Abnormal features of human self-domestication in bipolardisorder

RESEARCH REPORT Abnormal features of human self-domestication in bipolar disorder Antonio Benítez-Burraco 1 | Ethan Hansen 2 1 Department of Spanish, Linguistics, and Theory of Literature (Linguistics), Faculty of Philology, University of Seville, Seville, Spain 2 School of Medicine, University of Washington, Seattle, Washington, USA Correspondence Antonio Benítez-Burraco, Departamento de Lengua Española, Lingüística y Teoría de la Literatura,Facultad de Filología, Universidad de Sevilla, C/Palos de la Frontera, s/n, 41004 Sevilla, Spain. Email: [email protected] Funding information This research was funded by the Spanish Ministry of Science and Innovation (grant PID2020-114516GB-I00 by MCIN/ AEI/10.13039/501100011033 and by the “European Union”to ABB). Edited by: John Foxe Abstract Bipolar disorder (BD) is a severe mental condition characterized by episodes of elevated mood and depression. Being a heritable condition, it features a complex genetic architecture, although it is not still clear how genes contribute to the onset and course of the disease. In this paper, we adopted an evolutionary-genomic approach to this condition, focusing on changes occurred during human evolution as a source of our distinctive cognitive and behavioural phenotype. We show clinical evidence that the BD phenotype can be construed as an abnormal presentation of the human self-domestication phenotype. We further demonstrate that candidate genes for BD significantly overlap with candidates for mammal domestication and that this common set of genes is enriched in functions that are important for the BD phenotype, especially neurotransmitter homeostasis. Finally, we show that candidates for domestication are differentially expressed in brain regions involved in BD pathology, particularly, the hippocampus and the prefrontal cortex, which have been subject to recent changes in our species. Overall, this link between human self-domestication and BD should facilitate a better understanding of the BD etiopathology. KEYWORDS bipolar disorder, differentially expressed genes, human evolution, neurotransmitter homeostasis, self-domestication 1|INTRODUCTION Bipolar disorder (BD) is a severe psychiatric condition characterized by recurrent episodes of elevated mood (mania) and depression, together with changes in activity levels, with depression being usually more common and longer lasting than mania (Anderson et al., 2012; Judd et al., 2008; Rantala et al., 2022). BD is one of the most heritable psychiatric conditions, but like similar diseases, it exhibits a complex genetic architecture, with dozens of candidate genes and risk factors that overlap with the genetic determinants of other high-prevalence cognitive conditions, especially schizophrenia (SZ) and major depressive disorder (MDD) (see Gordovez & McMahon, 2020, for a recent review). These findings are in line with the so-called “omnigenic”theories of complex diseases, according to which they result from changes in the expression of most of the genes expressed Received: 9 September 2022 Revised: 19 February 2023 Accepted: 7 March 2023 DOI: 10.1111/ejn.15959 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd. 1406 Eur J Neurosci. 2023;57:1406–1431. wileyonlinelibrary.com/journal/ejn in the affected tissues (Boyle et al., 2017; Peedicayil & Grayson, 2018a,2018b). Still, one can expect that specific regulatory pathways and biological mechanisms are more affected than others and, ultimately, that intermediate, disease-specific phenotypes can be identified with finite genetic determinants (Jakobson & Jarosz, 2019). As noted by Gordovez and McMahon (2020), this is also the case with BD, as some specific biological pathways are expected to be differentially impaired in this condition. At the same time, environmental factors have been also hypothesized to contribute to BD. For instance, some authors have linked this condition to a desynchronization of internal circadian rhythms, resulting from neuroinflammatory processes caused by modern lifestyle (Rantala et al., 2021). One promising approach to make more tractable the genetic study of complex diseases like BD is adopting an evolutionary perspective. A robust link exists between evolution and abnormal development. Genes positively selected in our species are enriched in candidates for high-prevalent, complex cognitive conditions, like SZ (Srinivasan et al., 2016) or autism spectrum disorders (ASD) (Polimanti & Gelernter, 2017). Even in conditions with a neat genetic origin, like Williams syndrome (WS), abnormally expressed genes outside the WS region are enriched in genes that have been positively selected in modern humans compared with extinct hominins (Benítez-Burraco, 2020a). A possible explanation of this overlap between genes involved in the evolution of the human brain, cognition, and behaviour, and genes causing complex cognitive and behavioural human conditions is that recently evolved components of the human phenotype are less resistant to gene mutations (and more generally, to developmental perturbations) because they lack compensatory mechanisms to damage, as commonly found in biological functions shaped by prolonged selective pressures (see Toro et al., 2010, for a useful discussion on ASD). This ultimately suggests that recent changes in our genome resulting in evolutionary advantages might have also uncovered (or “decanalized”) widespread cryptic variation, this resulting in complex disease (see Gibson, 2009, for