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, Richard E. Straub, Joey W. Trampush, Yuan Gao, Ningping Feng, Bin Xie, Joo Heon Shin, Hun Ki Lim, Gianluca Ursini, Kristin Bigos, Bhaskar Kolachana, Ryota Hashimoto, Masatoshi Takeda, Graham L. Baum, Dan Rujescu, Joseph H. Callicott, Thomas Hyde, Karen F. Berman, Joel Kleinman, Daniel Weinberger

Research output: Contribution to journalArticle

Abstract

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 Ref Seq 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.

Original languageEnglish (US)
Pages (from-to)647-656
Number of pages10
JournalJAMA Psychiatry
Volume71
Issue number6
DOIs
StatePublished - 2014

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Aptitude
Schizophrenia
Messenger RNA
Brain
Genotype
Cognition
RNA Sequence Analysis
Siblings
Sodium Channels
Cognitive Ability
Physiology
National Institute of Mental Health (U.S.)
Brain Diseases
Prefrontal Cortex
Short-Term Memory
Single Nucleotide Polymorphism
Germany
Psychiatry

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health

Cite this

Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals. / Dickinson, Dwight; Straub, Richard E.; Trampush, Joey W.; Gao, Yuan; Feng, Ningping; Xie, Bin; Shin, Joo Heon; Lim, Hun Ki; Ursini, Gianluca; Bigos, Kristin; Kolachana, Bhaskar; Hashimoto, Ryota; Takeda, Masatoshi; Baum, Graham L.; Rujescu, Dan; Callicott, Joseph H.; Hyde, Thomas; Berman, Karen F.; Kleinman, Joel; Weinberger, Daniel.

In: JAMA Psychiatry, Vol. 71, No. 6, 2014, p. 647-656.

Research output: Contribution to journalArticle

Dickinson, D, Straub, RE, Trampush, JW, Gao, Y, Feng, N, Xie, B, Shin, JH, Lim, HK, Ursini, G, Bigos, K, Kolachana, B, Hashimoto, R, Takeda, M, Baum, GL, Rujescu, D, Callicott, JH, Hyde, T, Berman, KF, Kleinman, J & Weinberger, D 2014, 'Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals', JAMA Psychiatry, vol. 71, no. 6, pp. 647-656. https://doi.org/10.1001/jamapsychiatry.2014.157
Dickinson, Dwight ; Straub, Richard E. ; Trampush, Joey W. ; Gao, Yuan ; Feng, Ningping ; Xie, Bin ; Shin, Joo Heon ; Lim, Hun Ki ; Ursini, Gianluca ; Bigos, Kristin ; Kolachana, Bhaskar ; Hashimoto, Ryota ; Takeda, Masatoshi ; Baum, Graham L. ; Rujescu, Dan ; Callicott, Joseph H. ; Hyde, Thomas ; Berman, Karen F. ; Kleinman, Joel ; Weinberger, Daniel. / Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals. In: JAMA Psychiatry. 2014 ; Vol. 71, No. 6. pp. 647-656.
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abstract = "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 Ref Seq 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.",
author = "Dwight Dickinson and Straub, {Richard E.} and Trampush, {Joey W.} and Yuan Gao and Ningping Feng and Bin Xie and Shin, {Joo Heon} and Lim, {Hun Ki} and Gianluca Ursini and Kristin Bigos and Bhaskar Kolachana and Ryota Hashimoto and Masatoshi Takeda and Baum, {Graham L.} and Dan Rujescu and Callicott, {Joseph H.} and Thomas Hyde and Berman, {Karen F.} and Joel Kleinman and Daniel Weinberger",
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T1 - Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals

AU - Dickinson, Dwight

AU - Straub, Richard E.

AU - Trampush, Joey W.

AU - Gao, Yuan

AU - Feng, Ningping

AU - Xie, Bin

AU - Shin, Joo Heon

AU - Lim, Hun Ki

AU - Ursini, Gianluca

AU - Bigos, Kristin

AU - Kolachana, Bhaskar

AU - Hashimoto, Ryota

AU - Takeda, Masatoshi

AU - Baum, Graham L.

AU - Rujescu, Dan

AU - Callicott, Joseph H.

AU - Hyde, Thomas

AU - Berman, Karen F.

AU - Kleinman, Joel

AU - Weinberger, Daniel

PY - 2014

Y1 - 2014

N2 - 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 Ref Seq 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.

AB - 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 Ref Seq 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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