In this MR study, we provided novel genetic evidence for the causal effect of education on cholelithiasis and cholecystitis, with each 4.2-year-increment of schooling attenuating an approximately 27% risk of cholelithiasis and 31% risk of cholecystitis. In addition, we demonstrated causal associations of cognition and intelligence with cholelithiasis and cholecystitis. Each increasing 0.99 point of cognitive performance and each higher SD of intelligence resulted in a decreased risk of cholelithiasis of approximately 20% and 17%, respectively, with neither being significantly less than the educational effect nor showing a causal association with cholecystitis, which was inconsistent with education. Nevertheless, none of the above causal effects persisted when the associations were adjusted for other one or two other exposures. These results show that each of the three exposures—education, cognition, and intelligence—all play a crucial role in the causal process of cholelithiasis and can be influenced by other factors. Thus, we explored the mediating factor from each exposure to cholelithiasis, and ultimately selected 5, 1, and 1 out of 21 factors, respectively, in the pathogenesis from education, cognition, or intelligence to cholelithiasis.
In our MR study, three broadly concerned events—educational attainment, cognitive performance, and intelligence level—were perceived to be the exposures. These exposures are interrelated with others phenotypically and genetically, and hard to separate, strongly based on a previous GWAS and an MR study, demonstrating the mutually bidirectional associations among them [25, 27]. Emerging evidence from observational studies and MR studies has illustrated that higher educational attainment (more years of schooling) is a protective factor for cholelithiasis [22, 24, 53, 54]. To date, this novel research area, which dissects the association between cognitive performance or intelligence level and cholelithiasis, has not yet been entirely elaborated. For the first time, we used genetic inference to reveal that either better cognitive performance or a higher intelligence level is a protective factor for cholelithiasis. These results are in tune with our general perspectives, for those who have higher cognition and intelligence may be less likely to enjoy high-calorie, high-carbohydrate, and low-fiber diets, or neglect physical activities, all of which prompt gallstone formation [55, 56]. As recent epidemiological studies show, gallstone diseases mainly affected adult individuals, notably elderly individuals [1], whose education, cognitive performance, and intelligence level have already been determined. However, earlier educational attainment profoundly affects later life, including cognitive training, knowledge acquisition, and notably health promotion [57]. This study elucidates the importance of improving academic qualifications, cognitive performance, and intelligence level to reduce the risk of gallstone diseases as much as possible. Nonetheless, considering the difficulty and near-impossibility of altering one’s the living environment owing to poverty and other difficult obstacles, a better lifestyle and a healthier diet are strongly recommended for those who cannot obtain prioritized educational sources to prevent the onset of gallstone diseases.
Cholecystitis is the most ubiquitous complication of cholelithiasis and is typically ascribed to calculus in the gallbladder, disrupting patients’ quality of life and threatening their lives [3, 58]. Due to the bile duct obstruction caused by gallstones or sludge or lithogenic bile, these individuals are subjected to suffer from cholecystitis-induced right upper quadrant mass, pain, tenderness, and fever [59]. Once diagnosed with acute cholecystitis, within-3-day laparoscopic cholecystectomy (to remove the inflammatory or diseased gallbladder) is the first-line therapy to prevent severe complications [5, 6]. Due to the economic burden and postsurgical psychiatric disorders, prevention should receive more attention than the treatment procedure [60, 61]. From a clinical perspective, among the general population with gallstone diseases, approximately 80% are asymptomatic [62]. Thus, patients might pay little attention to lifestyle improvement and dieting alteration, despite being diagnosed with cholelithiasis. Suboptimal daily lifestyle habits, especially high-calorie and low-fiber eating habits, predispose individuals to the process from gallstone formation to inflammation in the gallbladder or in the bile duct. Among the three exposures, only education attainment played a causal role in attenuating the prevalence of cholecystitis. Furthermore, after adjusting for cholelithiasis, education still acted as an independent protective factor (Table 2), while neither cognition nor intelligence could do the same. In tune with the general acknowledgment, our results convey that individuals obtaining high educational qualifications may have a lower risk of cholecystitis, due to their predominant awareness, optimal lifestyles, balanced diets, etc. Nonetheless, the Nationwide Inpatient Sample database has indicated that White patients have significantly lower rate of emergent admission of acute cholecystitis compared with nonwhite patients, suggesting the disparities in health care [63]. Our results are therefore not suppressed to be suitable for other ethnic populations and non-White community dwellers.
Concurrently, massive cardiometabolic risk factors are considered in many syndromes, including cardiovascular diseases [64, 65], hepatobiliary disorders [66, 67], nervous system disruption [68, 69], and reproductive disturbance [70]. For instance, metabolic traits [1, 2, 8, 9], dietary behaviors [15–17], physical activity [18, 19], and socioeconomic factors [21] have attracted drawn ubiquitous attention, playing protective roles or serving as risk factors in the process of gallstones. Previous MR studies and observational research have demonstrated the inverse causal association between educational attainment and gallstone disease [24, 54], while whether these putative mediators mediate in this process remains unclear. Cardiometabolic risk factors were divided into several categories: metabolic traits, dietary behaviors, physical activities, and socioeconomic factors, all of which were perceived as candidate mediators. Only those who met the above criteria could be considered as actual mediators.
