Identification of a schizophrenia-associated functional noncoding variant in NOS1AP.
OBJECTIVE
The authors previously demonstrated significant association between markers within NOS1AP and schizophrenia in a set of Canadian families of European descent, as well as significantly increased expression in schizophrenia of NOS1AP in unrelated postmortem samples from the dorsolateral prefrontal cortex. In this study the authors sought to apply novel statistical methods and conduct additional biological experiments to isolate at least one risk allele within NOS1AP.


METHODS
Using the posterior probability of linkage disequilibrium (PPLD) to measure the probability that a single nucleotide polymorphism (SNP) is in linkage disequilibrium with schizophrenia, the authors evaluated 60 SNPs from NOS1AP in 24 Canadian families demonstrating linkage and association to this region. SNPs exhibiting strong evidence of linkage disequilibrium were tested for regulatory function by luciferase reporter assay. Two human neural cell lines (SK-N-MC and PFSK-1) were transfected with a vector containing each allelic variant of the SNP, the NOS1AP promoter, and a luciferase gene. Alleles altering expression were further assessed for binding of nuclear proteins by electrophoretic mobility shift assay.


RESULTS
Three SNPs produced PPLDs >40%. One of them, rs12742393, demonstrated significant allelic expression differences in both cell lines tested. The allelic variation at this SNP altered the affinity of nuclear protein binding to this region of DNA.


CONCLUSIONS
The A allele of rs12742393 appears to be a risk allele associated with schizophrenia that acts by enhancing transcription factor binding and increasing gene expression.
Wratten
Naomi S
NS
Rutgers University Department of Genetics, 145 Bevier Road, Piscataway, NJ 08854, USA.
Memoli
Holly
H
Huang
Yungui
Y
Dulencin
Anna M
AM
Matteson
Paul G
PG
Cornacchia
Michelle A
MA
Azaro
Marco A
MA
Messenger
Jaime
J
Hayter
Jared E
JE
Bassett
Anne S
AS
Buyske
Steven
S
Millonig
James H
JH
Vieland
Veronica J
VJ
Brzustowicz
Linda M
LM
D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics / Q000473:pathology; D002170:Canada; D002460:Cell Line; D015870:Gene Expression; D017930:Genes, Reporter / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D052248:Nitric Oxide Synthase Type I / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000473:pathology; D011618:Psychotic Disorders / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology
D005819:Genetic Markers; D052248:Nitric Oxide Synthase Type I