GRIK3 rs490647 is a Common Genetic Variant between Personality and Subjective Well-being in Chinese Han Population

Personality and subjective well-being (SWB) have been suggested to be strongly related in previous studies. This study was intended to confirm the relationship between personality and SWB and tried to seek out the genetic variants which underlie both personality and SWB. The subjects were 890 participants from Chinese Han population. We evaluated their personality using the Big Five Inventory (BFI) and used the Satisfaction With Life Scale (SWLS) to reflect their SWB. Five single nucleotide polymorphisms (SNPs) were selected from the literature (rs1426371, rs2164273, rs322931, rs3756290, rs490647) and genotyped for genetic association study. We found negative correlations between neuroticism and SWB. On the contrary, extraversion and agreeableness were positively associated with SWB. Three SNPs (rs2164273, rs3756290, rs490647) out of the five were found to connect with personality (extraversion, neuroticism, conscientiousness and openness to experience) and rs490647 variants of GRIK3 was also associated with SWB. Individuals carrying G allele at this site were predisposed to have lower risk to be neuroticism and greater chance to be extraverted, open and satisfied with their life. In summary, our study revealed that rs490647 might be a good candidate genetic variant for personality and SWB in Chinese Han population.

and neuroticism showed opposite pattern: extraversion has been repeatedly positively associated with life satisfaction while neuroticism was negatively correlated [8][9][10]. Furthermore, both the two dimensions acted as strong predictors for SWB, with the same opposite pattern [11,12]. However, the results on the other three dimensions (i.e. agreeableness, conscientiousness and openness to experience) were inconsistent. Although most studies were mainly based on western cohorts, similar conclusions have been achieved from Asian individuals. Studies carried out in Indian, Japan, South Korea and China have showed that neuroticism and extraversion were associated with life satisfaction [13][14][15][16].
Above and beyond the phenotypic associations between personality and SWB, their genetic components and overlap have been the focus of a substantial amount of research. A meta-analysis of twin studies found that about 40% of individual differences in personality were caused by genetic factors [17,18]. Genome-wide association studies (GWAS) have probed several remarkable variants associated with personality [19][20][21], especially for extraversion and neuroticism [22][23][24]. SWB is also moderately heritable. Twin and family studies showed that genetic variations may typically account for 30% to 40% of the variance of SWB [10,[25][26][27]. Simultaneously, SNPs significantly associated with SWB were observed as well [23,[28][29][30]. While personality and SWB have been found to be correlated at a behavioural level and literature point to possible molecular mechanistic and genetic overlaps, only one study [10] demonstrated that SWB was associated with personality through common genes, but neither a certain gene nor specific molecular loci was presented.
The purpose of this study was to reveal the underlying genetic relations of personality and SWB. We selected five SNPs associated with personality traits or SWB based on the prior GWAS [22][23][24]30].

2-1-Subjects
We recruited 890 unrelated Chinese Han college students (339 males and 551 females, age: 20.24 ± 1.59). All participants signed the informed consents and filled out the questionnaires measuring SWB and personality traits. The study protocol has been appraised and confirmed by the Ethics Committee of the Bio-X Institutes, Shanghai Jiao Tong University. The peripheral blood was collected for each student and the standard phenol-chloroform method was used in DNA extraction.

2-2-SNP Selection and Genotyping
The SNPs were selected according to the previous GWAS [22][23][24]30]. These genetic variants were discovered to be associated with SWB or personality traits. The minor allele frequency (MAF) should be higher than 0.05 in East Asians. We included five SNPs (rs1426371, rs2164273, rs322931, rs3756290, rs490647). All SNPs are located in the intron region except for the downstream rs490647. More detailed information about the SNPs analysed is provided in Table 1.
Genotyping of all five SNPs applied the matrix-assisted laser desorption/ionization time of flight(MALDI-TOF) mass spectrometer on MassARRAY® Analyzer 4 platform (Sequenom, San Diego, CA). Assay Design Suite v2.0 from the Mysequenom online software was employed in probes and primers design.

