Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals.
OBJECTIVE
One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation.


OBJECTIVE
To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals.


METHODS
Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals.


METHODS
We studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts.


RESULTS
The schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10(-10)). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide significant (P = 1.75 × 10(-9)). Siblings showed a genotype association with g parallel to the schizophrenia group and the same interaction pattern. Parallel, but weaker, associations with cognition were found in independent schizophrenia samples. Imaging analyses showed a similar pattern of genotype associations by group and genotype-by-group interaction. Sequencing of RNA in brain revealed reduced expression in 2 of 3 SCN2A alternative transcripts in the patient group, with genotype-by-group interaction, that again paralleled the cognition effects.


CONCLUSIONS
The findings implicate SCN2A and sodium channel biology in cognitive impairment in schizophrenia cases and unaffected relatives and may facilitate development of cognition-enhancing treatments.
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Dwight
D
Dickinson
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland.
Richard E
RE
Straub
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Joey W
JW
Trampush
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland.
Yuan
Y
Gao
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Ningping
N
Feng
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland.
Bin
B
Xie
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland.
Joo Heon
JH
Shin
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland.
Hun Ki
HK
Lim
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland3Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy.
Gianluca
G
Ursini
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland.
Kristin L
KL
Bigos
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Bhaskar
B
Kolachana
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan5Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
Ryota
R
Hashimoto
Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan5Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
Masatoshi
M
Takeda
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Graham L
GL
Baum
Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany7Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle, Germany.
Dan
D
Rujescu
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Joseph H
JH
Callicott
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland2Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland.
Thomas M
TM
Hyde
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Karen F
KF
Berman
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland2Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland.
Joel E
JE
Kleinman
Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland2Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland8Depar.
Daniel R
DR
Weinberger
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D016022:Case-Control Studies; D003071:Cognition / Q000502:physiology*; D005260:Female; D059907:Functional Neuroimaging; D015870:Gene Expression / Q000235:genetics / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000502:physiology; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012565:Schizophrenic Psychology; D035781:Siblings; D055815:Young Adult
D062551:NAV1.2 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C568251:SCN2A protein, human