Association Between COMT rs4680 (Val158Met) Polymorphism and Academic Performance among Medical Students

By Kulsoom Farhat¹, Fozia Fatima², Muhammad Faisal Afridi³

Affiliations

1. Department of Pharmacology, Army Medical College, Rawalpindi, Pakistan
2. Department of Health Professions Education, National University of Medical Sciences, Rawalpindi, Pakistan
3. Department of Public Health, Army Medical College, Rawalpindi, Pakistan

doi: 10.29271/jcpsp.2025.08.987

ABSTRACT
Objective: To examine the association between the catechol-O-methyltransferase (COMT) rs4680 polymorphism — a common genetic variation in the gene, which regulates dopamine metabolism in the prefrontal cortex — and academic performance among medical students at a public-sector medical college in Rawalpindi, Pakistan.
Study Design: A cross-sectional analytical study.
Place and Duration of the Study: Department of Pharmacology, Army Medical College, Rawalpindi, in collaboration with the Institute of Biomedical and Genetic Engineering, Islamabad, Pakistan, from January to March 2025.
Methodology: One hundred MBBS students were included. Academic performance was categorised into high (≥80% marks), average (60-79%), and low (<60%). COMT genotyping was performed using allele-specific PCR, and the relationship with academic performance was analysed using the Chi-square tests in SPSS.
Results: Genotype distribution of the COMT rs4680 polymorphism was consistent with the Hardy-Weinberg equilibrium (p = 0.16), with observed frequencies of 30% Val/Val, 43% Val/Met, and 27% Met/Met. A significant association was found between COMT genotype and academic performance (p = 0.003), with Met/Met carriers (10/20) dominating the high-performance group compared to Val/Val (3/30) and Val/Met (7/43). Female students significantly outperformed males (p = 0.021), with 16 out of 20 high achievers being female. Maternal education level strongly predicted academic success (p = 0.013), whereas paternal education showed no significant association (p = 0.992).
Conclusion: The Met/Met genotype was linked to superior academic performance, particularly among females, suggesting a gene- gender interaction. Maternal education emerged as a key environmental predictor, underscoring the interplay of genetic and socio- familial factors in academic achievement.

Key Words: COMT rs4680 polymorphism, Academic performance, Medical education, Dopamine metabolism, Genetic influences, Maternal education.

INTRODUCTION

Academic performance in medical education is critical for developing competent healthcare professionals equipped to handle the challenges of clinical practice. It reflects not only mastery of knowledge but also the ability to apply it in high-pressure scenarios, thereby reinforcing clinical reasoning, decision- making, and patient care skills. Academic success is influenced by a combination of cognitive abilities, environmental factors, and genetic predispositions, such as the Catechol-O-methyltransferase (COMT) rs4680 polymorphism.

This polymorphism impacts dopamine metabolism in the pre-frontal cortex — a brain region essential for attention, working memory, and executive functions.^1,2

The COMT enzyme critically regulates dopamine level in the prefrontal cortex, which modulates higher-order cognitive processes directly linked to academic performance. These process include working memory (essential for retaining complex medical concepts), cognitive flexibility (important for clinical problem-solving), and stress response (critical for exams and practical assessments). The rs4680 polymorphism fine- tunes these functions, creating a genetic trade-off between stability under stress and adaptability to dynamic learning environments.³

The COMT rs4680 polymorphism produces two key alleles: Val and Met.⁴ The Val allele, associated with higher COMT enzymatic activity, supports cognitive performance under low-stress conditions, while the Met allele, linked to lower activity and higher dopamine levels, enhances focus but may impair performance under stress.^5,6

In the demanding context of medical education, where students must be able to balance vast amount of information with high- stakes exams, this balance becomes particularly consequential. For instance, Met carriers may excel in structured, self- paced learning due to sustained dopamine-enhanced focus, whereas Val carriers might outperform in time-pressured clinical simulations where rapid dopamine clearance prevents cognitive overload.

However, this relationship remains underexplored in culturally and socioeconomically diverse populations, such as those in Pakistan, where disparities in educational resources and societal expectations may interact uniquely with genetic predispositions.

Environmental factors such as socioeconomic status, parental education, access to resources, and study habits also significantly shape academic outcomes. Maternal education, in particular, positively influences academic success by fostering structured support. Gender differences further affect performance, with female students often excelling academically.⁷ Notably, female medical students in Pakistan often face dual pressures of academic rigour and societal expectations, which may amplify or mitigate COMT-related effects, a dimension absent in Western studies. These influences, coupled with unique challenges faced by Pakistani medical students, highlight the need for a comprehensive understanding of genetic and environ- mental   interactions.