2-3-Behavioural Measures
The personality was measured using the Big Five Inventory (BFI) [31]. The BFI is a 44-item questionnaire measuring the personality on the Big Five dimensions including Extraversion, Neuroticism, Agreeableness, Conscientiousness and Openness to experience. The final scores on five factors for individuals are decided by 8-10 items. Each item uses a Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree).
The life satisfaction reflecting one's SWB was assessed by the Satisfaction With Life Scale (SWLS) [7], which contains 5 items in a 7-point response format ranging from 1(strongly disagree) to 7 (strongly agree).

2-4-Statistical Analysis
SHEsisPlus (http://shesisplus.bio-x.cn/SHEsis.html) was applied to analyse allelic and genotypic distributions and Hardy-Weinberg equilibrium [32]. We detected the association between the candidate SNPs with behavioural measures (i.e. personality and SWB) in five genetic models by "SNPassoc" R package (http://www.r-project.org/). Heat map illustrating correlations was also achieved on R software through "Corrplot" package. Hierarchical regression analysis was performed using SPSS ® Statistics version 24.0. For all analysis, two tailed p values were adapted and statistical significance was set for p < 0.05. Research methodology is summarized in Figure 1.

3-1-Phenotypic Correlations between Personality Traits and SWB
Baseline characteristics of the 890 recruited students are shown in Table 2. Their mean scores on SWB and five dimensions of personality were described. And other factors we assumed to have impacts on SWB are also summarized in Table 2.
To test whether personality explained a significant amount of variance over the other demographic variables, we conducted hierarchical regression analysis (Table 3). In step 1, five personality traits were added as variables and they accounted for total 48.4% variance in SWB. Extraversion (t (875) = 2.749, p = 0.006), neuroticism (t (875) = -6.586, p < 0.001) and agreeableness (t (875) = 5.466, p < 0.001) were considered significant predictors for SWB. In step 2 and step 3, demographic variables were added. Contrasting with personality traits, the added variance explained by sociodemographic variables was only 7.1%, suggesting that personality is a greater contributor to SWB than sociodemographic.

