Discussion

This meta-analysis provides a crucial synthesis of the genetic factors that influence metabolic disorders in dairy cows, addressing a key challenge in dairy cattle breeding. Metabolic disorders, such as MA, KE, and DA, are among the most common health problems in dairy herds and result in significant economic losses due to reduced milk production, increased veterinary costs, and premature culling (Rasmussen et al., Reference Rasmussen, Barkema, Osei, Taylor, Shaw, Conrady, Chaters, Muñoz, Hall, Apenteng, Rushton and Torgerson2024). These disorders are multifactorial and involve complex interactions between genetic, environmental, and management factors (Ghavi Hossein-Zadeh and Ardalan, Reference Ghavi Hossein-Zadeh and Ardalan2011a, Reference Ghavi Hossein-Zadeh and Ardalan2011b; Chegini et al., Reference Chegini, Ghavi Hossein-Zadeh, Hosseini-Moghadam and Shadparvar2019; Ghavi Hossein-Zadeh, Reference Ghavi Hossein-Zadeh2022; Kapusniaková et al., Reference Kapusniaková, Juráček, Hanušovský, Duchoň, Rolinec, Gálik, Džima, Rajčok and Šimko2024).

The results indicate significant variation in the incidence rates of metabolic disorders in dairy cows. CM is one of the most common and economically damaging diseases in dairy production, with the highest incidence rate. This high incidence is attributed to its multifactorial nature, involving environmental, genetic, immune response, and management factors such as milking practices and hygiene conditions. In contrast, DA has a relatively low incidence rate, likely due to improved management practices and veterinary interventions for this specific disease. However, it remains economically significant due to the high costs of treatment and the associated production losses (Ghavi Hossein-Zadeh and Ardalan, Reference Ghavi Hossein-Zadeh and Ardalan2011c; Janevski et al., Reference Janevski, Nikolovski, Cvetkovikj, Andreevska, Todorovski and Mitrov2023; de Jong et al., Reference de Jong, van der Velden, Smid, Ida, Reyher, Kelton and Barkema2024).

The heritability estimates for metabolic disorders in dairy cows suggested a generally low genetic contribution to these disorders. This suggests that environmental and management factors play a more important role in their incidence. However, despite the low heritability estimates, the results are statistically significant, meaning that there is still a genetic influence on these disorders, albeit limited. Therefore, while genetic selection could potentially reduce the incidence of these diseases, its impact may not be as strong as improvements in management practices (Pryce et al., Reference Pryce, Parker Gaddis, Koeck, Bastin, Abdelsayed, Gengler, Miglior, Heringstad, Egger-Danner, Stock, Bradley and Cole2016; Brito et al., Reference Brito, Bedere, Douhard, Oliveira, Arnal, Peñagaricano, Schinckel, Baes and Miglior2021).

The significant and positive genetic correlations between metabolic disorders observed in the study highlight the connection between these health problems in dairy cows. These positive correlations suggest that metabolic disorders share common genetic pathways, meaning cows genetically predisposed to one disorder are more likely to develop others as well. Particularly noteworthy is the strong correlation between KE and DA (0.522). Both disorders are related to energy metabolism and nutrient imbalances, particularly in the postpartum period when cows are under significant metabolic stress due to high milk production requirements (Klein et al., Reference Klein, Scheper, May and König2020; Ghavi Hossein-Zadeh, Reference Ghavi Hossein-Zadeh2022). KE is often associated with a negative energy balance (NEB), where the body mobilizes fat reserves, resulting in the production of ketones (Koeck et al., Reference Koeck, Miglior, Jamrozik, Kelton and Schenkel2013; Ghavi Hossein-Zadeh, Reference Ghavi Hossein-Zadeh2022; Tufarelli et al., Reference Tufarelli, Puvača, Glamočić, Pugliese and Colonna2024). DA, on the other hand, can occur when reduced feed intake or a high-fat diet leads to gas accumulation that displaces the abomasum (Mekuriaw, Reference Mekuriaw2023). The genetic connection between these two diseases suggests that animals genetically prone to energy metabolism disorders are at higher risk of developing both diseases. This finding is consistent with other studies showing that cows in ketosis are more likely to develop DA due to underlying metabolic stress (Atalay, Reference Atalay2024). Likewise, the genetic correlation between RP and ME (0.472) reflects the physiological connection between these two reproductive disorders. RP is a risk factor for ME, an infection of the uterus, as it provides a favorable environment for bacterial growth in the postpartum period (Ghavi Hossein-Zadeh and Ardalan, Reference Ghavi Hossein-Zadeh and Ardalan2011c). The genetic correlation suggests that cows with a genetic predisposition to one disease are also more likely to develop the other (Kašná et al., Reference Kašná, Zavadilová, Krupová, Šlosárková and Fleischer2023).

