Abstract
Unbiased genome-wide approaches can provide novel insights into the biological pathways that are important for human behavior and psychiatric disorder risk. The association of α-endomannosidase gene (MANEA) variants and cocaine-induced paranoia (CIP) was initially described in a study that used a whole-genome approach. Behavioral effects have been reported for other mannosidase genes, but MANEA function in humans and the clinical potential of the previous findings remain unclear. We hypothesized that MANEA would be associated with psychiatric phenotypes unrelated to cocaine use. We used a multi-stage association study approach starting with four psychiatric disorders to show an association between a MANEA single-nucleotide polymorphism (SNP; rs1133503) and anxiety disorders. In the first study of 2073 European American (EA) and 2459 African American subjects mostly with comorbid drug or alcohol dependence, we observed an association in EAs of rs1133503 with panic disorder (PD) (191 PD cases, odds ratio (OR)=1.7 (95% confidence interval (CI): 1.22–2.41), P=0.002). We replicated this finding in an independent sample of 142 PD cases (OR =1.53 (95% CI: 1.00–2.31), P=0.043) and extended it in an independent sample of 131 generalized social anxiety disorder cases (OR=2.15 (95% CI: 1.27–3.64), P=0.004). MANEA alleles and genotypes were also associated with gene expression differences in whole blood cells. Using publically available data, we observed a consistent effect on expression in brain tissue. We conclude that pathways involving α-endomannosidase warrant further investigation in relation to anxiety disorders.
Highlights
Understanding the genetic contributions to psychiatric disorders could provide crucial insight into the mechanisms underlying these disorders, which as a group have a lifetime prevalence in US adults of 46.4%.1 There is moderate heritability for many psychiatric disorders, for example, for panic disorder (PD) it is estimated to be as high as 0.43, and for generalized anxiety disorder as high as 0.32.2 Further, the genetic risk can be shared between different psychiatric disorders
Shared genetic effects have recently been described for five major psychiatric disorders: schizophrenia, bipolar disorder, autism, major depressive disorder (MDD) and attention deficit-hyperactive disorder based on a large mega-analysis of GWAS data.[4]
They observed that the minor allele of a single-nucleotide polymorphism (SNP) in the MANEA gene was less frequent in subjects affected with cocaine-induced paranoia (CIP), a transient effect of cocaine observed in 60–80% of cocaine-dependent individuals
Summary
Understanding the genetic contributions to psychiatric disorders could provide crucial insight into the mechanisms underlying these disorders, which as a group have a lifetime prevalence in US adults of 46.4%.1 There is moderate heritability for many psychiatric disorders, for example, for panic disorder (PD) it is estimated to be as high as 0.43, and for generalized anxiety disorder as high as 0.32.2 Further, the genetic risk can be shared between different psychiatric disorders. This study, which examines the association of a MANEA 3'UTR SNP, rs1133503, with psychiatric disorder risk, is based on previous reports of the behavioral effects of the α-endomannosidase gene (MANEA) and related pathways. Yu et al.[5] used a low-density whole-genome association study to investigate the genetic basis for substance dependence phenotypes in European American (EA) and African American (AA) families They observed that the minor allele of a SNP in the MANEA gene (rs1133503*C) was less frequent in subjects affected with cocaine-induced paranoia (CIP), a transient effect of cocaine observed in 60–80% of cocaine-dependent individuals. We limited our association analysis to rs1133503 because it tags the two major common haplotypes that span the gene, and, in two previous family-based studies, this particular SNP was associated with CIP in EAs and AAs.[5,6] Both previous studies reported that individuals carrying the rs1133503 minor allele (rs1133503*C) were less likely to be affected with CIP. The effects of MANEA variants on post-transcriptional and transcriptional gene regulatory mechanisms were tested in vitro
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