A comprehensive family-based replication study of schizophrenia genes

Karolina A. Aberg, Youfang Liu, Jozsef Bukszár, Joseph L. McClay, Amit N. Khachane, Ole A. Andreassen, Douglas Blackwood, Aiden Corvin, Srdjan Djurovic, Hugh Gurling, Roel Ophoff, Carlos N. Pato, Michele T. Pato, Brien Riley, Todd Webb, Kenneth Kendler, Mick O'Donovan, Nick Craddock, George Kirov, Mike Owen & 7 others Dan Rujescu, David St Clair, Thomas Werge, Christina M. Hultman, Lynn E. Delisi, Patrick Sullivan, Edwin J. Van Den Oord*

*Corresponding author for this work

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

Importance: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets. 

Objective: To identify SCZ susceptibility genes. 

Design: We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1 085 772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. 

Setting: Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. 

Patients: We included 11 185 cases and 10 768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. 

Main Outcomes and Measures: Case-control status for SCZ. 

Results: Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P < .01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 × 10-16) and 93% in subjects of European ancestry only (P < 2.20 × 10-16). Our results supported the major histocompatibility complex region showing a 3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 × 10 -10) and NOTCH4 (P = 3.16 × 10-7) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 × 10-7), AS3MT (P = 9.01 × 10-7), CNNM2 (P = 6.07 × 10-7), and NT5C2 (P = 4.09 × 10-7). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction) and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). 

Conclusions and Relevance: We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.

Original languageEnglish
Pages (from-to)573-581
Number of pages9
JournalJAMA Psychiatry
Volume70
Issue number6
DOIs
Publication statusPublished - 1 Jun 2013

Fingerprint

Schizophrenia
Single Nucleotide Polymorphism
Genes
Meta-Analysis
Databases
Genome-Wide Association Study
Quality Control
Neuronal Cell Adhesion Molecules
Neural Cell Adhesion Molecule L1
Immunological Synapses
Genetic Databases
Quantitative Trait Loci
Antigen Presentation
Cell Adhesion Molecules
Gene Expression Profiling
Disease Management
Major Histocompatibility Complex
Nuclear Family
Pharmaceutical Preparations
Psychiatry

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Aberg, K. A., Liu, Y., Bukszár, J., McClay, J. L., Khachane, A. N., Andreassen, O. A., ... Van Den Oord, E. J. (2013). A comprehensive family-based replication study of schizophrenia genes. JAMA Psychiatry, 70(6), 573-581. https://doi.org/10.1001/jamapsychiatry.2013.288

A comprehensive family-based replication study of schizophrenia genes. / Aberg, Karolina A.; Liu, Youfang; Bukszár, Jozsef; McClay, Joseph L.; Khachane, Amit N.; Andreassen, Ole A.; Blackwood, Douglas; Corvin, Aiden; Djurovic, Srdjan; Gurling, Hugh; Ophoff, Roel; Pato, Carlos N.; Pato, Michele T.; Riley, Brien; Webb, Todd; Kendler, Kenneth; O'Donovan, Mick; Craddock, Nick; Kirov, George; Owen, Mike; Rujescu, Dan; St Clair, David; Werge, Thomas; Hultman, Christina M.; Delisi, Lynn E.; Sullivan, Patrick; Van Den Oord, Edwin J.

In: JAMA Psychiatry, Vol. 70, No. 6, 01.06.2013, p. 573-581.

