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Original Article |

A Comprehensive Family-Based Replication Study of Schizophrenia Genes

Karolina A. Aberg, PhD; Youfang Liu, PhD; Jozsef Bukszár, PhD; Joseph L. McClay, PhD; Amit N. Khachane, PhD; Ole A. Andreassen, PhD; Douglas Blackwood, PhD; Aiden Corvin, PhD; Srdjan Djurovic, PhD; Hugh Gurling, PhD; Roel Ophoff, PhD; Carlos N. Pato, MD; Michele T. Pato, MD; Brien Riley, PhD; Todd Webb, PhD; Kenneth Kendler, MD; Mick O’Donovan, PhD; Nick Craddock, PhD; George Kirov, PhD; Mike Owen, PhD; Dan Rujescu, PhD; David St Clair, PhD; Thomas Werge, PhD; Christina M. Hultman, PhD; Lynn E. Delisi, MD; Patrick Sullivan, MD; Edwin J. van den Oord, PhD
JAMA Psychiatry. 2013;70(6):573-581. doi:10.1001/jamapsychiatry.2013.288.
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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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Figures

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Figure 1. Histograms of P values from the family-based association analyses. Results are given in subjects from European (A and E), Asian (B and F), and African (C and G) ancestry. The combined analyses (D and I) present results from the test statistics across the 3 groups while taking the direction of effects into account. Plots are given for single-nucleotide polymorphisms not including (A-D) and including (F-I) the major histocompatibility complex region.

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Graphic Jump Location

Figure 2. Comparison of single-nucleotide polymorphisms selected through data integration (blue), that have a top genome-wide association study (GWAS) meta-analysis P value (red), or both (green). P values in the family-based replication study are calculated on a −log10 scale.

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