, Fernando Rivadeneira, Albert Hofman, Andre G Uitterlinden, Lambertus A Kiemeney, Sita H M Vermeulen, Anna Birve, Stefan Waibel, Thomas Meyer, Simon Cronin, Russell L McLaughlin, Orla Hardiman, Peter C Sapp, Martin D Tobin, Louise V Wain, Barbara Tomik, Agnieszka Slowik, Robin Lemmens, Dan Rujescu, Claudia Schulte, Thomas Gasser, Robert H Brown, John E Landers, Wim Robberecht, Albert C Ludolph, Roel A Ophoff, Jan H Veldink, Leonard H van den Berg

PMID20685689

摘要

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.