Research output: Contribution to journalArticle

Aberg, KA, Liu, Y, Bukszár, J, McClay, JL, Khachane, AN, Andreassen, OA, Blackwood, D, Corvin, A, Djurovic, S, Gurling, H, Ophoff, R, Pato, CN, Pato, MT, Riley, B, Webb, T, Kendler, K, O'Donovan, M, Craddock, N, Kirov, G, Owen, M, Rujescu, D, St Clair, D, Werge, T, Hultman, CM, Delisi, LE, Sullivan, P & Van Den Oord, EJ 2013, 'A comprehensive family-based replication study of schizophrenia genes', JAMA Psychiatry, vol. 70, no. 6, pp. 573-581. https://doi.org/10.1001/jamapsychiatry.2013.288
Aberg KA, Liu Y, Bukszár J, McClay JL, Khachane AN, Andreassen OA et al. A comprehensive family-based replication study of schizophrenia genes. JAMA Psychiatry. 2013 Jun 1;70(6):573-581. https://doi.org/10.1001/jamapsychiatry.2013.288
Aberg, Karolina A. ; Liu, Youfang ; Bukszár, Jozsef ; McClay, Joseph L. ; Khachane, Amit N. ; Andreassen, Ole A. ; Blackwood, Douglas ; Corvin, Aiden ; Djurovic, Srdjan ; Gurling, Hugh ; Ophoff, Roel ; Pato, Carlos N. ; Pato, Michele T. ; Riley, Brien ; Webb, Todd ; Kendler, Kenneth ; O'Donovan, Mick ; Craddock, Nick ; Kirov, George ; Owen, Mike ; Rujescu, Dan ; St Clair, David ; Werge, Thomas ; Hultman, Christina M. ; Delisi, Lynn E. ; Sullivan, Patrick ; Van Den Oord, Edwin J. / A comprehensive family-based replication study of schizophrenia genes. In: JAMA Psychiatry. 2013 ; Vol. 70, No. 6. pp. 573-581.
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abstract = "Importance: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets. Objective: To identify SCZ susceptibility genes. Design: We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1 085 772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. Setting: Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. Patients: We included 11 185 cases and 10 768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. Main Outcomes and Measures: Case-control status for SCZ. Results: Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P < .01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89{\%} in the combined ancestry group (sign test, P < 2.20 × 10-16) and 93{\%} in subjects of European ancestry only (P < 2.20 × 10-16). Our results supported the major histocompatibility complex region showing a 3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 × 10 -10) and NOTCH4 (P = 3.16 × 10-7) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 × 10-7), AS3MT (P = 9.01 × 10-7), CNNM2 (P = 6.07 × 10-7), and NT5C2 (P = 4.09 × 10-7). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction) and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). Conclusions and Relevance: We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.",
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T1 - A comprehensive family-based replication study of schizophrenia genes

AU - Aberg, Karolina A.

AU - Liu, Youfang

AU - Bukszár, Jozsef

AU - McClay, Joseph L.

AU - Khachane, Amit N.

AU - Andreassen, Ole A.

AU - Blackwood, Douglas

AU - Corvin, Aiden

AU - Djurovic, Srdjan

AU - Gurling, Hugh

AU - Ophoff, Roel

AU - Pato, Carlos N.

AU - Pato, Michele T.

AU - Riley, Brien

AU - Webb, Todd

AU - Kendler, Kenneth

AU - O'Donovan, Mick

AU - Craddock, Nick

AU - Kirov, George

AU - Owen, Mike

AU - Rujescu, Dan

AU - St Clair, David

AU - Werge, Thomas

AU - Hultman, Christina M.

AU - Delisi, Lynn E.

AU - Sullivan, Patrick

AU - Van Den Oord, Edwin J.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - Importance: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets. Objective: To identify SCZ susceptibility genes. Design: We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1 085 772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. Setting: Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. Patients: We included 11 185 cases and 10 768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. Main Outcomes and Measures: Case-control status for SCZ. Results: Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P < .01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 × 10-16) and 93% in subjects of European ancestry only (P < 2.20 × 10-16). Our results supported the major histocompatibility complex region showing a 3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 × 10 -10) and NOTCH4 (P = 3.16 × 10-7) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 × 10-7), AS3MT (P = 9.01 × 10-7), CNNM2 (P = 6.07 × 10-7), and NT5C2 (P = 4.09 × 10-7). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction) and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). Conclusions and Relevance: We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.

AB - Importance: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets. Objective: To identify SCZ susceptibility genes. Design: We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1 085 772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. Setting: Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. Patients: We included 11 185 cases and 10 768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. Main Outcomes and Measures: Case-control status for SCZ. Results: Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P < .01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 × 10-16) and 93% in subjects of European ancestry only (P < 2.20 × 10-16). Our results supported the major histocompatibility complex region showing a 3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 × 10 -10) and NOTCH4 (P = 3.16 × 10-7) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 × 10-7), AS3MT (P = 9.01 × 10-7), CNNM2 (P = 6.07 × 10-7), and NT5C2 (P = 4.09 × 10-7). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction) and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). Conclusions and Relevance: We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.

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