In this study, three major metabolic stratifications are incorporated into the candidate mediators: adiposity, glucose-related traits, and serum lipid levels. Adiposity can be displayed in several hierarchies—BMI, BF%, waist circumference, WHR, childhood obesity, etc. The detrimental role of these phenotypes in gallstone disease has been emphasized in previous observational and MR studies [71, 72]. Four of these factors—BMI, BF%, waist circumference, and WHR—are perceived as the mediators from education to gallstones, excluding childhood obesity, which might account for the cumulative formation process of lithiasis requiring tens of years. Moreover, after adjusting for education, each mediator remained a statistically significant to be the risk factor for gallstones. Among them, waist circumference had the highest mediating proportion (44.4%), followed by BF% (40.9%), WHR (32.9%), and BMI (28.4%) (Table 3), which is equivalent to mediating the corresponding extent of the risk of gallstones ascribed to low educational attainment. Commonly, adiposity traits are easily able to reflect the defects of long-range lifestyles and dieting habits. In addition, obesity is closely associated with high-fat, high-carbohydrate, and low-fibre intakes and less movement. Notably, these obesity-relevant and interrelated indexes carry substantial public health implications, as they are prone to exist as comorbidities and have common biological mechanisms, including genetics, energy metabolism, neuroendocrine regulation, and immunoinflammatory activation [73, 74]. Thus, to attenuate the prevalence of gallstones, none of these phenotypes should receive less attention, instead, they deserve more consideration.
Glucose-related traits have been extensively discussed as risk factors for gallstone disease in previous studies [11, 12]. Yuan, S., et al. validated the causal association between type 2 diabetes and gallstone disease (OR: 1.13 [95% CI: 1.09–1.17]) through the two-sample MR method, demonstrating its facilitating effectiveness [24]. Considering that the foremost presence of pancreatic impairment in type 2 diabetes is the abnormal serum sugar-relevant level [75], fasting glucose and fasting insulin alike were embodied in our candidate mediators. However, none of the putative mediators were estimated to be definite mediators, which does not indicate a lack of the unimportance or necessity for taking precautions against diabetes-induced factors, which might concurrently promote gallstone shaping.
In general, the major proportion of gallstones in the Western world are cholesterol gallstones, instead of pigment components. Surprisingly, serum lipid levels were excluded as mediators in our study, although hyperlipidemia has been illustrated to be involved in gallstone diseases, based on compelling observational studies [13, 14, 76, 77]. To our knowledge, high LDL-C levels, high triglycerides levels, and high total cholesterol are the risk factors and high HDL-C is a protective factor against gallstones. Commonly, cholesterol gallstone formation is frequently the consequence of an imbalance of physical–chemical cholesterol solubility, contributing to a disturbance in biliary cholesterol homeostasis and promoting cholesterol crystallization and gallstone formation [78]. Despite lipid index not causally kicking in the education—gallstone pathway, approaches to maintain physiological-state serum lipid are steered to be emphasized, especially reducing high fat intake. More recently, smoking and alcohol consumption have been considered to accelerate gallstone formation, while coffee and tea intake might have adverse effects, but the precise mechanism has not been elucidated [15–17]. Moreover, socioeconomic factors, notably higher income individuals are less likely to suffer from gallstone disease [21]. Considering that the major proportion of GWAS statistics utilized in this study were extracted from European populations from high-education and high-income regions, the economic or educational disparity seems not too apparent, explaining to a certain extent why income did not play a mediating role.
Physical activity has been demonstrated to play a preventive role in the process of gallstone formation, based on recent observational and MR studies [20, 79, 80]. Generally, watching TV is an intriguing way to ease anxiety, obtain pleasure and kill time. Nonetheless, a long-term sedentary lifestyle increases the risk of subhealth problems, notably obesity, nonalcoholic fatty liver diseases (NAFLD), and even cancer [81–84]. This study first illustrated that increasing TV watching time has a causal effect on the formation of gallstones, from a genetic perspective. Importantly, after adjusting for educational attainment, cognitive performance, or intelligence, long-term watching TV still causally increased the risk of gallstone disease. Moreover, it played a mediating role in the process from education to gallstone (mediated proportion: 41.6%), as well as from cognitive performance (20.4%) or intelligence level to the counterpart (28.4%). It has been acknowledged that those who have undergone many years of schooling are more able to perceive the detrimental effects of watching TV, instead, they prefer other beneficial events. A putative inference of the hazardous pathogenesis can be explained as follows: when absorbed into the colorful scenes in TV series, individuals are more likely to stay motionless for several hours, inhibiting intestinal motility and restraining cholecystokinin-dependent gallbladder emptying [85, 86]. Apart from the time spent watching TV, we simultaneously focused on two other candidate mediators: MVPA and computer use. Although neither factor was not perceived to be a mediator, they deserve to be considered for individuals at homes: who should perform certain physical activities frequently and compulsorily avoid long-term concentrated computer use.
In conclusion, this is the first MR study to reveal that the causal effects of education on gallstone disease are independent of cognition and intelligence, although either can play a causal role in gallstone pathogenesis. Second, we are also the first to illustrate that individuals with high-education attainment may be substantially less likely suffer from cholecystitis, after being diagnosed with gallstone disease. Third, we strictly screened out the causal mediator, meeting the set rigorous criteria, in the independent association of education, cognition or intelligence, with gallstones, and afterward estimated the mediated proportion, individually.
Nevertheless, this study also has several limitations to be addressed. First, several prevalent and crucial cardiometabolic risk factors were incorporated into the potential mediators in disease development. Second, given gallstone diseases might be affected by heritage factors [87], future MR studies are required to take within-family genetic data into account, not least their parent–offspring and sibling traits. Third, the heterogeneity of SNPs persists throughout our MR analysis, leading to potential bias and influencing the inference robustness. Fourth, given the utmost GWASs applied were performed in high-income European populations, signifying their superior lifestyles, dieting habits, and even the awareness to seek medical attention, limiting its substantial generalizability to middle- and even low-income countries and residents. Fifth, sample overlap between GWASs, though it accounted for a small proportion, might have biased MR estimates toward observational association estimates.