Multivariate analysis of subjective responses to d-amphetamine in healthy volunteers finds novel genetic pathway associations.

Rationale: Researchers studying behavioral and physiologic effects of d-amphetamine have explored individual response differences to the drug. Concurrently, genome-wide analyses have identified several single-nucleotide polymorphisms (SNPs) associated with these traits. Univariate methods can identify SNPs associated with behavioral and physiological traits, but multivariate analyses allow identification of clusters of related biologically relevant SNPs and behavioral components.

Objectives: The aim of the study was to identify clusters of related biologically relevant SNPs and behavioral components in the responses of healthy individuals to d-amphetamine using multivariate analysis.

Methods: Individuals (N = 375) without substance abuse histories completed surveys and detailed cardiovascular monitoring during randomized, blinded sessions: d-amphetamine (10 and 20 mg) and placebo. We applied parallel independent component analysis (Para-ICA) to data previously analyzed with univariate approaches, revealing new associations between genes and behavioral responses to d-amphetamine.

Results: Three significantly associated (p < .001) phenotype-genotype pairs emerged. The first component included physiologic measures of systolic and diastolic blood pressure (BP) and mean arterial pressure (MAP) along with SNPs in calcium and glutamatergic signaling pathways. The second associated components included the "Anger" items from the Profile of Mood States (POMS) questionnaire and the marijuana effects from the Addiction Research Center Inventory (Cuyas, Verdejo-Garcia et al.), with enriched genetic pathways involved in cardiomyopathy and MAPK signaling. The final pair included "Anxious," "Fatigue," and "Confusion" items from the POMS questionnaire, plus functional pathways related to cardiac muscle contraction and cardiomyopathy.

Conclusions: Multifactorial genetic networks related to calcium signaling, glutamatergic and dopaminergic synapse function, and amphetamine addiction appear to mediate common behavioral and cardiovascular responses to d-amphetamine.