Bipolar disorder is a brain disease of unknown origin characterized by recurrent manic and depressive episodes with a prevalence rate of approximately 1% worldwide (Peng et al., 2015). Bipolar disorder has two established subtypes: bipolar disorder-I and bipolar disorder-II. Although the pathogenesis of bipolar disorder is still under-discovered, there is overwhelming evidence that genetic factors play a critical role in the development of bipolar disorder. Our previous genetic study identified a variant rs1344706 in the zinc finger protein 804A (ZNF804A) gene conferring susceptibility to bipolar disorder-I in Han Chinese. Literature documented that the risk allele of rs1344706 reduces expression of ZNF804A mRNA in human fetal brain (Tao et al., 2014) and alters transcriptional regulation of its target genes (Hill and Bray, 2012). Accordingly, the variant rs1344706 of ZNF804A may affect brain structure and function.
Cognitive impairment is one of the core symptoms in bipolar disorder, which presents during acute episodes and stable periods of remission. Recent evidence indicated that rs1344706 may increase susceptibility to abnormal cortical thickness (Schultz et al., 2014) and white matter microstructure (Mallas et al., 2017). Accordingly, the rs1344706 polymorphism is likely to influence cognitive processing through modulating functional connectivity in brain (Chen et al., 2018). Therefore, we hypothesized that ZNF804A rs1344706 polymorphism may play an important role in cognitive function in patients with bipolar disorder-I. In this study, we first carried out a cross-sectional study to verify this hypothesis. Second, a recent study showed that rs1344706 is associated with bipolar disorder in a sex-specific manner (Rao et al., 2017). Here, we attempted to identify whether such manner is also seen in the association of rs1344706 with cognitive function in bipolar disorder-I.
All procedures for this study were reviewed and approved by the Institutional Review Boards of the Jinhua Second Hospital and other participating institutions. This study was performed in strict accordance with the Declaration of Helsinki and other relevant national and international regulations. Written informed consent was obtained from each participant prior to the performance of any procedures related to this study.
We recruited bipolar disorder-I patients in remission period from four mental hospitals in Eastern China including Jinhua Second Hospital, third People’s Hospital of Yuebei, Wenzhou Kangning Hospital and Shanghai Mental Health Center. All patients were diagnosed with bipolar disorder-I strictly according to The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Standard diagnostic assessments were supplemented with clinical information obtained by a review of medical records and interviews with family informants. The inclusion criteria and recruitment procedures were described in our previous publication (Zhang et al., 2016). After selection, 177 cases were enrolled, including 85 male and 92 female. Range of ages was from 21 to 55 years old. The mean (SD) age was 32.53 (7.09) years old. Range of age of onset was from 16 to 37 years old. The mean (SD) age of onset was 27.51 (5.02) years old. Range of years of education was from 6 to 13 years. The mean (SD) years of education was 9.46 (1.80) years. Range of duration of illness was from 3 to 104 months. The mean (SD) duration of illness was 45.69 (16.19) months.
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to evaluate the cognitive function, because it has good validity and reliability in Chinese people (Cheng et al., 2011; Wang et al., 2016; Zhang et al., 2017; Fang et al., 2019). The single nucleotide polymorphisms (SNP) rs1344706 was genotyped using TaqMan assays. The possible effects of the rs1344706 genotypes on cognitive function were examined using analysis of covariance (ANCOVA) by comparing the mean RBANS scores of each genotype, after controlling demographic characteristics. To adjust for multiple testing, the level of significance was set at 0.01 (Bonferroni correction for five subsets of RBANS, α(0.05)/k = 5).
The effects of rs1344706 polymorphism on the cognitive scores in bipolar disorder-I patients are shown in Table 1. After controlling sex, age, age at onset, years of education, and duration of illness, ANCOVA analysis showed a significant genotypic effect on RBANS immediate memory (P = 0.002) and total score (P = 0.001). Post hoc analysis showed that the patients with T/T genotype have lower RBANS immediate memory and total scores than those with T/G or G/G genotypes. When the patients were stratified by sex, such significances are only seen in male patients, but not female patients.
