We implemented a two-sample MR analysis to assess the causal relationships between genetically determined metabolites and human intelligence. Using genetic variants as IVs, we found that the genetically determined levels of 5-oxoproline were associated with better performance in human intelligence tests. This causal relationship was confirmed by sensitivity analyses. Our study also identified other metabolites and metabolic pathways involved in biological processes related to human intelligence, such as dihomo-linoleate (20:2n6) and p-acetamidophenylglucuronide. To the best of our knowledge, this is the first study combining information from genomics and metabolomics to assess the causal effects of metabolome traits on human intelligence.
5-oxoproline, also known as pyroglutamic acid, is a cyclized derivative of L-glutamic acid that participates substantially in the glutamate and glutathione metabolism [30]. Disturbances in glutamate and glutathione metabolism can lead to a series of neurologic phenotypes, including developmental delay, ataxia, seizures, and intellectual disability [31]. Moreover, 5-oxoproline was also developed and sold as an over-the-counter “smart drug” for cognitive and memory improvement [32, 33]. However, it was also demonstrated that metabolic acidosis could be caused by excessive 5-oxoproline generation, with multiple adverse effects on many organ systems [34]. Our study found that elevated levels of 5-oxoproline were associated with a higher score in intelligence tests, supporting the potential usefulness of 5-oxoproline in improving intelligence-related performance. However, more work aimed at understanding the molecular mechanisms involved is needed to further clarify the role of this compound in human intelligence.
Genetic factors played a central role in our study of the causal relationship between metabolic traits and intelligence. The SNP rs11986602 (corresponding to the EXOSC4 gene) was the most significantly associated to both 5-oxoproline levels and human intelligence. Although rarely discussed in the past literature, EXOSC4 is known to be related to the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, encoded by the EIF2AK3 gene), which regulates gene expression [35]. A recent study reported that locally reduced PERK expression or activity could enhance neuronal excitability and improve memory and cognitive function in young mice [36]. Another study provided evidence that PERK is a key regulator of memory impairments and neurodegeneration in Alzheimer’s disease [37]. Thus, EXOSC4 might be a causal risk gene participating in physiological processes important for human intelligence.
We further focused on the metabolic pathways that might be involved in the biological processes associated to human intelligence. The only identified metabolic pathway in our study was Alpha linolenic acid and linoleic acid metabolism. Alpha linolenic acid and linoleic acid are long-chain polyunsaturated fatty acids, which are essential nutrients in the development and functioning of the brain [38]. Many related compounds, such as alpha linolenic acid and docosahexaenoic acid, are involved in the rapid growth and development of the infant brain [39, 40]. Our study thus reinforced the importance of alpha linolenic acid and linoleic acid metabolism for human intelligence, providing valuable information for understanding the biological mechanisms related to human intelligence.
The current study has several strengths. First, we implemented a novel MR study design to assess the causal relationships between genetically determined metabolites and human intelligence. By using genetic variants as IVs, the MR approach prevents confounding, reverse causation, and various biases common in observational epidemiological studies. Second, our study provides, indirectly, a comprehensive assessment of the causal effects of metabolites assessed by non-targeted metabolomics on human intelligence. Third, by integrating genomics and metabolomics, our study provides novel insight into the biological mechanisms underlying differences in intelligence.
Some limitations of this study should also be noted. First, while our study identified multiple metabolites and metabolic pathways involved in the biological processes related to human intelligence, these findings need to be further verified in experimental studies. Second, our study highlighted the role of genetics in determining the causal relationships between metabolites and intelligence, but further work is needed to understand the molecular mechanisms through which these genetic variants act.
In summary, our study identified multiple metabolites that might have causal effects on human intelligence, among which 5-oxoproline presented significant association signals after Bonferroni correction. The association was shown to be robust by sensitivity analyses. Our study also highlighted that genetic factors (e.g. the EXOSC4 gene) contributed substantially to the variation of metabolite levels and differences in human intelligence. Moreover, our findings suggest that alpha linolenic acid and linoleic acid metabolism might be involved in the biological processes underlying intelligence. Our study provides novel insight by integrating genomics and metabolomics to estimate causal relationships between genetically determined metabolites and human intelligence, which could help our understanding of the biological mechanisms related to human intelligence.