In this study, we conducted an observational and GWEIS analysis to explore the relationship between born by CS and adult anxiety and self-harm. We found significant associations between born by CS and the risk of anxiety and self-harm respectively. In addition, GWEIS identified multiple genes interacted with born by CS for anxiety and self-harm.
It has been suggested by a previous systematic review and meta-analysis that birth by cesarean delivery is associated with certain neurodevelopmental and psychiatric disorders. For example, the researchers have shown that delivery by CS is associated with a modest increased odds of autism spectrum disorders and attention-deficit/hyperactivity disorder when compared to vaginal delivery. According to a Swedish population-based cohort, elective CS is associated with an increase in offspring psychosis. In a longitudinal study of Australian children, Polidano et al. observed a negative relation between cesarean birth and a range of cognitive outcomes measured from ages 4 to 9. However, there is no study focus on the risk of born by CS on adult anxiety and self-harm. Our study identified significant associations between born by CS and its risk on anxiety and self-harm in UK Biobank cohort, suggesting an important role of born by CS in affecting anxiety and self-harm in adults.
Our GWEIS also revealed several candidate genetic variants interacting with born by CS for anxiety, such as DKK2 and ANTX1. DKK2 is an important member of the DKK gene family. The DKK gene family is an ancient and evolutionarily conserved gene family. In recent years, a large number of studies showed that DKK gene family plays an important role in embryonic development, neural regeneration, synaptogenesis and so on. Therefore, its role in neuropsychiatric disorders, such as cognitive impairment and emotional disorder, has attracted increasing attention. According to a previous study, DKK2 converges on β-catenin using distinct transduction pathways required to activate Wnt/β-catenin signaling and induce neural crest cells. Zhao et al. have demonstrated an anxiety-specific response and contribution of activated neural stem cells to chronic pain through Wnt/β-catenin signaling, which may be targeted for treating chronic pain- or other diseases-associated anxiety. However, there is few studies about the effect of DKK2 on anxiety. We found DKK2 interacting with born by CS for anxiety. Further in vivo and in vitro functional studies are needed on this effect.
Ataxin-1 (ATXN1), the gene mutated in spinocerebellar ataxia type 1 (SCA1), is another significant candidate genetic variants interacting with born by CS for anxiety. Lu et al. performed a series of behavioral tests on the ATXN1–with its paralog ataxin 1–like (ATXN1L) conditional knockout mouse lines to assess general activity, anxiety, learning and memory, and social behavior. In the elevated plus-maze test, conditional knockout mice spent more time in the open arm and less time in the closed arm than control mice which was possibly as a result of reduced anxiety. According to a previous study which modeled early-life unpredictable stress in developing rats and found enhanced levels of anxiety when tested in adulthood compared to control, non-stressed adult rats. The results showed that these behavioral changes were associated with upregulated ANTX1 gene within the amygdala.
For self-harm, GWEIS also identified several candidate genetic variants interacting with born by CS, such as ALDH1A2 and DAB1. According to a previous study, after nonfatal self-harm, adolescents and young adults were at markedly elevated risk of suicide. It has been reported that self-harm and suicide are predominant causes of decreased survival in patients suffering from schizophrenia. ALDH1A2, encodes an enzyme for astrocyte-derived retinoic acid, is a key neuronal morphogen with relevance for schizophrenia. For example, Wan et al. observed a positive association between ALDH1A2 and schizophrenics in the Chinese population. In a methylome-wide association study of schizophrenia, ALDH1A2 was identified to be the second-most significant site. DAB1, a key component of the Reelin pathway, is sufficient to induce behavioral deficits related to psychiatric disorders. A recent study revealed that DAB1 conditional knockout mice showed hyperactivity, decreased anxiety-like behavior, and deficit in spatial reference and working memory. The results indicated that the Reelin-DAB1 signaling in the cortex can be an important molecular basis for the regulation of the behaviors. Teixeira et al. observed a causal relation between the downregulation of DAB1 protein levels during development and the structural and behavioral deficits associated with psychiatric diseases in the adult.
In contrast with GWAS, GWEIS discovered some novel genes that might influence the risk of anxiety and self-harm. Previous studies focused on the genetic effect on mental disorders, less study have assessed the interaction role of gene and environment on the mechanism of these complex diseases. Our study demonstrated the interaction association between born by CS and anxiety, self-harm. As far as we known, this is the first systemic study exploring the effect of born by CS as environmental factor on mental disorders for adults. Our study holds great potential for clarifying the functional relevance of born by CS with mental disorders and provide novel clues for the pathogenesis of those mental disorders.
However, some limitations of this study should be noted. First, like GWAS, some significant SNPs found by GWEIS are located in non-coding region, which still pose challenges for us to better illustrate our results. Second, all subjects in this study are from European ancestry. Therefore, it should be careful to apply our study results to other ethnic groups. Furthermore, although several genes have been reported to have interaction effects with born by CS, further experimental studies are needed to validate its specific biological functions and mechanisms.
In summary, we observed significant association between born by CS and the risk of adult anxiety and self-harm using UK Biobank cohort. GWEIS analysis identified multiple candidate genes which may serve as the underlying genetic mechanisms of the observed association. Further studies are expected to validate our findings and clarify the potential mechanism of identified gene-environment interaction.