This study aimed to examine the association between the COMT rs4680 polymorphism and academic performance among medical students in a public sector medical college in Rawalpindi.^8-10

METHODOLOGY

This cross-sectional analytical study was carried out on 100 MBBS students at the Department of Pharmacology, Army Medical College, Rawalpindi, Pakistan. Ethical approval was obtained from the Ethical Review Committee of Army Medical College, Rawalpindi, Pakistan (Ref. No: 02/2025/441), and all participants were provided written informed consent. These participants were purposively selected to ensure proportional representation across performance categories. Students who achieved aggregate marks ≥80% were labelled as high achievers. Those with marks in the range of 60-79% were considered average, performers while students with <60% marks were classified as low performers. Inclusion criteria required enrolment in the MBBS programme, complete academic records, and consent to provide blood samples. Students with incomplete records, inadequate DNA samples, or special circumstances affecting performance were excluded.

Demographic and academic data were collected via a structured proforma, and academic performance was verified through official records. Blood samples (2 mL) were collected and processed for DNA extraction using the Phenol-Chloroform method. The quality was assessed via gel electrophoresis and spectrophotometry. Genotyping for the COMT rs4680 polymorphism was performed using allele-specific PCR, and results were confirmed through the agarose gel electrophoresis.

Academic performance was categorised as the dependent variable, with COMT genotypes (Val/Val, Val/Met, Met/Met) as the independent variable, gender, and parental education as confounding variables. Data analysis included descriptive statistics and Chi-square tests. All analyses were conducted in SPSS, with a significance threshold of p ≤0.05. Ethical guidelines were strictly followed, including informed consent, confidentiality, and safety protocols.

RESULTS

A total of hundred undergraduate MBBS students from a public sector medical college in Rawalpindi were analysed for the COMT rs4680 polymorphism by using allele-specific PCR. Gel electrophoresis revealed bands at 393 bp for a common amplicon, 249 bp for the Val allele, and 216 bp for the Met allele (Figure 1).

Genotype distribution was consistent with the Hardy-Weinberg equilibrium (χ² = 0.16, p >0.05), with 30% Val/Val, 43% Val/Met, and 27% Met/Met genotypes. The Hardy-Weinberg equilibrium analysis indicates that the observed genotype frequencies are consistent with expected frequencies, suggesting no significant deviation from genetic equilibrium in the study population (p = 0.16, Table I). This genetic equilibrium confirms that the sample is a representative of the general population, validating subsequent association analyses between the COMT genotypes and academic performance.

Academic performance was significantly associated with genotype (p = 0.003). Of 27 high performers, the majority (10) had Met/Met genotype group, followed by Val/Met (7/43) and Val/Val (3/30). Average performance was predominant in the Val/Met group (30/60), while in the low performers, the majority had Val/Val genotype group (12/20). The predominance of Met/Met genotypes among high performers (10/27) supports the hypothesis that slower dopamine clearance enhances cognitive functions crucial for academic achievement, particularly in deman-ding medical education. Conversely, the over-representation of Val/Val genotypes among low performers (12/20) suggests that rapid dopamine metabolism may impair sustained attention and working memory which are essential for complex learning tasks. The intermediate performance of Val/Met heterozygotes (30/43 in the average category) demonstrates a gene-dose effect, consistent with the COMT’s codominant inheritance pattern.

Gender also influenced academic performance significantly, with females outperforming males (p = 0.021, Table II). This finding aligns with known oestrogen-COMT interactions, where oestrogen downregulates COMT activity, potentially amplifying the cognitive benefits of Met alleles in female students. The similar proportion of low performers across genders suggests that this genetic advantage may be more relevant to high achievement rather than to preventing poor performance.

Table I: COMT genotype distributions.

Genotypes	Observed frequencies	Expected frequencies	Chi-square contributions χ2	p-values
Val/Val	0.30	0.2652	0.463	0.16
Val/Met	0.43	0.4996	0.967
Met/Met	0.27	0.2352	0.518
Total	1.00	1.00	1.95
The Chi-square test was used to determine the p-value. Hardy-Weinberg equilibrium analysis showed Val allele frequency (p) = 0.515, and Met allele frequency (q) = 0.485, with a Chi-square value of 1.95 and a p-value of 0.16 (greater than 0.05).

Table II: The distribution of academic performance across the COMT genotype groups and gender.

Academic performances	Females (n = 55)	Males (n = 45)	Val/Val	Val/Met	Met/Met
High (n = 20)	16	4	3	7	10
Average (n = 60)	27	33	15	30	15
Low (n = 20)	12	8	12	6	2
Total	55	45	30	43	27
p-value	0.021		0.003
The Chi-square test was used to determine the p-value.

Table III: The impact of maternal and paternal education on the academic performance of the students.

