Association between NR4A2 genetic variation and schizophrenia: A comprehensive systematic review and meta-analysis

Highlights

• Comprehensively quantified the impact of all the reported variants of NR4A2 on schizophrenia risk.

• Summarized all the genotype distribution of NR4A2 variants and made a comprehensive meta-analysis of three SNPs in case-control studies.

• Five variants of NR4A2 were present only in cases.

• Failed to reveal significant association between NR4A2 variation and SZ risk.

Abstract

The homo sapiens nuclear receptor subfamily 4, group A (NR4A2) genetic variation has been implicated as a risk factor for schizophrenia (SZ). Nevertheless, the results are inconclusive. We conducted a comprehensive systematic review and meta-analysis to quantify the impact of NR4A2 variation on the risk of SZ. All eligible case-control studies published up to September 2014 were identified by searching PubMed OVID, EBSCO, PsycINFO and ISI web of knowledge. Pooled odds ratio with 95% confidence interval were used to access the strength of association in fixed- or random-effects model. Seven studies that reported 17 variants with a total of 3027 participants were included. Of these variants, five ones (rs143618355, rs199674295, c.366-369 del TAC, c.-469delG and P4) were present only in cases, and three ones (rs35479735, rs3832066 and rs397706674) were available for meta-analysis. Overall, there was no significant association between the three variants and SZ risk under allele model, dominant model and recessive model. The results failed to reveal significant link between NR4A2 polymorphism and SZ risk. However, large-sized and well-designed studies are warranted to validate our findings.

Introduction

Schizophrenia (SZ), a chronic, severe, and disabling brain disorder, affects approximately 1 of 100 people worldwide (about 26.3 millions of people) [41]. The underlying pathology of SZ remains unclear. Multiple hypotheses have been proposed to elucidate the pathogenic mechanism of SZ [12], [21], [31], among which, the dopamine hypothesis has been drawing growing attention during the past two decades [11].

The homo sapiens nuclear receptor subfamily 4, group A (NR4A2, also known as NURR1/NOT/TINUR/RNR-1/HZF-3), a member of the steroid/thyroid hormone nuclear receptor superfamily [40], [25], [38], plays a vital role in development, survival and functional maintenance of midbrain dopaminergic neurons [2], [7], [25], [37]. Recently, numerous studies indicated that NR4A2 might be a potential susceptibility gene for SZ. Some single nucleotide polymorphisms (SNPs) of NR4A2, which resulted in significant reduction of NR4A2 mRNA [45] and sharp decreased expression in cell density or staining intensity in the dorsolateral prefrontal cortex of SZ patients [16], were identified only in patients rather than in controls [5], [8]. The SZ patients who carried recessive genotypes of tag single nucleotide polymorphisms (SNPs) (rs1150143, rs1150144, rs834830, and rs707132) in NR4A2 showed worse performance on a sustained attention task [1]. Thus, we reasonably hypothesize that NR4A2 gene mutation induces gene expression as well as dopamine-related dysfunction and abnormal behavior of SZ afterwards. The same observations were made in animal research as well, and NR4A2 heterozygous (+/−) mice has been suggested as a potential animal model for the studies on some of the behavioral and molecular mechanisms underlying SZ [43], [35].

However, the results are inconsistent. Some other studies did not support the notion that NR4A2 gene played a major role in risk of SZ [14], [23], [36]. Whether the NR4A2 gene mutation is a risk factor for SZ remains conflicting. Therefore, we conducted a systematic review and meta-analysis by combining all the available studies to evaluate the overall effect between them in the present study.