KE is widely known as a metabolic disorder in dairy cows, which is primarily due to energy metabolism disorders during periods of metabolic stress, particularly during early lactation. It often occurs together with other metabolic disorders such as DA, RP, and ME, which are based on common mechanisms such as NEB, inflammation, and immunosuppression. This network supports their classification as a metabolic disorder. As a result, KE is recognized as a metabolic disorder due to its pathophysiological basis in the dysregulation of energy metabolism, its established classification in the literature and its genetic correlations with other metabolic diseases (Tufarelli et al., Reference Tufarelli, Puvača, Glamočić, Pugliese and Colonna2024). The rumen microbiome plays an important role in the breakdown of dietary components and the production of volatile fatty acids (VFAs), which are the primary energy source for dairy cows (Firrincieli et al., Reference Firrincieli, Minuti, Cappelletti, Ferilli, Ajmone‐Marsan, Bani, Petruccioli and Harfouche2024). Dysbiosis, which is often triggered by highly concentrated diets or stress, can disrupt this process and lead to metabolic diseases such as subacute ruminal acidosis (SARA). SARA predisposes cows to systemic inflammation and diseases such as LA and KE. In addition, an unbalanced rumen microbiome can lead to increased production of endotoxins, which may weaken immune function and increase the risk of infections such as MA (Ma et al., Reference Ma, Guo, Li, Xu, Zhang, Chang, Loor and Shen2024; Melendez and Serrano, Reference Melendez and Serrano2024; Tufarelli et al., Reference Tufarelli, Puvača, Glamočić, Pugliese and Colonna2024).

The genetic correlation between MA and MF (0.365) suggests that these two seemingly unrelated diseases may also share common genetic influences. While MA is an infectious disease and MF is a metabolic disorder related to calcium deficiency, cows suffering from one disease may be at increased risk of developing the other disease due to weakened immune function. Cows with MF often have weakened immune systems, making them more susceptible to infections like MA (Fredebeul-Krein et al., Reference Fredebeul-Krein, Schmenger, Wente, Zhang and Krömker2022). This association could be due to common genetic factors that influence immune competence and metabolic regulation, further complicating health management in dairy herds (Ghavi Hossein-Zadeh and Ardalan, Reference Ghavi Hossein-Zadeh and Ardalan2011c; Ohtsuka et al., Reference Ohtsuka, Fukuda, Kudo, Tomioka, Koiwa and Kimura2013).

