Parenting and the serotonin transporter gene (5HTTLPR), which association? A systematic review of the literature

The current systematic review examines whether there is an association between the genetic 5-HTTPLR polymorphism and parenting and the mechanisms by which this association operates. The literature was searched in various databases such as PubMed, Scopus and ScienceDirect. In line with our inclusion criteria, nine articles were eligible out of 22. Most of the studies, analysed in this review, found an association between 5HTTLPR and parenting. Four studies found a direct association between 5-HTTLPR and parenting with conflicting findings: two studies found that mothers carrying the short variant were more sensitive to their infants, while two studies found that parents carrying the S allele were less sensitive. In addition, several studies found strong interaction between genetic and environmental factors, such as childhood stress and disruptive child behaviour, quality of early care experiences, poor parenting environment, and quality of environment. Only one study found an association between children’s 5HTTLPR and parenting. Parenting can be described as a highly complex construct influenced by multiple factors, including environmental, parenting and child characteristics. According to the studies, maternal 5-HTTLPR polymorphism is most likely associated with sensitive parenting.

held belief about mothers: there are innate rules, shaped by evolutionary history and embedded in DNA, that drive all mothers to respond to, nurture, and educate their children [6]. Parenting is shaped by various contextual or "external" influences, and much research has been conducted in this area. A small but growing number of studies have addressed the heritable aspects of mothering, looking more closely at genetic variation at the molecular level to determine how DNA might structure parenting. Throughout the literature, several genes have been considered. Specifically, most studies have focused on the relationship between the serotoninergic system and parenting [2].
Although a genetic influence of 5HTTLPR on nurturing behaviour in animals and other mammals is well established in the literature [7], studies in humans are still pending [2]. However, animal studies have shown that 5-HT plays a role in parental behaviour, suggesting that the serotonin system, either alone or in combination with the dopamine and oxytocin systems, may be a critical modulator of parental behaviour.
Serotonin is a neurotransmitter involved in the regulation and control of various physiological and psychological processes [8]. In this system, the serotonin transporter (SERT or 5-HTT) plays a crucial role in regulating the availability of serotonin in the synaptic space. Therefore, much of the research has focused on the study of the gene responsible for its encoding (SLC6A4) and its polymorphic variants (5-HTTLPR) [9,10].
The 5-HTTLPR polymorphism is a functional polymorphism that involves the insertion and/or deletion of 44 pairs of nucleotide base pairs, resulting in two genetic variants: the long variant (L) and the short variant (S) [11]. The long variant is associated with higher SERT functionality and consequently lower availability of serotonin in the synaptic space [9]. The S variation, on the other hand, is linked to decrease serotonin transporter gene transcription, resulting in increased serotonin levels in the synaptic cleft [12].
However, studies focusing on the relationship between 5-HTTLPR and parenting have come to different conclusions [2]. While the short (S) variant has been associated with higher maternal sensitivity in some studies [1,13], other researchers have found opposite results [2,14].
To explain this discrepancy, some researchers hypothesised that genetic factors might interact with environmental components through epigenetic mechanisms (gene-X-environment interactions) [12,15,16].
Considering these aspects, the present review investigated the association between the genetic polymorphism 5-HTTPLR and parenting. Moreover, the study aims to draw attention to the mechanisms moderating/mediating this relationship to better understand the psychological transitions. To identify, evaluate, and synthesize the literature relevant to this topic, two questions two questions guided our search: 1. Has there ever been found a relationship between 5HTTLPR and parental parenting in

Materials and Methods
Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used to review quantitative research [17]. According to our aims, we based our questions for the literature search strategy, screening phase, and extraction of the final data.
First, screening questions were combined with inclusion and exclusion criteria [18].
Second, for quantitative studies, the acronym PICOS (Population, Intervention, Comparison, Outcome measures, and Study) was used to refine the questions and establish criteria [19].
Inclusion and exclusion criteria were: Inclusion criteria: Full-text articles that were peer-reviewed; written in English, quantitative and focused on parenting skills.
Exclusion criteria: studies in languages other than English; discussion papers or systematic reviews; studies conducted on animals that do not focus on parents.
PubMed, Scopus, and ScienceDirect were used to find articles with the following search term: 5HTTLPR AND parenting AND polymorphism in title/abstract.
The literature was reviewed to determine whether it was relevant and met the inclusion criteria. Additional articles related to the review topic were found in the reference lists of all included studies.
To determine if a study could be included in this review, the literature was first searched by abstract and title. The search yielded 23 articles. After screening titles and abstracts, 9 articles were included ( Figure 1).