details). Overall, we expect that this evolutionary-genomic approach to BD help to gain some useful insight into its (molecular) aetiopathogenesis. Considering that BD impacts key aspects of our species-specific distinctive cognitive and behavioural phenotype, we have built on a recent hypothesis about the origins of our cognition and behaviour, namely, the self-domestication account of human evolution (Hare, 2017). In brief, this hypothesis claims that humans experienced an evolutionary process similar to mammal domestication, although in response to intraspecies drivers, such as co-parenting, changes in human foraging ecology, or the rise of community living (Hare et al., 2012; Pisor & Surbeck, 2019). This selfdomestication resulted in more prosocial individuals and facilitated the emergence of many of our species-specific biological, cognitive, and behavioural features, including our sophisticated technology and culture (see Hare, 2017, for review; see also Brüne, 2007; Wrangham, 2019). As hypothesized for domesticated animals, the ultimate triggering factor of human self-domestication was a reduction in reactive aggression responses, which promoted the emergence of the features associated to domestication through a complex physiological mechanism involving the hypothalamic–pituitary–adrenal (HPA) axis and perhaps the neural crest (NC) cells, a type of stem cells that contribute to many body organs during embryonic development (Progovac & Benítez-Burraco, 2019; Wilkins, 2020; Wilkins et al., 2014). Overall, the human self-domestication hypothesis is supported by the finding that, compared with extant primates and extinct hominins, our species exhibit many of the features commonly found in domesticated mammals, including smaller skulls/brains, juvenile-like faces, hairlessness, paedomorphic features, a prolonged juvenile period, less marked sexual dimorphism, reduced reactive aggression, increased prosocial behaviour, and increased play behaviour, among others (Herrmann et al., 2011; Leach, 2003; Plavcan, 2012; Shea, 1989; Somel et al., 2009; Stringer, 2016; Zollikofer & Ponce de Le on, 2010; see Hare, 2017, for review). In further support of this view, regions positively selected in modern humans compared with extinct hominins are enriched in candidate genes for domestication in mammals (Theofanopoulou et al., 2017; Benítez-Burraco, Chekalin, et al., 2021). Interestingly for our concerns here, complex genetic conditions involving cognitive deficits, behavioural anomalies, and abnormal socialization patterns, like SZ and ASD, are characterized by abnormal presentations of traits associated with self-domestication; moreover, candidate genes for domestication are overrepresented among the candidates for these conditions and/or exhibit altered expression profiles in the brains of affected people (Benítez- Burraco et al., 2016; Benítez-Burraco et al., 2017 Benítez- Burraco, 2020b). Overall, this supports the view that a deep link might exist, specifically, between cognitive/ behavioural impairment and human self-domestication. BD should not be then an exception. In this paper, we explore the presentation of altered self-domestication features in subjects with BD. We also examine the overlap between candidate genes for BD and domestication. We provide a functional characterization of the common genes as well as some hints about their expression pattern in the brains of affected people. We conclude with a discussion about the benefits (and BENÍTEZ-BURRACO and HANSEN 1407 14609568, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.15959 by Readcube (Labtiva Inc.), Wiley Online Library on [26/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License limitations) of construing BD as an abnormal ontogenetic itinerary for human cognition and behaviour resulting from changes in genes involved in self-domestication. 2|MATERIALS AND METHODS 2.1 |Abnormal presentation of selfdomestication features in BD In order to know about the presentation of selfdomestication features in people with BD, we conducted a literature search of the PubMed database (https:// pubmed.ncbi.nlm.nih.gov/). We first determined a set of traits of interest based on the existing literature on animal domestication (see S anchez-Villagra et al., 2016; Wilkins et al., 2014) and self-domestication in humans, including cognitive disorders (SZ, ASD, and Williams syndrome) (see Benítez-Burraco et al., 2016,2017; Cieri et al., 2014; Hare, 2017; Niego & Benítez-Burraco, 2019). The full list of features can be found in Supporting Information S1. The search strategy included “bipolar disorder”and keywords likely to capture each of the traits of interest. For instance, because domestication results in smaller skulls and brains, we looked for publications examining craniofacial features in BD patients combining the keywords “microcephaly”AND “bipolar disorder”; search terms such as “neoteny,”“reactive aggression,” “stress response,”“oxytocin,”and the like were used similarly. Approximately 200 publications resulted initially, with 115 included, ranging in years from 1985 to 2019; reviews and metanalyses were favoured for inclusion, with primary literature included in the absence of these, and case reports included parenthetically as needed to illustrate rare but relevant manifestations of domestication-associated features. We excluded papers just mentioning the features of interest without providing direct measures or quantitative estimations (e.g., levels of cortisol in the blood or values of cephalic perimeter). 