Genetic correlates of insight in schizophrenia

Rose Mary Xavier, Allison Vorderstrasse, Richard S.E. Keefe, Jennifer R. Dungan

Research output: Contribution to journalArticle

Abstract

Insight in schizophrenia is clinically important as it is associated with several adverse outcomes. Genetic contributions to insight are unknown. We examined genetic contributions to insight by investigating if polygenic risk scores (PRS) and candidate regions were associated with insight. Method: Schizophrenia case-only analysis of the Clinical Antipsychotics Trials of Intervention Effectiveness trial. Schizophrenia PRS was constructed using Psychiatric Genomics Consortium (PGC) leave-one out GWAS as discovery data set. For candidate regions, we selected 105 schizophrenia-associated autosomal loci and 11 schizophrenia-related oligodendrocyte genes. We used regressions to examine PRS associations and set-based testing for candidate analysis. Results: We examined data from 730 subjects. Best-fit PRS at p-threshold of 1e-07 was associated with total insight (R 2 =0.005, P =0.05, empirical P =0.054) and treatment insight (R2 =0.005, P =0.048, empirical P =0.048). For models that controlled for neurocognition, PRS significantly predicted treatment insight but at higher p-thresholds (0.1 to 0.5) but did not survive correction.Patients with highest polygenic burden had 5.9 times increased risk for poor insight compared to patients with lowest burden. PRS explained 3.2% (P = 0.002, empirical P = 0.011) of variance in poor insight. Set-based analyses identified two variants associated with poor insight- rs320703, an intergenic variant (within-set P = 6e. -04, FDR P = 0.046) and rs1479165 in SOX2-OT (within-set P = 9e. -04, FDR P = 0.046). Conclusion: To the best of our knowledge, this is the first study examining genetic basis of insight. We provide evidence for genetic contributions to impaired insight. Relevance of findings and necessity for replication are discussed.

Original languageEnglish (US)
JournalSchizophrenia Research
DOIs
StateAccepted/In press - 2017

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Schizophrenia
Genome-Wide Association Study
Oligodendroglia
Genomics
Antipsychotic Agents
Psychiatry
Clinical Trials
Therapeutics
Genes

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Genetic correlates of insight in schizophrenia. / Xavier, Rose Mary; Vorderstrasse, Allison; Keefe, Richard S.E.; Dungan, Jennifer R.

In: Schizophrenia Research, 2017.

Research output: Contribution to journalArticle

Xavier, Rose Mary ; Vorderstrasse, Allison ; Keefe, Richard S.E. ; Dungan, Jennifer R. / Genetic correlates of insight in schizophrenia. In: Schizophrenia Research. 2017.
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abstract = "Insight in schizophrenia is clinically important as it is associated with several adverse outcomes. Genetic contributions to insight are unknown. We examined genetic contributions to insight by investigating if polygenic risk scores (PRS) and candidate regions were associated with insight. Method: Schizophrenia case-only analysis of the Clinical Antipsychotics Trials of Intervention Effectiveness trial. Schizophrenia PRS was constructed using Psychiatric Genomics Consortium (PGC) leave-one out GWAS as discovery data set. For candidate regions, we selected 105 schizophrenia-associated autosomal loci and 11 schizophrenia-related oligodendrocyte genes. We used regressions to examine PRS associations and set-based testing for candidate analysis. Results: We examined data from 730 subjects. Best-fit PRS at p-threshold of 1e-07 was associated with total insight (R 2 =0.005, P =0.05, empirical P =0.054) and treatment insight (R2 =0.005, P =0.048, empirical P =0.048). For models that controlled for neurocognition, PRS significantly predicted treatment insight but at higher p-thresholds (0.1 to 0.5) but did not survive correction.Patients with highest polygenic burden had 5.9 times increased risk for poor insight compared to patients with lowest burden. PRS explained 3.2{\%} (P = 0.002, empirical P = 0.011) of variance in poor insight. Set-based analyses identified two variants associated with poor insight- rs320703, an intergenic variant (within-set P = 6e. -04, FDR P = 0.046) and rs1479165 in SOX2-OT (within-set P = 9e. -04, FDR P = 0.046). Conclusion: To the best of our knowledge, this is the first study examining genetic basis of insight. We provide evidence for genetic contributions to impaired insight. Relevance of findings and necessity for replication are discussed.",
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