MA is primarily an infectious disease. However, it is closely linked to metabolic processes for the following reasons: 1. Dairy cows suffer from metabolic stress caused by a NEB that suppresses immune function. Immunosuppression makes cows more susceptible to MA pathogens. Studies show the interplay between metabolic disorders and immune function disorders that lead to MA (Zhao et al., Reference Zhao, Nan, Wang, Liu, Yang, Yao and Xiong2024). 2. Energy requirements in early lactation often exceed dietary intake, resulting in the mobilization of body reserves and increased production of NEFA and beta-hydroxybutyrate (BHBA). Increased levels of these metabolites have been associated with an increased risk of MA (Chen et al., Reference Chen, Hu, Deng, Li, Zhang, Zhang, Shen, Liu, Zhang and Lu2024). 3. Metabolic diseases such as KE and acidosis increase the likelihood of MA due to impaired immune defenses and tissue integrity (Wang et al., Reference Wang, Ma, Tian, Jia, Zhang, Mao, Yang, Zhu and Li2024). Thus, although MA is not a metabolic disorder in the strict sense, its occurrence is closely related to metabolic homeostasis and imbalances, which warrants its inclusion in metabolic health studies (Khan et al., Reference Khan, Huang, Kou, Chen, Liang, Ullah, Khan, Khan, Chai and Wang2024). Hu et al. (Reference Hu, Li, Mu, Guo, Zhao, Cao, Zhang and Fu2022) reported that dairy cows fed a high-concentrate diet for eight weeks developed SARA, a condition marked by prolonged low rumen pH. This dietary intervention not only disrupted rumen function but also led to systemic inflammation and MA. Their results also revealed that SARA-induced mastitis arises through an endogenous pathway, where disturbances in the rumen microbiota and subsequent leakage of bacterial toxins into the bloodstream play a central role. Zhao et al. (Reference Zhao, Hu, Qiu, Bao, Wu, Meng, Zhao, Feng, Duan, He, Zhang and Fu2023) concluded that sialic acid aggravates gut dysbiosis-induced MA by promoting gut microbiota disturbance through the microbiota-gut-mammary axis. This finding indicates the important role of this axis in MA pathogenesis and suggests a potential strategy for MA intervention based on gut metabolism regulation.

The positive genetic correlation between LA and DA (0.147) highlights another important interaction between metabolic and physical disorders. LA can lead to reduced feed intake, which in turn increases the risk of DA due to changes in rumen function and gas production (Thorup et al., Reference Thorup, Nielsen, Robert, Giger-Reverdin, Konka, Michie and Friggens2016; Llonch et al., Reference Llonch, Mainau, Ipharraguerre, Bargo, Tedó, Blanch and Manteca2018). The positive genetic relationship between these two disorders suggests that cows with poor structural traits may also be more susceptible to metabolic problems, suggesting that selection for both traits is critical to improving overall herd health. LA is a multifactorial disorder that is often due to claw disease (such as laminitis), infections, or injuries. Its metabolic basis is supported by the following points: 1. SARA leads to systemic inflammation and damage to the laminar corium of the hooves, leading to laminitis and subsequent LA. The onset of laminitis highlights the metabolic origin of many cases of LA in dairy cows (Jukna et al., Reference Jukna, Meškinytė, Urbonavičius, Bilskis, Antanaitis, Kajokienė and Juozaitienė2024; Sadiq et al., Reference Sadiq, Ramanoon, Mansor, Mossadeq, Syed-Hussain, Yimer, Kaka, Ajat and Abdullah2024). 2. LA is often aggravated by systemic inflammatory responses associated with NEB and metabolic stress during early lactation (Jukna et al., Reference Jukna, Meškinytė, Urbonavičius, Bilskis, Antanaitis, Kajokienė and Juozaitienė2024). 3. Dietary imbalances, such as too much starch in the diet or too little fiber, interfere with rumen fermentation and contribute to metabolic acidosis and subsequent hoof health problems. These factors underscore the metabolic dimensions of LA. Given these links, LA can be considered a metabolic disorder when it is due to systemic metabolic disorders or imbalances (Garvey, Reference Garvey2022; Urban‐Chmiel et al., Reference Urban‐Chmiel, Mudroň, Abramowicz, Kurek and Stachura2024).

Overall, significant and positive genetic correlations suggest that improving genetic resistance to one metabolic disorder may have cascading benefits in reducing the incidence of other metabolic disorders. However, this networking also presents challenges. Selecting for resistance to a disease without considering its genetic relationship to other traits could inadvertently lead to increased susceptibility to other health problems. Therefore, a more holistic approach to genetic selection that takes into account the complex relationships between multiple diseases is needed to improve the overall health and productivity of dairy cows. The results highlight the importance of multiple trait selection strategies in breeding programs, where improving one health trait could have a positive impact on others (Schmidtmann et al., Reference Schmidtmann, Segelke, Bennewitz, Tetens and Thaller2023). However, the genetic correlations also highlight the potential risks of undesirable correlated responses when selection pressure is applied exclusively to a single trait. These results highlight the need for balanced breeding programs that take into account the broader genetic connections between metabolic disorders and other economically important traits (Pegolo et al., Reference Pegolo, Momen, Morota, Rosa, Gianola, Bittante and Cecchinato2020).