2.2 |Overlap between candidate genes for BD and domestication In order to test whether candidate genes for BD are enriched in candidates for domestication and NC development and function, we first compiled a list of BD- associated genes. For this, we relied on two different curated databases: The Genetic Database for Bipolar Disorder (Bdgene) (http://bdgene.psych.ac.cn/) and the Psychiatric disorders Gene association NETwork (PsyGeNet) (www.psygenet.org/). The Bdgene database (Chang et al., 2013) contains candidates resulting from different methodological approaches: Genome-wide association analyses (GWAs), candidate-gene association studies, linkage studies, mutational studies, copy number variation (CNV) analyses, and meta-analyses for association or linkage studies. Candidate genes may bear pathogenic SNPs, be associated to pathological haplotypes or CNVs, be found mutated in familial forms of the disease, result from candidate gene approaches and functional studies, result from linkage studies, association studies, or GWAs, be part of pathways associated to the disease, or interact with known candidates for BD (see http:// bdgene.psych.ac.cn/data.do for details). Of the 1192 genes discussed in the BD database, we considered only the 599 genes categorized as positive (see Supporting Information S2, column A), for which at least one significant study has been found under the significance criteria used by the database’s authors (see http://bdgene. psych.ac.cn/data.do#summary, tab. 3). Regarding the PsyGeNet database, it has been developed by automatic extraction of information from PubMed abstracts using the text mining tool BeFree (http://ibi.imim.es/befree/), followed by curation by experts in the domain (see Gutiérrez-Sacrist an et al., 2015, for details). The number of genes associated to BD and related disorders in the PsyGeNet database is 514. However, we considered only the genes for which the evidence index was 1 (n=374), implying that all the evidence reviewed by the experts supports the existence of an association between the gene and the disease (for each gene, experts validate a maximum of five publications, selected among the most recent ones) (see Supporting Information S2, column B). The entire list of candidate genes for BD considered in our study resulted from merging these two lists (599 plus 374 genes) and removing the overlapping genes (see Supporting Information S2, column C). We then compiled a list of candidates for domestication. For this, we considered papers looking for signals of positive selection in genes of domesticated mammals, including the Guinea pig, the pig, the rat, the dog, the cat, the cattle, the domesticated the fox, the horse, the rabbit, and the sheep (Albert et al., 2012; Axelsson et al., 2013; Bellone et al., 2013; Benítez-Burraco et al., 2017; Cagan & Blass, 2016; Carneiro et al., 2014; Freedman et al., 2016; Montague et al., 2014; Pendleton et al., 2018; Qanbari et al., 2014; Schubert et al., 2014; Theofanopoulou et al., 2017; Trut et al., 2009; Wilkins et al., 2014; Womack, 2005; Wright, 2015; Zapata et al., 2016). The list encompasses 764 genes (see Supporting Information S2, column D). Because of the purported involvement, as noted in Section 1, of the NC in the domestication process (see Wilkins et al., 2014; Wilkins, 2020, for details), we also considered candidate genes for NC development and function. For 1408 BENÍTEZ-BURRACO and HANSEN 14609568, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.15959 by Readcube (Labtiva Inc.), Wiley Online Library on [26/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License this, we relied on the list compiled by Benítez-Burraco and colleagues (2017) for their work on the presentation of self-domestication features in people with SZ. This list comprises 89 genes (see Supporting Information S2, column E), which were gathered following pathogenic and functional criteria: Neurocristopathy-associated genes annotated in the OMIM database (http://omim. org/), NC markers, genes that are functionally involved in NC induction and specification, genes involved in NC signalling (within NC-derived structures), and genes involved in cranial NC differentiation. To determine the significance of the overlap between the list of BD candidates and the lists of candidates for domestication or NC candidates, a Fisher’s exact test was conducted, using protein-coding genes obtained from the Ensembl BioMart (GRCh38.p12) as background. 2.3 |Functional characterization of genes of interest Genes found related to both BD and domestication were examined in detail to know more about their potential roles in the aetiopathogenesis of BD. With this aim, we first conducted gene ontology analyses (GO) of the set of common candidates for BD and domestication. Functional enrichment analyses were performed with Enrichr (https://maayanlab.cloud/Enrichr/; Chen et al., 2013; Kuleshov et al., 2016). We considered biological processes, molecular functions, cellular components, or human pathological phenotypes with associated pvalues <0.05 as enriched. This functional characterization was subsequently improved through literature search for each gene of interest via PubMed, aimed to provide a detailed functional characterization of the common candidates for BD and domestication (see Supporting Information S3). Additionally, we looked for potential functional links between common candidates for BD and domestication. For this, we used String 11.0 (www.string-db.org), a license-free software that predicts direct/physical