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.
Blauw
Hylke M
HM
Department of Neurology, Rudolf Magnus Institute of Neuroscience, Genetics, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
Al-Chalabi
Ammar
A
Andersen
Peter M
PM
van Vught
Paul W J
PW
Diekstra
Frank P
FP
van Es
Michael A
MA
Saris
Christiaan G J
CG
Groen
Ewout J N
EJ
van Rheenen
Wouter
W
Koppers
Max
M
Van't Slot
Ruben
R
Strengman
Eric
E
Estrada
Karol
K
Rivadeneira
Fernando
F
Hofman
Albert
A
Uitterlinden
Andre G
AG
Kiemeney
Lambertus A
LA
Vermeulen
Sita H M
SH
Birve
Anna
A
Waibel
Stefan
S
Meyer
Thomas
T
Cronin
Simon
S
McLaughlin
Russell L
RL
Hardiman
Orla
O
Sapp
Peter C
PC
Tobin
Martin D
MD
Wain
Louise V
LV
Tomik
Barbara
B
Slowik
Agnieszka
A
Lemmens
Robin
R
Rujescu
Dan
D
Schulte
Claudia
C
Gasser
Thomas
T
Brown
Robert H
RH
Landers
John E
JE
Robberecht
Wim
W
Ludolph
Albert C
AC
Ophoff
Roel A
RA
Veldink
Jan H
JH
van den Berg
Leonard H
LH
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009046:Motor Neurons; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics*; D012307:Risk Factors; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics
D008565:Membrane Proteins; C478824:NIPA1 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases