Nogo Receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches.
BACKGROUND
NOGO Receptor 1 (RTN4R) regulates axonal growth, as well as axon regeneration after injury. The gene maps to the 22q11.2 schizophrenia susceptibility locus and is thus a strong functional and positional candidate gene.


RESULTS
We evaluate evidence for genetic association between common RTN4R polymorphisms and schizophrenia in a large family sample of Afrikaner origin and screen the exonic sequence of RTN4R for rare variants in an independent sample from the U.S. We also employ animal model studies to assay a panel of schizophrenia-related behavioral tasks in an Rtn4r-deficient mouse model. We found weak sex-specific evidence for association between common RTN4R polymorphisms and schizophrenia in the Afrikaner patients. In the U.S. sample, we identified two novel non-conservative RTN4R coding variants in two patients with schizophrenia that were absent in 600 control chromosomes. In our complementary mouse model studies, we identified a haploinsufficient effect of Rtn4r on locomotor activity, but normal performance in schizophrenia-related behavioral tasks. We also provide evidence that Rtn4r deficiency can modulate the long-term behavioral effects of transient postnatal N-methyl-D-aspartate (NMDA) receptor hypofunction.


CONCLUSIONS
Our results do not support a major role of RTN4R in susceptibility to schizophrenia or the cognitive and behavioral deficits observed in individuals with 22q11 microdeletions. However, they suggest that RTN4R may modulate the genetic risk or clinical expression of schizophrenia in a subset of patients and identify additional studies that will be necessary to clarify the role of RTN4R in psychiatric phenotypes. In addition, our results raise interesting issues about evaluating the significance of rare genetic variants in disease and their role in causation.
Hsu
Ruby
R
Department of Neuroscience, Columbia University, New York, New York, United States of America.
Woodroffe
Abigail
A
Lai
Wen-Sung
WS
Cook
Melloni N
MN
Mukai
Jun
J
Dunning
Jonathan P
JP
Swanson
Douglas J
DJ
Roos
J Louw
JL
Abecasis
Gonçalo R
GR
Karayiorgou
Maria
M
Gogos
Joseph A
JA
D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal; D058851:GPI-Linked Proteins; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009185:Myelin Proteins / Q000737:chemistry / Q000235:genetics*; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; C000603199:RTN4 protein, human; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface; C000603201:Rtn4 protein, mouse