and indirect/functional associations between proteins derived from several sources (high-throughput experiments, conserved co-expression, genomic context, and knowledge previously gained from text mining) (Szklarczyk et al. 2015). To make our results stronger, we only relied on curated databases of molecular interactions and on experimentally determined interactions between proteins, and used a confidence value of 0.04, indicating a 40% probability that a predicted link exists between two proteins in the same map in the KEGG database (http://www. genome.jp/eg/pathway.html). Finally, we improved our biological characterization of common candidates for both BD and domestication by examining their expression profiles in different body tissues. With this aim, we retrieved a heat map of their expression levels in the samples of the Human tissue compendium (Novartis) (Su et al., 2004), as generated by Gene Set Enrichment Analysis (GSEA) software (http:// software.broadinstitute.org/gsea/index.jsp). In order to make our approach as biologically friendly as possible, we also examined the expression profiles in vivo of candidates for domestication in samples brain areas known to be altered in BD and that have experienced recent changes in the human species. For this, we relied on available datasets of differentially expressed genes (DEGs) as found in the GEO repository (https://www. ncbi.nlm.nih.gov/gds). Specifically, we made use of recent data produced by Lanz et al. (2019) (GSE53987; supplemental table 5), who analysed DEGs in postmortem samples of the prefrontal cortex (PFC), the hippocampus (HIP), and the striatum (STR) of people with BD. We considered only DEGs with expression pvalues <0.01 (see Supporting Information S4 for details). We then conducted Fisher’s exact test (95% confidence interval), to check whether these three sets of genes overlap significantly with candidates for domestication. To calculate this, we considered (i) the number of overlapping genes, (ii) the number of DEGs in the brain of patients, (iii) the number of domestication genes, and (iv) the total number of genes present in the microarray (see Supporting Information S4 for details). Our methodological approach is summarized in Figure 1. 3|RESULTS 3.1 |Abnormal presentation of selfdomestication features in BD As noted in Section 1, domestication results in a set of morphological, neuroendocrine, cognitive, and behavioural traits that usually co-occur. As also noted, most of these traits are found in modern humans compared with extinct hominins and most extant primates. Many of these features are altered in human-specific cognitive conditions, like SZ, ASD, or WS (see Supporting Information S1; see Benítez-Burraco et al., 2016,2017; Niego & Benítez-Burraco, 2019, for details). As we discuss below, these features are also found altered in patients with BD, with some of them being attenuated, but with others appearing augmented. 3.1.1 | Minor physical anomalies (MPAs) MPAs are more common in those with neurodevelopmental disorders and are considered to reflect altered BENÍTEZ-BURRACO and HANSEN 1409 14609568, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.15959 by Readcube (Labtiva Inc.), Wiley Online Library on [26/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License brain development given the common neuroectodermal origin of the brain and skin, with shared sensitivity to genetic and/or environmental perturbation during embryogenesis (Myers et al., 2017). Evidence surrounding MPAs in BD is mixed (Tényi et al., 2009), with some studies showing no significant difference in total MPA rate compared with SZ, others showing no significant difference compared with healthy controls (Sanches et al., 2008), and some indicating increased MPA rate within specific body regions (Akabaliev et al., 2011; Berecz et al., 2017). When comparing patients with affective psychosis to those with non-affective psychosis and healthy controls, no significant differences in total MPA scores were found by McGrath et al. (2002), but those with affective psychosis (including BD) were found to have wider skulls, shorter lower thirds of the face, and more brachycephalic skulls, reminiscent of domestication features. Significant increases in dermatoglyphic malformations such as ridge dissociation have also been reported (Gutiérrez et al., 1998) (though the evidence in this area is also mixed; see Vonk et al., 2014) and were associated with earlier age of onset of BD. Increased dermatoglyphic malformations and genetic correlations led Vonk et al. (2014) to conclude that smaller brain volumes in those at risk for BD are related to abnormal development of foetal ectoderm, from which both brain and skin tissue are derived, between the tenth and fifteenth weeks of gestation. Specific examples or areas of statistically significantly increased MPA in BD include furrowed tongue, enlarged gap between toes I and II, high or steepled palate, and lowered eye fissures, with abnormal ear size/ shape/attachment, flat occiput, and other MPAs shared with SZ patients (Akabaliev et al., 2011; Berecz et al., 2017; Lloyd et al., 2008; Trixler et al., 2001). Surface imaging of BD patients compared with SZ patients and controls by 3D laser describes anomalies found in male and female patients with BD including widening of the nose and face overall, narrowing of the mouth, and chin displacement upward, as well as sex-specific changes in nose length (shorter in females, longer in males) (Hennessy et al., 2010). Compared with controls and patients with SZ, the jaws of patients with BD were wider (in males) and upwardly displaced (in females). Additionally, patients with BD and SZ were found to share common, especially frontonasal dysmorphology, such as mouth narrowing. In a study demonstrating significant differences between the three groups, a pattern emerges with decreasing levels of (especially cephalofacial) MPAs from SZ, to BD, to normal controls, suggesting “a continuum of neurodevelopmental adversity”to match the clinical spectrum of psychotic disorders (Akabaliev et al., 2014). FIGURE 1 Analytical workflow of the research conducted in the paper. Analytical tasks are displayed as rectangular shapes, whereas the resulting data are shown as oval shapes. Shapes are coloured following a chronological order. 