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S071-5

Schizophrenia-Associated Genetic Variants on Chromosome 22Q13 Regulate
Naga Gene Expression in Dorsolateral Prefrontal Cortex

Kazutaka Ohi1, Joo Heon Shin3, Ming Li4, Tianzhang Ye4, Kristin L. Bigos2, Yankai Jia4, Ran Tao4,
Gianluca Ursini5, Andrew E. Jaffe2, Joel E. Kleinman2, Daniel R. Weinberger2

1Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Japan; Lieber Institute for Brain
Development, Johns Hopkins Medical Campus, USA 2Lieber Institute for Brain Development, Johns Hopkins
Medical Campus, USA 3Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Korea 4Lieber
Institute for Brain Development, Johns Hopkins Medical Campus, China 5Lieber Institute for Brain Development,
Johns Hopkins Medical Campus, Italy

Background/Objective: PGC II, the largest available genome-wide association study (GWAS)
interrogating genetic risk factors for schizophrenia, has identified four linkage-disequilibrium
(LD)-independent schizophrenia-associated genetic variants in three genomic loci on 22q13 (2014,
Ripke et al.). However, the molecular effects of these GWAS-implicated variants remain unknown.

Method: To investigate whether these variants affect gene expression in prefrontal human
postmortem brain, we performed exon-level and junction-level as well as gene-level analyses using
next-generation RNA-sequencing technology.

Result: The PGC II schizophrenia-associated variants were independently associated with NAGA
(rs134873 P CYP2D6-corrected=2.12×10-8, rs1023499 P CYP2D6-corrected=2.39×10-3) and
CYP2D6 expression (rs134873 P NAGA-corrected=4.66×10-20, rs1023499 P
NAGA-corrected=8.36×10-4) in a combined cohort of 129 patients with schizophrenia and 195
non-neurologic non-psychiatric controls. NAGA was more highly expressed in schizophrenia
compared to control subjects (P=2.59×10-4), while there was no difference in CYP2D6 expression
between patients and controls (P>0.05). Both risk associated SNPs were also associated with
expression of a transcript-specific 3’UTR of NAGA (ENST00000396398) (rs134873 P=1.66×10-11,
rs1023499 P=1.66×10-6).

Conclusion: Our findings demonstrate that LD-independent schizophrenia-associated variants in the
22q13 locus regulate NAGA expression in adult human brain. These findings provide the first
demonstration of the molecular pathology of risk for schizophrenia from genetic variation at 22q13.