Genetic control of temperament traits across species: association of autism spectrum disorder risk genes with cattle temperament

Abstract

Background: Temperament traits are of high importance across species. In humans, temperament or personality traits correlate with psychological traits and psychiatric disorders. In cattle, they impact animal welfare, product quality and human safety, and are therefore of direct commercial importance. We hypothesized that genetic factors that contribute to variation in temperament among individuals within a species will be shared between humans and cattle. Using imputed whole-genome sequence data from 9223 beef cattle from three cohorts, a series of genome-wide association studies was undertaken on cattle flight time, a temperament phenotype measured as the time taken for an animal to cover a short-fixed distance after release from an enclosure. We also investigated the association of cattle temperament with polymorphisms in bovine orthologs of risk genes for neuroticism, schizophrenia, autism spectrum disorders (ASD), and developmental delay disorders in humans. Results: Variants with the strongest associations were located in the bovine orthologous region that is involved in several behavioural and cognitive disorders in humans. These variants were also partially validated in independent cattle cohorts. Genes in these regions (BARHL2, NDN, SNRPN, MAGEL2, ABCA12, KIFAP3, TOPAZ1, FZD3, UBE3A, and GABRA5) were enriched for the GO term neuron migration and were differentially expressed in brain and pituitary tissues in humans. Moreover, variants within 100 kb of ASD susceptibility genes were associated with cattle temperament and explained 6.5% of the total additive genetic variance in the largest cattle cohort. The ASD genes with the most significant associations were GABRB3 and CUL3. Using the same 100 kb window, a weak association was found with polymorphisms in schizophrenia risk genes and no association with polymorphisms in neuroticism and developmental delay disorders risk genes. Conclusions: Our analysis showed that genes identified in a meta-analysis of cattle temperament contribute to neuron development functions and are differentially expressed in human brain tissues. Furthermore, some ASD susceptibility genes are associated with cattle temperament. These findings provide evidence that genetic control of temperament might be shared between humans and cattle and highlight the potential for future analyses to leverage results between species.

Adrenergic Tone as an Intermediary in the Temperament Syndrome Associated With Flight Speed in Beef Cattle

“…Several further points are noteworthy. Early studies on temperament in cattle and other farm animal species focused (Valente et al, 2016;Dos Santos et al, 2017;Garza-Brenner et al, 2017;Chen et al, 2020;Costilla et al, 2020;Paredes-Sánchez et al, 2020 on consistent individual differences in behavior during handling (Tulloh, 1961;Burrow et al, 1988;Grandin, 1993). Nonetheless, it was also recognized that temperament is an enduring characteristic of the animal that persists in the absence of humans (Lyons et al, 1988;Sebastian et al, 2011) and which "represents an individual's basic stance toward continuing changes and challenges in its environment" (Mason, 1984), cited by (Lyons et al, 1988).…”

“…Thus, candidate genes differ between studies and between breeds of cattle. Where quantified, SNP contribute up to a few percent of additive genetic variation in FS (Dos Santos et al, 2017;Costilla et al, 2020). The large number of candidate genes and their small individual additive genetic variation in FS is in accord with the additive genetic variation seen in heritability estimates of FS (Haskell et al, 2014).…”

“…Single nucleotide polymorphisms (SNP) pointing to candidate genes associated with FS have been identified by several groups. Candidates include BARHL2, MAGEL2, NDN, SNRPN (Costilla et al, 2020; Brahman and two tropical composite herds), NCKAP5, PARK2, ANTXR1, GUCY1A2, CPE, DOCK1 (Valente et al, 2016;Nallore), PWWP2A, GABRG2 (Chen et al, 2020; Brahman and Yunling), DRD3, HTR2A (Garza-Brenner et al, 2017; Charolais), POU1F1, DRD3, VWA3A, ZBTB20, EPHA6, SNRPF, NTN4 (Dos Santos et al, 2017;Guzerat), ACER3, VRK2, FANCL, SLCO3A1, NRXN3, EXOC4, CACNG4, and SLC9A4 (Paredes-Sánchez et al, 2020; Brahman) ( Table 1). Hanna et al (2014) identified candidate genes involved in sodium ion transport and voltage gated ion channel functions associated with subjectively scored temperament in Nellore Angus cross cattle.…”

“…GWAS studies point to a prominent role of neural functions in generating the internal environment that tunes somatic activities into the characteristic patterns associated with flightiness in a top down manner. In this model, orchestration of temperament would lie within the neural activities modulated by structural and functional variation associated with the candidate genes identified by GWAS (e.g., Dos Santos et al, 2017;Costilla et al, 2020). Conversely, the potential for epigenetic patterning of peripheral tissue functions during ontogeny and mature life is well-recognized in the somatic activities associated with FS (Bell and Greenwood, 2016).…”

“…In view of the importance of centripetal (afferent) nervous and blood borne messaging from peripheral tissues to the central nervous system (Kleckner et al, 2017;Dantzer et al, 2018;Quigley et al, 2021), a multiplex bi-directional model seems more plausible than a top down model driven by external environmental cues like proximity to humans. Thus, the persistent character of FS and its associated peripheral traits (Haskell et al, 2014) could arise from the influence of genetic variants (e.g., Dos Santos et al, 2017;Costilla et al, 2020) and prenatal epigenetic effects such as maternal stress on ontogenetic development in utero (Littlejohn et al, 2020), then be reinforced in postnatal life by feedback from peripheral tissues functioning within an autonomic and neurohormonal environment patterned by the earlier developmental programming (Kleckner et al, 2017;Dantzer et al, 2018;Quigley et al, 2021). The quantitative character of FS and its associated traits (Haskell et al, 2014) suggest that the balance of these influences may well differ between populations of cattle.…”