1410 BENÍTEZ-BURRACO and HANSEN 14609568, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.15959 by Readcube (Labtiva Inc.), Wiley Online Library on [26/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 3.1.2 | Brain and cognition In BD and SZ, total cerebral volume is decreased, suggesting a shared neurodevelopmental aetiology (Nasrallah, 1991); this finding is significantly associated with BD duration (Hallahan et al., 2011). The brain in patients with BD is also notable for increased amygdala volume (Altshuler et al., 1998,2000; Hallahan et al., 2011; Strakowski et al., 1999), decreased hippocampus volume (Hajek et al., 2012; Han et al., 2019) (though increased with lithium treatment according to Yucel et al., 2008, and Hallahan et al., 2011), increased ventricle:brain ratio (Post et al., 2003), enlarged caudate nuclei (Noga et al., 2001), and increased right putamen volumes (Hallahan et al., 2011). As noted, the brain of domesticated animals is smaller than the brain of their wild conspecific. Contrary to people with BD, some domesticated animals like domesticated rats exhibit reduced volumes of the striatal regions (Kruska & Schott, 1977). With regards to the hippocampus, evidence concerning domesticated animals is somehow opposite. Similarly to treatment naïve subjects with BD, many domesticated mammals (laboratory rats, pigs, sheep, poodles, and llamas) exhibit reduced hippocampal volumes (and seemingly, hippocampal function) (Kruska, 1988, 2005). Nonetheless, there is evidence as well of increased hippocampal volumes in domestic pigeons (Rehkämper et al., 2008) and of increased neurogenesis in domesticated foxes (Huang et al., 2015), with cell proliferation being more sensitive to environmental influences in domesticates, even in the adulthood (Schaefers, 2013). Interestingly, hippocampal volumes have increased in modern humans (Schilder et al., 2019), with one third of the loci more strongly associated to this hippocampal enlargement being also candidates for mammal domestication (Hibar et al., 2017). These findings can be explained by the diverse functions performed by the hippocampus, which range from spatial navigation and cognition, to episodic memory, to stress management (Maguire et al., 1998; McEwen et al., 2012; Vinogradova, 2001). Accordingly, increased hippocampal volumes in pigeons have been associated to their adaptation to homing (Rehkämper et al., 2008). Likewise, changes in the hippocampus in humans, a selfdomesticated primate, have been related to our enhanced episodic memory, that enables us to mental travel in time and space and that supports human language among other species-specific cognitive abilities (Corballis, 2019). Finally, domesticated animals also exhibit altered expression patterns of stress-related genes in the hippocampus (Løtvedt et al., 2017), which can be related to differences in the management of aggression compared with their wild conspecifics. In sum, findings in people with BD of reduced hippocampal volumes can be construed as a sign of reduced self-domestication, but more importantly, help explain differences with controls in domains like cognition and behaviour (see below). The same can be said of the amygdala, which is also part of the limbic system, which regulates important behavioural and cognitive functions such as emotion, motivation, and long-term memory (see Rolls, 2015, for review). Many domesticated animals show increased amygdala volumes (Kruska, 1988,2005; Welniak-Kaminska et al., 2019). Also bonobos—another primate species thought to have been self-domesticated—have a larger amygdala compared with chimpanzees (Rilling et al., 2012), although different subregions might exhibit different trends (Stimpson et al., 2016). At the same time, in domesticated rabbits, the amygdala shows a marked reduction in size (Brusini et al., 2018) and reduced amygdalar volumes have also been reported for the domesticated Bengalese finch relative to the wild white-rumped munia (Suzuki et al. 2014). Whereas the amygdala is disproportionately large in people with ASD (Mosconi et al., 2009; Murphy et al., 2012), a condition entailing hypodomesticated features, it is usually reduced in patients with SZ (Li et al., 2015; Okada et al., 2016; Rich et al., 2016), involving hyperdomesticated traits. Evidence as to impairment of social cognition in BD is also mixed: On one measure of social cognition (MSCEIT), patients with SZ evidenced social cognition deficits compared with controls, while those with BD did not—even separately assessing BD with and without psychotic features (Nitzburg et al., 2015). On the other hand, theory of mind (ToM) deficits as assessed with the MASC tool have been found in patients with BD and their firstdegree relatives (Santos et al., 