Abstract

While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis.

Highlights

  • Genetic factors clearly play a substantial role in the etiology of schizophrenia, as evidenced by twin and other family studies that indicate a heritability of up to 80% for this disorder [1]

  • Prior to conducting association analyses, we performed some initial assessments of the primary endophenotypes and secondary endophenotypic measures to validate their informativity in the 219 subjects of European ancestry

  • We assessed six neurophysiological and neurocognitive primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary endophenotypic measures derived from the endophenotype test paradigms

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Summary

Introduction

Genetic factors clearly play a substantial role in the etiology of schizophrenia, as evidenced by twin and other family studies that indicate a heritability of up to 80% for this disorder [1]. One strategy that may aid in identifying the genetic substrates of a complex disorder, like schizophrenia, is to interrogate specific candidate genes thought to be associated with the underlying neurobiology of the disorder or with its associated endophenotypes [5]. To this end, we have constructed a custom SNP array containing 1,536. SNPs in 94 genes that were chosen based on hypotheses regarding biological systems of relevance to schizophrenia, as well as an extensive review of published linkage, association, gene expression, brain imaging, and model organism studies [6]. A similar approach has been used in recent studies of addictive disorders [7] and eating disorders [8,9]

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