The genetic links between metabolic disorders and performance traits in dairy cows uncovered in the study provide important insights into the complex genetic relationships that influence both health and productivity. These correlations help breeders understand the trade-offs or synergies between health traits (e.g. metabolic disorders) and important performance traits (Schmidtmann et al., Reference Schmidtmann, Segelke, Bennewitz, Tetens and Thaller2023). The negative and low genetic correlations between KE, DA, RP, and MY suggest a trade-off between production and health. High-yielding cows may be more susceptible to metabolic disorders due to the metabolic stress they experience during lactation. KE occurs when high-yielding cows enter a negative energy balance early in lactation. As cows mobilize body fat reserves, they are more susceptible to metabolic disorders such as KE, which in turn reduces feed intake and MY (Ghavi Hossein-Zadeh, Reference Ghavi Hossein-Zadeh2022; Tufarelli et al., Reference Tufarelli, Puvača, Glamočić, Pugliese and Colonna2024). DA has a similar effect on feed efficiency and rumen function, affecting energy intake and milk production. In RP, cows may experience delayed uterine recovery after calving, resulting in reduced energy for milk production during this period (Ghavi Hossein-Zadeh, Reference Ghavi Hossein-Zadeh2013).

The negative and low genetic correlations between KE, DA, RP, and MY suggest that cows genetically predisposed to these metabolic disorders may have slightly reduced milk production. Although the correlations are not statistically significant, this finding is consistent with the general understanding that metabolic stress, particularly during the transition phase, negatively affects MY (Ghavi Hossein-Zadeh, Reference Ghavi Hossein-Zadeh2022; Schmidtmann et al., Reference Schmidtmann, Segelke, Bennewitz, Tetens and Thaller2023). For example, cows suffering from KE or DA often have a reduced appetite, resulting in reduced energy intake, which negatively impacts milk production and is also associated with poor uterine health and reduced lactation performance (van Soest et al., Reference van Soest, Mourits, Blanco-Penedo, Duval, Fall, Krieger, Sjöstrom and Hogeveen2019; Lei and Simões, Reference Lei and Simões2021; Tufarelli et al., Reference Tufarelli, Puvača, Glamočić, Pugliese and Colonna2024). However, these correlations suggest that while the genetic relationship exists, it is not strong enough to suggest that these disorders significantly affect milk production at the genetic level. In contrast to the negative genetic correlations, some metabolic disorders such as MA, MF, and LA showed positive correlations with MY (Oliveira Junior et al., Reference Oliveira Junior, Schenkel, Alcantara, Houlahan, Lynch and Baes2021; Ren et al., Reference Ren, Lu, Wang, Yan, Liu, Chu, Yang, Bao, Yu, Zhang and Zhang2024; Zhang et al., Reference Zhang, Han, Zhang, Hu, Sheng, Yang, Zhang, Wen, Ma, Ma and Wang2024). High milk production can lead to increased metabolic stress, weakening the immune response and making cows more susceptible to infections such as mastitis. High-yielding cows often have lower calcium reserves, which makes them more susceptible to milk fever (hypocalcemia), especially in early lactation. Likewise, heavier cows (due to higher productivity) may suffer from LA due to the increased physical stress on their feet (Arechiga-Flores et al., Reference Arechiga-Flores, Cortés-Vidauri, Hernández-Briano, Lozano-Domínguez, López-Carlos, Macías-Cruz and Avendaño-Reyes2022; Jukna et al., Reference Jukna, Meškinytė, Urbonavičius, Bilskis, Antanaitis, Kajokienė and Juozaitienė2024). These results highlight the importance of monitoring health traits in high-yielding cows, as the pursuit of productivity can inadvertently exacerbate these disorders. Positive genetic correlations were observed between metabolic disorders (such as DA, MA, and LA) and milk composition traits such as FY and PY. These correlations suggest that the same genetic factors that contribute to high milk yield may also promote increased fat and protein content, but at the expense of increased metabolic burden. This reflects a complex biological balance where cows genetically predisposed to high milk solids may also be more susceptible to metabolic disorders. Such findings highlight the need for careful genetic selection strategies that promote both yield and health without sacrificing one for the other (Mota et al., Reference Mota, Giannuzzi, Pegolo, Trevisi, Ajmone-Marsan and Cecchinato2023). The negative genetic correlations between