2017). ToM deficits in BD have been reported in symptomatic (both depressed and manic) patients (Kerr et al., 2003), as well as in euthymic and remitted patients (Bora et al., 2005), although deficits are more severe during the manic phase, especially if psychotic symptoms are present (Hawken et al., 2016). Also, greater impairment is seen in cognitive than emotional ToM (Barrera et al., 2013). Furthermore, another aspect of social cognition—facial emotion recognition (FER)— has been found to be a moderate, stable deficit in BD in a quantitative review by Kohler et al. (2011). This deficit can be seen across mood states in both adults and children with BD as well as children with first-degree relatives with BD (Brotman et al., 2008; Van Rheenen & Rossell, 2014). As assessed with fMRI, patients with BD displayed greater amygdalar activation, compared with healthy controls, when processing fearful facial expressions (Yurgelun-Todd et al., 2000). Empathic responses by self-report in BD have been shown to be decreased relative to controls (and higher relative to patients with SZ), though actual performance on empathy behavioural tasks was similar to that of controls (Derntl et al., 2012; BENÍTEZ-BURRACO and HANSEN 1411 14609568, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.15959 by Readcube (Labtiva Inc.), Wiley Online Library on [26/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Seidel et al., 2012), consistent with previous findings of reduced cognitive empathy (perspective taking) and increased personal distress at others’negative experiences in BD (Cusi et al., 2010). Contrary to people with BD, domesticated animals (dogs vs. wolves, domestic vs. wild foxes, and bonobos vs. chimpanzees) show more sensitivity and attentiveness to human social cues, like eye or facial movements (Hare, 2017). Finally, regarding language (dis)abilities, it should be noted that human self-domestication has been proposed as a key facilitator of language evolution (Benítez-Burraco & Kempe, 2018;Thomas&Kirby,2018). Language impairment is a central if overlooked component of BD, with meta-analysis indicating verbal fluency as moderately impaired, with significantly greater impairment in euthymic than manic patients (Raucher-Chéné et al., 2017). Language differences in BD also include impaired accuracy when emotionally labelling “happy intonations”in males (Van Rheenen & Rossell, 2013) and abnormal prefrontal activation during language tasks (Curtis et al., 2007). 3.1.3 | Behavioural traits and neuroendocrine impairments The HPA axis, which regulates a great number of body functions and is thought to underlie stress reactivity changes in domestication, has been shown to be hyperactive in patients with BD, with hypersecretion of cortisol compared with controls (Cervantes et al., 2001; Girshkin et al., 2014). HPA axis dysfunction has been suggested as a trait abnormality in BD given enhanced cortisol response in the dexamethasone/corticotropin-releasing hormone test relative to healthy controls, without significant difference between remitted and non-remitted patients (Watson et al., 2004). Basal plasma adrenocorticotropic hormone (ACTH) levels are also elevated in BD, according to a 2016 meta-analysis (Belvederi Murri et al., 2016), and glucocorticoid receptor responsiveness is reduced (Fries et al., 2014). This HPA axis dysfunction has been hypothesized to underlie the cyclicity of BD mood phases by Daban et al. (2005), who suggest that increases in ACTH and cortisol precede manic states, while depressive states may be caused by chronically elevated cortisol levels. In support of this, HPA axis hyperactivity in BD appears to be most pronounced during mania (Belvederi Murri et al., 2016). HPA axis dysfunction also appears to factor into the illness progression of BD, as post-dexamethasone cortisol levels—elevated in patients with BD compared with controls overall— positively correlate with total number of mood episodes experienced (Fries et al., 2014). By contrast, in domesticated animals, the function of the HPA axis is significantly reduced compared with wild conspecifics, resulting in decreased levels of glucocorticoids, basal plasma ACTH levels, and adrenal response to stress, as well as less pronounced cortisol response to novelties (Kaiser et al., 2015; Kruska, 1988; Naumenko & Belyaev, 1980; Trut et al., 2009; Zipser et al., 2014). Relatedly, oxytocin (OT) and vasopressin (AVP; also known as antidiuretic hormone, ADH) have been proposed as factors in the aetiology of BD as well as, in different ways, SZ, WS, and ASD (Dai et al., 2012; Iovino et al., 2018; Perez-Rodriguez et al., 2015). OT has been described as a driver of social cognition and mentalization (Crespi, 2016; Striepens et al., 2011;W  ojciak et al., 2012), including the multimodality that characterizes higher-order linguistic abilities (Theofanopoulou, 2016). Specifically, OT inhibits the HPA axis’stress triggered activity (Neumann, 2002). While Rutigliano et al. (2016) found insufficient evidence for use of peripheral OT/AVP levels as biomarkers of psychiatric disorders, OT has been found to be elevated in BD type II compared with MDD and controls, pre- and post-treatment (Lien et al., 2017). This is consistent with the findings of Turan et al. (2013) in a study that also found serum OT to be highest in currently manic BD patients, compared with depressed and remitted BD patients (as well as healthy controls). Domesticated animals exhibit higher densities of both OT and AVP cells (Ruan & Zhang, 2016). Oxytocin