TY - JOUR
T1 - Replication of rs300774, a genetic biomarker near ACP1, associated with suicide attempts in patients with schizophrenia
T2 - Relation to brain cholesterol biosynthesis
AU - Li, Jiang
AU - Yoshikawa, Akane
AU - Meltzer, Herbert Y.
N1 - Funding Information:
Funding support for a genome-wide association study on suicide attempts was provided by a distinguished investigator innovation grants awarded to HYM from the American Foundation for Suicide Prevention (AFSP) (DIG-1-094-016; DIG-0-159-13).
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
KW - ACP1
KW - Cholesterol biosynthesis
KW - GABA
KW - Schizophrenia
KW - Stress response
KW - Suicide attempts
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U2 - 10.1016/j.jpsychires.2017.06.005
DO - 10.1016/j.jpsychires.2017.06.005
M3 - Article
C2 - 28668716
AN - SCOPUS:85021407482
VL - 94
SP - 54
EP - 61
JO - Journal of Psychiatric Research
JF - Journal of Psychiatric Research
SN - 0022-3956
ER -