Figure 1. Flow diagram
The assessment of eligibility for inclusion was done in accordance with the PRISMA criteria, and the authors then discussed them to formalize the agreement.
After studies met inclusion criteria, they were assessed using the Genetic Studies Quality Tool (Q-Genie), as presented in Table 1 [20]. This tool is used to assess and detect bias in To minimise loss of precision and reliability and to account for bias in the results, a Likerttype rating scale with seven categories anchored by 'poor' and 'very good' was used.
Two of the authors performed the scoring (ML and DS) and conferred in case of disagreement.
The main findings of each study were reviewed. The magnitude of the association between parental 5-HTTLPR and maternal sensitivity was assessed using the effect size reported in the article, if available, or calculated from the data reported in the study using 0.5 to 0.79 as medium effect; 0.8 and higher as strong effect; and finally, Cohen (1988) gave guideline values for for η 2 to define small (η 2 = 0.01), medium (η 2 = 0.06), and large (η 2 = 0.14) effects [21].

Results
As mentioned earlier, the analysis of the nine selected studies revealed a discrepancy in the results ( Table 2).
Four of these studies found a direct association between 5-HTTLPR and parenting [1,2,11,14], [11], who found a direct association between S/LG alleles and more sensitive parenting six months after birth.
In contrast, two studies found a direct association between the S allele and lower parental sensitivity [2,14]. The first research [14] indicated that women with the SS genotype were less responsive to their babies than mothers with the LL or LS genotype, even after controlling for differences in maternal education, depression, and marital strife. Morgan et al. [2] found similar outcomes: parents with the S allele (86 percent of moms) had considerably fewer favorable parenting behaviors than parents with the LL-genotype.
Moreover, several studies have found strong interactions between genetic and environmental factors [2,11,12,16]. Mileva-Seitz et al. [11] investigated whether genotype and early caregiving experiences were linked to three dimensions of maternal responsiveness (maternal sensitivity, maternal behaviour away from the child, and maternal attitudes-perceived attachment), and discovered highly significant GXE interactions with maternal behaviour and maternal attitudes. Specifically, mothers without S or LG alleles experienced more negative quality of early care and were more likely to distance themselves from their children. Conversely, mothers with S or LG alleles and better quality of early care reported higher scores on ratings of their perceived attachment to their baby. These findings are at odds with the observations of Morgan et al. [2], who found that child-related stress was negatively associated with observed negative parenting in parents with the SS or SL genotype.

