Replication of rs300774, a genetic biomarker near ACP1, associated with suicide attempts in patients with schizophrenia: Relation to brain cholesterol biosynthesis

J Psychiatr Res. 2017 Nov;94:54-61. doi: 10.1016/j.jpsychires.2017.06.005. Epub 2017 Jun 16.

Abstract

The aim of this study was to determine if three biomarkers for suicide attempts previously identified and replicated in a genome-wide association (GWAS) study of bipolar disorder (BD) suicide attempters also predicted suicide attempts in patients prospectively diagnosed with schizophrenia (SCZ) or schizoaffective disorder (SAD). 162 genetically-verified Caucasian patients with SCZ or SAD were phenotyped for presence (45.7%) or absence of a lifetime suicide attempt. Three single nucleotide polymorphisms (SNPs) were genotyped or partially imputed from a GWAS dataset. After controlling for genetic architecture and gender, we replicated rs300774 (p = 0.012), near ACP1 (acid phosphatase 1), the top predictor of suicide attempts in the BD study. The result of Willour et al. (2012) was replicated in males (p = 0.046) but not in females (p = 0.205). The other two SNPs, rs7296262, and rs10437629, were not associated with suicide attempts in this study. rs300774 could be a cis-eQTL for ACP1, with minor allele carriers having lower expression levels (p = 0.002). This SNP also functioned as a trans-eQTL for genes related to cholesterol biosynthesis and the wnt-β-catenin pathway (p ≤ 0.0001). Further, co-expression analysis of candidate genes in brain suggested ACP1 is important to the regulation of a number of brain mechanisms linked to suicide, including cholesterol synthesis, β-catenin-mediated signaling pathway, serotonin, GABA, and the stress response via ARHGAP35 (p190rhogap), a repressor of glucocorticoid receptor (NR3C1) transcription. This study provides an additional validation of rs300774 as a potential transdiagnostic biomarker for suicide attempts and evidence that ACP1 may have an important role in regulation of the multiple systems associated with suicide.

Keywords: ACP1; Cholesterol biosynthesis; GABA; Schizophrenia; Stress response; Suicide attempts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Brain / metabolism*
  • Cholesterol / biosynthesis*
  • Cholesterol / genetics
  • Female
  • Genetic Markers
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Protein Tyrosine Phosphatases / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Psychotic Disorders / genetics
  • Psychotic Disorders / physiopathology*
  • Quantitative Trait Loci / genetics*
  • Schizophrenia / genetics
  • Schizophrenia / physiopathology*
  • Sex Factors
  • Suicide, Attempted*
  • Young Adult
  • beta Catenin / genetics

Substances

  • CTNNB1 protein, human
  • Genetic Markers
  • Proto-Oncogene Proteins
  • beta Catenin
  • Cholesterol
  • ACP1 protein, human
  • Protein Tyrosine Phosphatases