Parental education levels	High (n = 20)	Average (n = 60)	Low (n = 20)	Total (n = 100)	p-values
Maternal education					0.013
Undergraduate	3	17	4	24
Graduate	7	28	15	50
Postgraduate	10	15	1	26
Paternal education					-
Undergraduate	4	15	5	24	0.992
Graduate	9	24	8	41
Postgraduate	7	21	7	35
The Chi-square test was used to determine the p-value.

Figure 1: Gel electrophoresis image depicting COMT polymorphism analysis. Lane (1) 100 bp molecular marker, lane (2) negative control, lane (3) positive control, lanes (4-12) DNA samples from study participants.

There was a statistically significant gender-based difference (χ² = 7.6768, p = 0.021) in academic performance, with female students outperforming male students in the high achievement category. While males were more likely to fall into the average category, the proportion of low-performing students was relatively similar across genders.

Table III indicated a statistically significant association (p = 0.013) between maternal education and students' academic performance. This suggested that higher maternal education is associated with better academic performance. A greater proportion of students whose mothers had postgraduate education fell into the high-performing category, while those whose mothers likely had lower levels of education tend to be in the average or low-performance categories. This environ-mental factor appears to interact with genetic predisposition, as educated mothers may provide cognitive stimulation that complements the neurobiological advantages of favourable COMT genotypes. The p-value for paternal education is 0.992, which indicates no statistically significant association between paternal education and the academic performance of the students. This suggests that, unlike maternal education, the educational level of fathers does not appear to have a strong impact on students’ academic performance, as the distribution of high, average, and low performers is relatively similar across different paternal education levels (Table III).

DISCUSSION

Academic achievement is a key indicator of an individual's educational status. This study examines the impact of the COMT polymorphism on academic performance, given its crucial role in cognitive differences that may influence students’ success. The most commonly observed genotype in this study was the heterozygous Met/Val, followed by the homozygous Val/Val and then the Met/Met genotype. This distribution is consistent with previous research indicating a higher prevalence of the Met/Val genotype in the Pakistani population.¹¹

A critical consideration is how these genetic findings intersect with Pakistan’s unique educational landscape. While the Met/ Met genotype’s cognitive advantages are well-documented in Western contexts, their manifestation in resource-constrained settings — where lecture-heavy paedagogy and exam-centric evaluation dominate — may differ. The results of this study suggest that even in such environments, neurobiological advantages persist, under-scoring COMT’s fundamental role in academic aptitude.

A key finding of this study is that individuals with the Met/Met genotype demonstrated better academic performance compared to other COMT genotypes. This aligns with the findings of the study conducted by Ballender et al., which reported that Met/Met carriers performed significantly better than Val/Val carriers.¹² The superior performance of Met/Met individuals may be attributed to increased dopamine availability in the prefrontal cortex, which enhances cognitive functions such as working memory and attention.¹³ However, this raises an ethical question: Should genetic profiling be used to inform educational streaming? While the data from this study support genotype-performance associations, implementing genetic-based interventions requires caution. For instance, the Val/Val students — though statistically disadvantaged — may excel in high-pressure clinical rota-tions, where rapid dopamine clearance prevents cognitive overload. Thus, the optimal genotype may be context-dependent, urging educators to balance genetic insights with holistic assessments.

Research has shown that the distribution of the Val158Met polymorphism varies significantly across populations. In European populations, the Val and Met alleles are more evenly distributed, whereas Asian populations tend to have a higher prevalence of the Val allele.¹⁴

A recent study by Khan et al. found that in the Pakistani population, the Val allele is more prevalent (58.5%), as the Val/Val genotype is observed in 44% of the cohort.¹⁵ This genotype is associated with increased COMT enzymatic activity, leading to faster dopamine breakdown, which may impact cognitive functions such as working memory, attention, and learning. These factors one essential for academic success. The distinct genetic profile of the Pakistani population, where the Val allele frequency is higher than in other Asian groups (28-40%), may contribute to specific cognitive challenges in educational settings. Recognising these genetic influences can help in developing personalised educational strategies to support cognitive abilities and academic performance.¹⁶

This population-specific genetic profile has profound impli-cations for medical education reform in Pakistan. With a higher Val allele frequency, curricula could be redesign to mitigate potential disadvantages, such as incorporating more spaced repetition for Val/Val students to offset working memory challenges, or stress-management training to optimise their performance under pressure.

The role of the COMT rs4680 polymorphism in cognitive function has been extensively studied in both clinical and healthy populations. The Val allele, which increases COMT activity, results in lower dopamine levels in the prefrontal cortex, potentially impairing cognitive flexibility and performance in tasks that require higher-order functions such as decision-making and problem-solving.¹⁶ In contrast, the Met allele, associated with lower enzymatic activity, allows for greater dopamine availability, which has been linked to enhanced cognitive abilities in complex problem-solving and multitasking.¹⁷

These findings have challenged the one-size-fits-all approach to medical education. For instance, Met/Met students might thrive in problem-based learning, whereas Val/Val students could benefit from structured, algorithmic approaches. Such differentiation could reduce attrition rates and improve competency acquisition, particularly in Pakistan’s high-stakes medical training system.