KE, DA, and PP suggest that cows susceptible to these disorders may produce milk with lower protein content. This could be due to the negative energy balance of cows with metabolic disorders, which affects protein synthesis and milk composition. The decline in milk protein percentage indicates a decline in the cow's metabolic efficiency, particularly in the way nutrients are used for milk production during times of illness (Klein et al., Reference Klein, Scheper, May and König2020; Lean and Golder, Reference Lean and Golder2024). The positive genetic correlations between KE and DA with FPR show that cows with these disorders tend to have higher FPR. This increased ratio often indicates a metabolic imbalance, as cows with these diseases have higher milk fat relative to protein, which is due to poor nutrient distribution (Klein et al., Reference Klein, Scheper, May and König2020; Tufarelli et al., Reference Tufarelli, Puvača, Glamočić, Pugliese and Colonna2024). Elevated FPR is commonly observed in cows suffering from KE as mobilization of fat reserves results in higher fat content in milk (Ghavi Hossein-Zadeh, Reference Ghavi Hossein-Zadeh2022). The significant genetic correlations between KE and MA with SCS highlight the genetic connection between metabolic and immune system function. MA directly increases somatic cell counts due to infection in the mammary gland (Chegini et al., Reference Chegini, Ghavi Hossein-Zadeh, Hosseini-Moghadam and Shadparvar2019), while KE impairs general immune function and makes cows more susceptible to infections such as MA. This suggests that improving health traits associated with metabolic disorders could simultaneously improve udder health and reduce MA incidence (Ren et al., Reference Ren, Lu, Wang, Yan, Liu, Chu, Yang, Bao, Yu, Zhang and Zhang2024). The significant genetic correlations between metabolic disorders and reproductive traits such as DO, DCFS, and CI indicate that cows predisposed to metabolic disorders experience delayed reproductive recovery. Metabolic stress from diseases such as MA and KE can affect the cow's reproductive system, leading to longer postpartum recovery times and a delayed return to fertility. This relationship reflects the overall burden that metabolic disorders place on a cow's physiological functions beyond pure productivity (Melendez and Serrano, Reference Melendez and Serrano2024). The negative genetic correlation between MA and BCS suggests that cows suffering from MA tend to have poorer body condition as energy is directed towards immune response rather than maintaining body reserves. Conversely, the positive genetic correlation between LA and BW suggests that heavier cows are more prone to lameness, likely due to the increased physical stress on their feet and legs (Köck et al., Reference Köck, Fuerst-Waltl, Steininger and Egger-Danner2016). The genetic correlations presented in this study highlight the complex relationship between metabolic health and production and reproductive traits in dairy cows. Breeding programs must take these correlations into account to avoid an unintentional increase in disease incidence when selecting for high milk production. Incorporating health traits into selection indices, particularly traits related to metabolic disorders, can improve herd health and productivity while minimizing genetic predisposition to metabolic diseases (Mota et al., Reference Mota, Giannuzzi, Pegolo, Trevisi, Ajmone-Marsan and Cecchinato2023; Schmidtmann et al., Reference Schmidtmann, Segelke, Bennewitz, Tetens and Thaller2023).

In conclusion, this meta-analysis consolidated genetic parameter estimates from multiple studies of metabolic disorders in dairy cows and showed that heritability estimates for these disorders are generally low but significant. The genetic correlations between metabolic disorders and performance traits were positive in most cases, with some correlations being statistically significant, suggesting that these traits are influenced by common genetic factors. Among the metabolic disorders, KE and DA showed higher genetic correlations with other disorders, suggesting their importance in genetic studies to improve overall herd health. Likewise, the significant correlations between certain metabolic disorders and milk production traits (e.g., milk yield, fat, and protein content) highlight the genetic link between metabolic health and productivity. Although the genetic contribution to metabolic disorders is relatively small, it remains an important factor that can be exploited through genetic selection to improve the health and productivity of dairy cows.