has been associated to human-animal interactions, especially when eye contact is involved in communicative settings (see Beetz et al., 2012, for review). Inasmuch as domestication entails a selection for hypersociality and low reactivity—in effect, tameness, the basis of selection in the famous fox farm experiment (Trut, 1999)—personality traits such extraversion and openness are worth noting. For instance, WS has been proposed as a condition of hyperdomestication and is characterized by hypersociability (Niego & Benítez- Burraco, 2019), with the genetic locus involved being correlated with hypersociability in dogs compared with wolves (VonHoldt et al., 2017). Perhaps not surprisingly, in subjects with WS, basal OT and AVP levels are increased, and the increase correlates with the tendency to approach strangers and emotionality (Dai et al., 2012). Reflecting the gregariousness associated with the manic state, trait extraversion and openness have been associated with hypomanic personality traits (Durbin et al., 2009; Meyer, 2002). Mania has also been correlated with trait extraversion, as well as neuroticism and negatively, agreeableness (Quilty et al., 2009). Finally, playful thinking has been associated with mania, compared with SZ, as measured on the Thought Disorder Index (Daniels et al., 1988). Domestication is known to increase play behaviour in animals (Hart, 1985; Himmler et al., 2013; Kaiser et al., 2015). 1412 BENÍTEZ-BURRACO and HANSEN 14609568, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.15959 by Readcube (Labtiva Inc.), Wiley Online Library on [26/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 3.1.4 | Other features of interest With neoteny a classic feature associated to domestication, it is notable that small head circumference (less than 32 cm at birth) has been found to correlate with later diagnosis of BD by Pugliese et al. (2019); inadequate maternal weight gain was inversely associated with BD (while positively associated with SZ). Considering another aspect of neoteny, evidence is mixed as to whether age at menarche is delayed (Bisaga et al., 2002) or not significantly different (Dunjic-Kostic et al., 2016) in women with BD compared with healthy controls (Tondo et al., 2017; Williams et al., 2007). Further complicating the picture, girls with early menarche experience higher rates of BD and other psychiatric conditions (Platt et al., 2017). Age of menarche in women with BD appears to indicate the course of the disorder, being strongly correlated with irritable temperament scores and inversely correlated with depressive and cyclothymic scores as well as duration of depressive episodes (Kesebir et al., 2013). Age at menarche has also been negatively associated with number of depressive episodes (Dunjic- Kostic et al., 2016). Looking to the reproductive cycle in BD more broadly (as domesticated animals typically show altered cycles), the impact of menstruation on mood in BD is instructive. A systematic review by Teatero et al. (2014) found that 64% to 68% of women with BD in retrospective studies reported mood changes with menses, as well as considerable diagnostic overlap with (DSM-4) premenstrual syndrome and premenstrual dysphoric disorder. In a study by Perich et al. (2017), 77% of women with BD reported increased mood symptoms during peri/menstrual and postnatal periods which—relative to women who did not report reproductive cycle-related changes in symptoms— was correlated with more severe BD course, including earlier age of onset with mood episodes and increased likelihood of rapid cycling and mixed mood states. Menorrhagia, polymenorrhea, oligomenorrhea, and amenorrhea are among the many reproductive cycle abnormalities reported among women with BD (Barron et al., 2008; Rasgon et al., 2003,2005; Williams et al., 2007). Indeed, women with BD experience menstrual dysfunction (irregularity or abnormally increased/ decreased length of menstrual cycles) prior to the onset of psychiatric illness at a significantly higher rate relative to women with unipolar depression and healthy controls (Joffe et al., 2006), and women with unipolar depression were not significantly likelier to experience such dysfunction than healthy controls. This serves to highlight the centrality of mania in BD and the potentially explanatory role of oxytocin in the disorder, as discussed by Crespi’s (2016) examination of the “symmetrical”comorbidities of ASD and polycystic ovarian syndrome (PCOS) on the one hand and BD and endometriosis on the other, proposed to be the results of decreased and increased oxytocin levels, respectively (though PCOS comorbidity with BD has also been reported by Qadri et al., 2018). Menstrual psychosis is also thought to be a manifestation of BD pathology (Abe & Ohta, 1995; Brockington, 2005,2011), and menses can trigger exacerbation of psychosis in BD and other psychotic disorders (Reilly et al., 2019). In line with this and with the reduction of androgen levels seen in domestication, BD is associated with decreased testosterone levels among untreated firstepisode patients (Feng et al., 2019) and remitted male patients (Keshri et al., 2018). Interestingly, in BD patients in a current depressive episode, testosterone levels were significantly decreased among male patients compared with healthy male controls and significantly increased among female patients compared with healthy female controls (Wooderson et al., 2015), consistent with findings of hyperandrogenemia in women with BD (Rasgon et al., 2005; Zerouni et al., 2013). In both