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Original Investigation |

Differential Effects of Common Variants in SCN2A on General Cognitive Ability, Brain Physiology, and messenger RNA Expression in Schizophrenia Cases and Control Individuals

Dwight Dickinson, PhD1; Richard E. Straub, PhD2; Joey W. Trampush, PhD1; Yuan Gao, PhD2; Ningping Feng, PhD1; Bin Xie, PhD2; Joo Heon Shin, PhD2; Hun Ki Lim, PhD2; Gianluca Ursini, MD2,3; Kristin L. Bigos, PhD2; Bhaskar Kolachana, PhD1; Ryota Hashimoto, MD4,5; Masatoshi Takeda, MD4,5; Graham L. Baum, BS1; Dan Rujescu, MD6,7; Joseph H. Callicott, MD1; Thomas M. Hyde, MD, PhD1,2; Karen F. Berman, MD1; Joel E. Kleinman, MD, PhD1,2; Daniel R. Weinberger, MD1,2,8,9,10,11
[+] Author Affiliations
1Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
2Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, Maryland
3Psychiatric Neuroscience Group, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
4Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Osaka, Japan
5Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan
6Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany
7Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle, Germany
8Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland
9Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
10Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
11McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
JAMA Psychiatry. 2014;71(6):647-656. doi:10.1001/jamapsychiatry.2014.157.
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Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

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Figure 1.
Manhattan and Quantile-Quantile Plots

A, Manhattan plot for SCN2A genomewide association study (GWAS) findings in 334 people with schizophrenia. Results are from 495 089 single-nucleotide polymorphisms tested for association with general cognitive ability in 334 individuals with schizophrenia. The red line denotes P = 5.0 × 10−8. Chr indicates chromosome. B, Quantile-quantile plot for SCN2A GWAS findings in 334 people with schizophrenia. The plot shows actual vs expected −2log(e)P for general cognitive ability in cases and control individuals. −2Log(e)P follows a χ2 distribution (df = 2) and can be used for statistical inference. Points above the horizontal line indicate an enrichment of low P values beyond what would be expected by chance.

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Figure 2.
Effect of SCN2A rs10174400 Genotype on General Cognitive Ability Composite Performance by Group in 334 Probands, 147 Siblings, and 363 Control Individuals

The triangles (schizophrenia), circles (siblings), and diamonds (controls) represent mean general cognitive ability values by genotype subgroups. The error bars are ±2 SEs.

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