A large genome scan for rare CNVs in amyotrophic lateral sclerosis

作者：Blauw Hylke M; Al Chalabi Ammar; Andersen Peter M; van Vught Paul W J; Diekstra Frank P; van Es Michael A; Saris Christiaan G J; Groen Ewout J N; van Rheenen Wouter; Koppers Max; van't Slot Ruben; Strengman Eric; Estrada Karol; Rivadeneira Fernando; Hofman Albert; Uitterlinden Andre G; Kiemeney Lambertus A; Vermeulen Sita H M; Birve Anna; Waibel Stefan; Meyer Thomas; Cronin Simon; McLaughlin Russell L; Hardiman Orla; Sapp Peter C; Tobin Martin D

来源：Human Molecular Genetics, 2010, 19(20): 4091-4099.

DOI：10.1093/hmg/ddq323

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 x 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 x 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 x 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 x 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.

• 出版日期2010-10-15