males and females with BD (and controlling for sex), testosterone levels positively correlated with number of manic episodes as well as number of suicide attempts (with no correlation found between testosterone levels and aggression) (Sher et al., 2012). Among females with BD, a positive correlation was found between testosterone levels and number of past major depressive episodes and number of suicide attempts (Sher et al., 2014). At followup, elevated baseline testosterone levels predicted suicide attempts such that a 10 ng/dL increase in testosterone translated to a 16.9-times increased probability of suicide attempt. While it should be noted that one study found no significant differences in salivary testosterone levels either between BD type I patients and healthy controls or between euthymic, depressed, and manic BD patients (Mousavizadegan & Maroufi, 2018), there are reports of hypomania (Freinhar & Alvarez, 1985) and mania (Elboga & Sayiner, 2018) induced by androgen administration, as well as homicide after a man with BD was administered testosterone for hypogonadism (Sher & Landers, 2014). In a case with comorbid Klinefelter syndrome, however, testosterone therapy has been reported to effectively treat a pattern of frequent manic episodes refractory to treatment with mood stabilizers and secondgeneration antipsychotics (Kawahara et al., 2015). Of note, testosterone therapy in early childhood has been shown to improve neurodevelopmental outcomes including language and intellectual ability in Klinefelter syndrome (47, XXY) patients, compared with untreated controls (Samango-Sprouse et al., 2013). BENÍTEZ-BURRACO and HANSEN 1413 14609568, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.15959 by Readcube (Labtiva Inc.), Wiley Online Library on [26/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 3.2 |Overlap between candidate genes for BD and domestication As noted in Section 1, BD has a strong genetic background. With the aim of testing whether our hypothesis is supported by available molecular evidence, we assessed whether genes that have been related to BD are overrepresented among candidates for domestication and NC development and function. We found a significant overlap (p=3.37e07) between candidates for BD and candidates for domestication. By contrast, the overlap between candidates for BD and candidates for NC development and function was not significant (p=0.168). Figure 2displays the list of 62 common candidates for BD and domestication. FIGURE 2 Candidates for BD that are also candidates for animal domestication. (a) List of genes that are cited as candidate for BD and that show signals of positive selection in domesticated animals. (b) Functional interactions among the genes that are candidates for BD and domestication. The diagram shows the network of known functional interactions among the proteins encoded by the genes. The networks were drawn with String (version 11.0; Szklarczyk et al. 2015) license-free software (http://string-db.org/), using the molecular action visualization. Coloured nodes symbolize the proteins. The colour of the edges represents different kinds of known protein–protein associations. Green: activation, red: inhibition, dark blue: binding, light blue: phenotype, dark purple: catalysis, light purple: posttranslational modification, black: reaction, yellow: transcriptional regulation. Edges ending in an arrow symbolize positive effects, edges ending in a bar symbolize negative effects, whereas edges ending in a circle symbolize unspecified effects. The medium confidence value was 0.0400 (a 40% probability that a predicted link exists between two enzymes in the same metabolic map in the KEGG database: http://www. genome.jp/kegg/pathway.html). The diagram only represents the attested connectivity between the involved proteins, derived from curated databases or experimentally determined, but it must be mapped onto particular biochemical networks, signalling pathways, cellular properties, aspects of neuronal function, or cell-types of interest to gain a more accurate view of its relevance for the presentation of domesticated features in BD (see the text and Supporting Information S2 for further details). 1414 BENÍTEZ-BURRACO and HANSEN 14609568, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.15959 by Readcube (Labtiva Inc.), Wiley Online Library on [26/02/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Pattabiraman et al., 2020). In our opinion, BD could be one of such conditions. Accordingly, BD could be linked to the changes in socialization patterns and social cognition that happened during our recent evolution, in turn associated to our increased self-domestication (or at least, to the decline in reactive aggression). In summary, because of its focus on the recent changes experienced by our species-specific behavioural and cognitive phenotype (specifically, those aspects linked to the control of reactive aggression), our hypothesis gives more room than others to interactional and socialization factors, as well as to evolutionary concerns, when it comes to account for the aetiology of BD. In other words, this self-domestication view of BD should be understood as a complementary view to the existing accounts of the aetiology of BD, which have traditionally focused on the alteration of brain mechanisms. AUTHOR CONTRIBUTIONS ABB conceived the paper, reviewed the available literature, performed the data analyses, and wrote and approved the final manuscript. 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