Discussion
The present review aimed to examine the relationship between 5HTTLPR and human parenting, highlighting the role of environment and other variables in this relationship.
Furtheraim of this study is to draw attention to the processes that moderate or mediate this link in order to better understand psychological transitions and address the objections raised in the literature.
As noted above, although the literature has demonstrated a genetic influence of 5HTTLPR on parental behaviour in animals and other mammals, very few studies have examined the relationship between 5 HT and parental care in humans [2,24].
However, the majority of studies included in this review found a relationship between 5HTTLPR and parenting. Four studies showed a direct relationship between 5-HTTLPR and parental caregiving [1,2,11,14], with contrasting results that may prompt future research and hypotheses about different mechanisms acting on this relationship. In addition, several studies found strong interactions between genetic and environmental factors [2,11,12,16], such as infant stress and disruptive infant behaviours [2] , the quality of early care-experiences [11], poor rearing conditions, and the quality of the Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 26 January 2022 doi:10.20944/preprints202201.0394.v1 environment [16]. Most psychological traits and behaviors are better explained by a combination of essential characteristics such as gender and socioeconomic status than by genetic markers alone, as Kagan et al. [25] recently argued, though the inclusion of both genetic and environmental factors can predict such outcomes with the greatest accuracy in certain groups. Other authors also investigated whether children's genotype was related to maternal parenting behaviours and sensitivity [1,22,23], but only one study found an association between children's 5HTTLPR and parenting behaviours.
Specifically, children carrying the S allele experienced higher maternal hostility and lower maternal support, but only when the mother reported lower quality parenting from the grandmother. These results can be considered consistent with infant twin studies showing that genetically influenced characteristics of children (e.g., temperament) trigger certain parenting behaviours [26].
To explain the nature of the results, there are several explanations. One of them links the 5HTTLPR polymorphism to cognitive aspects. Because the 5-HTTLPR polymorphism is linked to numerous elements of thinking function, it may have an impact on parenting due to its correlations with maternal characteristics. In both rat and human investigations, carriers of the S allele performed better on a variety of tasks, including cognitive flexibility, reversal learning, attention, and inhibition [27,28,29].
To practice empathic parenting, parents must have cognitive flexibility and attention to effectively perceive and respond to their children's signals [4]. For example, studies have shown that mothers with ADHD (attention deficit hyperactivity disorder) tend to show behavioural characteristics of poor parents [30,31]. Reactive parenting styles have also been associated with poor working memory [32]. 5-HTT binding in the putamen and midbrain is influenced by the 5-HTTLPR genotype in humans [33]. As a prominent dopaminergic projection site of the mesocorticolimbic dopamine system, the ventral tegmental area (VTA) in the midbrain is involved in motivation and reward.
Based on these findings, it can be hypothesised that differences in midbrain 5-HTT function are associated with differences in dopamine signalling that influence maternal behaviour. For instance, folate reduces 5 -HT reuptake, affecting maternal behavior in rats [34],and lesions of serotonergic neurotoxins in the median raphe, a key site for serotonin synthesis, reduce suckling and retrieval of pups [34,35].
Moreover, the 5-HTTLPR polymorphism may have a direct impact on parenting via its influence on maternal traits and neuronal and hormonal consequences. The role of oxytocin and vasopressin in determining parental behavior in various animals appears to be significant [36,37]. When serotonin is activated in the hypothalamus, the paraventricular nucleus (PVN) of the hypothalamus releases both chemicals [38]. The PVN also has serotonin receptors. According to research, oxytocin and vasopressin are where social support is lacking [40]. In primates (as opposed to rodents), the scales have tipped in favor of neocortex size and function, according to Numan and Insel [41,42].
Thus, primate parenting may be driven by cognitive rather than hormonal factors, at least in the absence of extreme conditions [41].
However, the medial preoptic area (MPOA) of the hypothalamus might still be involved in the development of complex voluntary response-strategies by signalling the degree of maternal motivation to the neocortex [41]. For mothers in disadvantaged circumstances, such as those characterised by high levels of stress or marital discord, the links between serotonin and oxytocin system genes and parenting might be even more pronounced.
Finally, several authors proposed the differential susceptibility model as an explanation.
For example, Hariri et al. [43] found that the S allele was associated with enhanced social cognition and increased amygdala sensitivity to emotional stimuli [44]. Here, it is possible that the S allele serves as a gene of adaptability; it is more beneficial in low-risk circumstances and more challenging in difficult ones [45,46]. Because of their greater susceptibility to mood disorders, genotypes containing one or two S alleles have been termed "vulnerability genotypes." Although it may increase maternal caregiving sensitivity in low-risk contexts by increasing the ability to detect environmental cues, it may also increase the risk of insensitive caregiving and hostility when the environment is more hostile.
Consistent with these observations, the expected direction of the association between 5HTTLPR and parenting is not clear [26]. However, this review has strengthened the understanding of the mechanisms involved in the relationship between genetic components and parenting.
The main limitation of current research on the influence of 5HTTLPR on parenting is the scarcity of studies and the lack of studies based on large samples. Future research could expand our knowledge of this relationship by considering other genotypes that have been identified as potential susceptibility markers (particularly MAOA, BDNF, and MR).
Future studies could also consider other factors such as ethnicity as an important moderator in GxE studies, including genetic differential susceptibility studies [26].

Conclusions
The exploration of the influence of genetics in explaining parenthood only began around the year 2000, so it is a relatively new branch. On the one hand, this is remarkable since Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 26 January 2022 doi:10.20944/preprints202201.0394.v1 parenting theory can be considered the first application of evolutionary theory to human development -after Charles Darwin, but before the development of so-called evolutionary psychology.
The genotypes of the parents were identified using molecular genetic techniques.
Maternal 5-HTTLPR polymorphism was associated with sensitive parenting. This study adds to the growing body of evidence showing that parenthood is a multifaceted concept.
According to Swain et al. [37], parenting is a complex interplay of genes, prior parenting, current experiences, psychological state, neurobiological systems, and environmental conditions. Parenting can be better understood if we acknowledge and provide more insight into the multifactorial processes that underlie it.
Exploring possible mediators of the relationship between 5-HTTLPR and maternal sensitivity, including cognitive flexibility and attention, could provide useful insights into the underlying biological processes and provide further evidence for a link between

5-HTTLPR and parenting
Funding: This research received no external funding

Conflicts of Interest:
The authors declare no conflict of interest