This study clearly demonstrates that genetic factors, parti-cularly a functional polymorphism in the COMT gene, play a significant role in individual differences in academic achieve-ment. Understanding students' genotype profiles can help educational practitioners and university authorities to identify individual cognitive strengths. This knowledge enables educators to tailor courses to align with students' most robust cognitive skills. Since each student leverages their cognitive abilities differently — some excelling in working memory, others in logic and reasoning — those who do not engage their strongest skills may lose interest in learning. Therefore, it is essential for educators to recommend courses that align with each student's strengths, thereby fostering greater interest in learning and enhancing academic performance.

This study included both males and females, recognising the differences in cognitive abilities between genders. The COMT gene, which is linked to dopamine levels in the brain, affects brain activity differently in males and females. Additionally, hormones such as oestrogen influence COMT gene activity, making the relationship between COMT and cognitive differences complex — shaped by an interplay genetics, hormones, and environmental factors. Notably, recent findings indicated that females with the Met/Met genotype of COMT excelled academically.¹⁸ This study further supports that females with the Met/Met genotype also achieved better academic performance, highlighting the intricate influence of COMT genotype and gender on cognitive outcomes. In this study, the gender differences in performance were observed, with females more likely to excel academically, as evidenced by their higher representation among high performers, while males were overrepresented in the low-performance category. 

The gender gap observed — where females outperformed males even after controlling of genotype — suggests that sociocultural factors, such as parental expectations and classroom participation norms, may amplify or mitigate genetic effects. Future studies should explore that whether interventions such as female-led study groups could further enhance the Met/Met advantage or compensate for Val/Val disadvantages.

The findings of this study align with previous research empha-sising the significant role of parental education in shaping students' academic performance. Numerous studies have demonstrated that maternal education, in particular, exerts a stronger influence on academic outcomes, as a study by Davis-Kean et al. highlighted that mothers with higher educational attainment are more likely to engage in cognitively stimulating activities and provide a supportive learning environment, contributing to better academic achievement in children.¹⁹ Similarly, Harding et al. reported that maternal education is a critical determinant of children’s educational success, as it influences parenting styles, expectations, and resource allo-cation.²⁰ Although paternal education also positively impacts academic performance, its influence tends to be less pro-nounced. These findings collectively underscore the importance of maternal education as a key factor in promoting academic excellence, corroborating the results of the current study.

However, this study has some limitations. Given the complexity of cognitive behaviour, academic achievement is influenced by multiple factors beyond genetics. The present study does not include assessments of cognitive abilities in relation to academic performance, leading to a gap in understanding the link between the COMT polymorphism and academic success. To address this, further research should be done to explore this relationship by examining detailed cognitive abilities and the educational environment of students. Additionally, studies involving students from various faculties and universities are essential to validate the effects of the COMT polymorphism on the academic performance of university students, particularly in Pakistan.

This article adds to existing knowledge by examining the impact of the COMT rs4680 polymorphism on academic performance in a culturally and socioeconomically distinct population — Pakistani medical students, a group under-represented in prior genetic studies. While previous research has established the Val/Met trade-off in cognitive perfor-mance, this study explores how these genetic effects mani-fested in a resource-constrained educational environment with unique societal pressures, such as gender-specific expectations and lecture-heavy pedagogy. It also highlights the interplay between genetic predispositions and local environmental factors (maternal education and gender disparities) that may amplify or mitigate COMT-related effects differently than in the Western contexts. Additionally, the study proposes culturally tailored interventions, such as stress-management protocols for Val/Val genotypes in high-stakes exams and gender-sensitive learning strategies, offering novel insights for personalised medical education in low-resource settings.

CONCLUSION

The study found that the Met/Met genotype for the COMT gene was associated with higher academic performance compared to the Val/Met and Val/Val genotypes. Females demonstrated significantly better academic performance than males. Parental education, particularly maternal education, positively influenced academic achievement. This empha-sised the multifaceted nature of academic performance, where a combination of genetic, biological, and environ-mental factors interacts to shape academic outcomes.

ETHICAL  APPROVAL: 
Ethical approval was granted by the Ethical Review Committee of the Army Medical College, Rawalpindi, Pakistan (ERC No: 02/2025/441) prior to the initiation of the research work.

PATIENTS’  CONSENT:
Written informed consent was obtained from all the participants.

COMPETING  INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
KF: Conceptualisation, data curation, writing and editing of the original draft.
FF: Supervision and project administration.
MFA: Methodology, investigation, validation, formal analysis, and review.
All authors approved the final version of the manuscript to be published.

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