Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia

Abstract

Objective: The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of Schizophrenia.

Method: Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects.

Results: Associations with endophenotypes were observed for 46 genes of potential functional significance, with three SNPs at p<10(-4), 27 SNPs at p<10(-3), and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility.

Conclusions: This study supports use of relevant endophenotypes and the bootstrap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias."

Figure 1

Results of the association analysis between 1,385 SNPs in 94 candidate genes and each of the 12 endophenotypes for schizophrenia. Each SNP association is represented by a dot and color-coded according to the endophenotype tested. Genes with at least one SNP with p<10⁻³ are indicated at the top of the figure.

Figure 2

Summary of the most significant p-value observed for each of the 46 genes with each of the 12 endophenotypes using a minimum p-value of <0.01 as a threshold. Note that not all associations to the same gene across endophenotypes reflect associations to the same SNP. Genes associated with four or more endophenotypes are indicated in bold. Numbers indicate 2 or 3 independent associations within the gene with p<0.01 in the secondary analyses. All other genes had only one independent association with no other SNP having p<0.01 after accounting for the most significant SNP.

Figure 3

Distribution of the 94 candidate genes in known biological pathways, as determined by Ingenuity Pathways Analysis. Associated (p<0.01) genes are indicated in bold, and those associated with more than one endophenotype are additionally indicated with an asterisk (*).

Figure 4

Path diagram detailing the types of molecular interactions that have been observed to occur between a subset of the 94 candidate genes on the COGS SNP Chip. Genes are represented as nodes, and the biological relationship between two nodes is represented as a line or arrow supported by at least one reference from the literature, a textbook, or canonical information derived from the human, mouse, and rat orthologs of the gene that are stored in the Ingenuity Pathways Knowledge Base. Solid and dashed lines/arrows indicate direct and indirect interactions, respectively, and are color-coded by interaction type as indicated. Genes found to be associated (p<0.01) with at least one endophenotype are highlighted in yellow, with an asterisk (*) indicating those genes associated with more than one endophenotype.