4-Discussion
In this work, we analysed both phenotypic and genotypic associations between personality and SWB among 890 college students within Chinese Han population. Strong phenotypic relations between personality traits and SWB have been shown, especially for neuroticism, extraversion and agreeableness. In addition, we tested for genetic associations considering five SNPs (rs1426371, rs2164273, rs322931, rs3756290, rs490647) extracted from the original GWAS [22][23][24]30]. Three SNPs (rs2164273, rs3756290, rs490647) were found to correlate with personality and our results point to rs490647 as a possible shared genetic site between personality and SWB.
In line with previous studies [8][9][10], we found neuroticism to be negatively and extraversion to be positively related to SWB. Besides, we revealed that agreeableness also exhibited strong relation with SWB, consistent with another study carried out in China [33]. Although moderate, the positive correlation between conscientiousness and openness to experience with SWB might help to target promising psychotherapic strategies to improve SWB.
To our knowledge, little previous research has been conducted to show the genetic variants of SWB, and only several GWAS have discovered significant SNPs for two personality dimensions. Here, we used a genetic association approach and we found that two SNPs (rs3756290, rs490647) are associated with extraversion. In accordance with previous findings, rs490647 showed a significant association for neuroticism [22]. Besides, we ascertained genetic variants rs2164273 associated with conscientiousness and rs490647 associated with openness to experience in Chinese Han population. Since the genetic correlations between personality and SWB have been revealed in previous meta-analysis studies [34,35], we further conducted association studies of SWB. rs490647 variant was found to be also significantly associated with SWB besides the three dimensions of personality. Therefore, it indicated that the SWB and personality might have shared gene loci.
As mentioned above, our results revealed rs490647 as the overlap significant SNP site for SWB and personality. rs490647 is an adenosine (A) / guanine (G) nucleotide variation. Previously, a study based on 106000 individuals has proved the significant association between rs490647 and neuroticism (p = 3.8 × 10 -8 ) [22]. In that study, the reference allele A had a positive linear correlation with neuroticism. We confirmed this finding in 890 college students from Chinese Han population. Allele G was considered as the reference allele wherein G/G genotype proclaimed lower risk for neuroticism. Additionally, we also described that allele G had the positive correlation with extraversion, openness to experience and happiness. People with G/G genotype tended to have higher scores on extraversion, openness to experience and life satisfaction. Overall these findings indicated that rs490647 might be a protective genetic variant lowering the risk for neuroticism and psychiatric disorders.
rs490647 is located at Chr1:36777142, downstream region of GRIK3 gene. The human gene GRIK3 encodes the glutamate ionotropic kainate receptor subunit GluR7 [36], which is involved in the regulation of glutamatergic synaptic neurotransmission [37]. GRIK3 gene possess a higher expression in brain tissues in contrast to non-brain tissues [38], especially enriched in mossy fibers and CA3 pyramidal cells synapses in hippocampus [37]. GluR7 is an important subunit of presynaptic kainate receptors that have low sensitivity to glutamate, conduct synaptic plasticity and facilitate glutamate release [39]. Excessive activation of glutamate receptors can lead to excitotoxicity [40], and GRIK3 has been proposed to be an excitotoxicity causing candidate [36]. Multiple studies have provided strong evidence for a significant correlation between GRIK3 and psychiatric disorders, such as schizophrenia and major depressive disorder(MDD) [41][42][43]. Associations have been reported between GRIK3 genetic variants and recurrent MDD [44] and several personality traits [45]. Hence, as for our results, we speculated that people with G/G genotype at rs490647 or linked variants may express GRIK3 in a relatively low level to decrease glutamate release, avoid excessive glutamate receptors activation and keep the normal neuronal ionic gradient. They are at lower risk for mental disorders, easier to feel satisfied with their life and own positive personality such as extraversion and openness to experience.
The limitations of our study naturally include two aspects. The first one is the relative small sample size. Besides, we selected SNPs according to the previous GWAS and five SNPs in our study were from different genes, causing the insufficient SNP coverage for each gene. Hence, larger size of samples should be included and complete SNP coverage for specific gene especially GRIK3 are desirable for further study.

5-Conclusion
In summary, our study confirmed both phenotypic and genotypic association between personality and SWB. Five personality traits were significantly correlated with SWB. Neuroticism showed the strongest negative correlation with SWB. The rest four personality aspects showed positive correlation. Genetic variant rs490647 in downstream of GRIK3 might be a shared genetic variant for personality and SWB in Chinese Han population. People with G/G genotype tended to be extraverted, open and satisfied with their life and had a lower tendency to develop neuroticism. Due to the pilot nature of our work, future research should further develop and replicate these initial findings in larger samples and different ethnic groups. Above all, this is an interdisciplinary study integrating psychology and life science, unearthing not only the surface but also the underlying genetic relations between personality and SWB. The effective loci and related gene was found to disclose why personality is correlated to SWB. Thus, our study has provided a deeper understanding than usual psychological researches.

6-Funding and Acknowledgements
We appreciate the contribution of the members participating in this study. This work was supported by the National Key Research and Development Program (2016YFC0906400, 2016YFC1307000, 2016YFC0905000), the National Nature Science Foundation of China (81421061, 81361120389), the Shanghai Key Laboratory of Psychotic Disorders (13dz2260500), the Shanghai Leading Academic Discipline Project (B205), Overseas students science and technology activities project merit funding, Woman and Children's Health (No.15GWZK0401), and the Fundamental Research Funds for the Central Universities (16JXRZ01).

7-Conflict of Interest
The authors declare no conflict of interest.