Table 1 -
Repeatable Battery for the Assessment of Neuropsychological Status performance comparisons of rs1344706 genotypic groups in patients with bipolar disorder-I
|Total sample (n = 177)
||Male (n = 85)
||Female (n = 92)
||T/T (n = 52)
||T/G (n = 92)
||G/G (n = 33)
||T/T (n = 30)
||T/G (n = 40)
||G/G (n = 15)
||T/T (n = 22)
||T/G (n = 52)
||G/G (n = 18)
||69.29 ± 7.19
||69.98 ± 8.82
||74.53 ± 8.68
||69.73 ± 6.36
||70.45 ± 7.58
||73.40 ± 9.96
||68.68 ± 8.31
||69.62 ± 9.73
||74.50 ± 9.76
||73.06 ± 4.82
||72.90 ± 4.62
||73.88 ± 5.16
||72.10 ± 4.57
||73.30 ± 4.55
||74.47 ± 5.76
||74.36 ± 4.93
||72.60 ± 4.69
||73.39 ± 4.72
||71.98 ± 4.44
||71.83 ± 4.79
||74.64 ± 5.56
||70.63 ± 4.29
||70.95 ± 4.48
||74.93 ± 5.51
||73.82 ± 4.03
||72.50 ± 4.96
||74.39 ± 5.74
||68.29 ± 9.31
||74.02 ± 14.19
||81.15 ± 14.61
||68.70 ± 9.99
||72.43 ± 13.72
||84.33 ± 20.54
||67.73 ± 8.48
||75.25 ± 14.55
||78.50 ± 17.61
||74.50 ± 9.21
||76.80 ± 8.83
||77.12 ± 9.55
||73.83 ± 10.36
||76.93 ± 9.00
||77.40 ± 8.53
||75.41 ± 7.48
||76.71 ± 8.78
||76.89 ± 10.56
||357.12 ± 17.47
||365.53 ± 22.27
||380.79 ± 23.60
||355.00 ± 16.33
||365.05 ± 21.45
||384.53 ± 28.55
||360.00 ± 18.91
||366.67 ± 23.03
||377.67 ± 28.73
Data presented as x ± s. P values were adjusted for age, age at onset, years of education, and duration of illness.
RBANS, Repeatable Battery for the Assessment of Neuropsychological Status.
Previous meta-analysis has identified rs1344706 as a susceptibility locus in bipolar disorder, although this SNP did not achieve a genome-wide level of statistical significance (Ou et al., 2017). In this study, our results indicated that SNP rs1344706 has a genotypic effect on cognitive performance in patients with bipolar disorder-I. To the best of our knowledge, this is the first study to determine the effect of rs1344706 polymorphism on cognitive function in bipolar disorder-I patients.
SNP rs1344706 is a functional variant that influences ZNF804A mRNA expression in hippocampus and occipital cortex (Zhang et al., 2016). A neuropsychological study performed in healthy volunteers showed that risk genotype of rs1344706 polymorphism is associated with less efficient functioning of executive control network (Balog et al., 2011). However, another neuroimaging study conducted in Norwegian and Swedish healthy subjects showed that rs1344706 has no significant effect on either cognitive phenotypes or white matter microstructure (Fernandes et al., 2014). Interestingly, a recent meta-analysis showed that rs1344706 polymorphism has a strong relationship with abnormalities of brain structure, but this association may be different in neuropsychiatric patients and healthy subjects (Wang et al., 2019). MRI data have shown the impact of rs1344706 polymorphism on white matter microstructure in patients with bipolar disorder (Mallas et al., 2017). Therefore, the effect of rs1344706 on cognitive performance in patients with bipolar disorder-I may be through conferring susceptibility to white matter microstructural abnormalities.
Another major finding of this study is that the association of rs1344706 with cognitive function is only seen in male patients with bipolar disorder-I, but not female patients. This implied that rs1344706 sex-specifically modulates cognitive function in patients with bipolar disorder-I. This finding is in line with previous studies in which rs1344706 was reported to be associated with bipolar disorder and schizophrenia in male patients (Rao et al., 2017; Schwab et al., 2013). Because the effect of rs1344706 on cognitive function may be dependent on sex, the following question naturally arises: whether sex steroids contribute to this effect? Further investigations are required for clarification.
There is a major limitation that must be acknowledged in this study. The size of our sample is relatively small, especially for the purposes of sex stratification, and it may not be representative of the population with bipolar disorder-I. Therefore, our findings should be considered as preliminary until replicated and independently validated.
In conclusion, our findings suggested a sex-specific effect of ZNF804A rs1344706 polymorphism on cognitive function in patients with bipolar disorder-I. However, these results need to be verified in further studies with larger samples from different ethnicities.
We are deeply grateful to all participants. This study was supported by the National Natural Science Foundation of China (81471358 and 81671326), the Shanghai Science and Technology Commission Foundation (19411969300).
B.S. and C.Z. contributed to the overall design of the study. B.S., C.Z., J.Z., W.T., and W.L. got involved in sample collection. B.S. undertook the statistical analysis and interpretation of data. B.S. and C.Z. wrote the manuscript. All authors contributed to have approved the final manuscript.
Conflicts of interest
There are no conflicts of interest.
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