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Updated: Jun 13, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Exploring Subpopulations for Epidemiological Precision Nutrition Research: The Example of Phenylalanine Hydroxylase
Anoushka Dhawan1, Sophia M Khan1, Madison L Fennell1
1Department of Human Health Sciences, College of Biological Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada.
None:
Background/Objectives: Biological factors such as genetics contribute to nutrition-related outcomes, but nutritional epidemiological studies often lack consideration of genetics despite evidence of their functional impacts on health and cognition. Phenylalanine hydroxylase (PAH) genetic variation has been hypothesized to influence health and cognitive outcomes due to evidence of metabolic perturbations in L-phenylalanine to L-tyrosine hydroxylation, including plausible downstream effects on catecholamine neurotransmitters among not only individuals with phenylketonuria (PKU) [homozygotes for PAH mutations] but also PKU carriers [heterozygotes]. Related to these metabolic perturbations, diminished executive functioning has been observed in individuals with PKU, even when treated, but research is lacking exploring this outcome in PKU carriers. The present study aims to detail methods for stratifying populations based on genetic variation, for use in epidemiological precision nutrition research. It further provides an exploratory exemplar of such research through population stratification by PAH genetic variation (i.e., PKU carriers vs. non-carriers), while providing the first descriptive data on executive functioning skills using the validated Executive Skills Questionnaire-Revised (ESQ-R) tool with PAH-genetically stratified groups (PKU carriers and non-carriers). Methods: Participants were ≥18 years of age and PAH heterozygotes (PKU carriers) or non-carriers. Levels of executive functioning were self-reported anonymously online and included the validated Executive Skills Questionnaire-Revised (ESQ-R) tool. Data were analyzed using t-tests, chi-square tests, ANOVAs, and ANCOVAs. Results: Respondents (n = 99, n = 79 carriers and n = 20 non-carriers) consisted of males (22.2%) and females (77.8%), primarily of European ancestry. There were no significant differences between groups (carriers vs. non-carriers) for total scores (mean ± SD ESQ-R score carriers = 17.41 ± 14.01; non-carriers = 14.95 ± 10.00), but carriers scored significantly worse than non-carriers for the ESQ-R item "I have trouble making a plan" in the adjusted model. Conclusions: This study provides a methodological exemplar for exploring genetically stratified subpopulations in epidemiological precision nutrition research.
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