Objective: To explore susceptibility genes associated with yang-deficiency constitution using single nucleotide polymorphism (SNP) genotyping. Methods: Based on an epidemiological survey, 30 volunteers with yang-deficiency constitution and 30 volunteers with a balanced constitution were included according to the Classification and Determination Standards of Constitutions in Traditional Chinese Medicine. Peripheral blood was collected and DNA was extracted from white blood cells. A genome-wide association study (GWAS) was conducted by SNP 6.0 genotyping at the Beijing Capital Bio Corporation Ltd. A minimum association P-value (Fisher's exact value) of less than 104 in the allele, genotype, dominant, and recessive models served as the standard for significant association of SNP with yang-deficiency constitution. Results: Among the four genetic models, a total of 42 SNPs were significantly associated with yang-deficiency constitution (Fisher's exact P-values 〈10^4). These SNPs were adjacent to more than 20 genes, including RGS6, mGluR5, GAPDHL19, and II〈ZF1. Conclusions: Yang-deficiency constitution exhibits the characteristics of polygenic inheritance. This pilot study suggests that the polymorphisms in RGS6, mGluR5, GAPDHL19, and IKZF1 are associated with changes in cyclic adenosine monophosphate and cyclic guanosine monophosphate levels, memory, metabolic energy status, and immune function, respectively in people with yang-deficiency constitution.