Genome-wide association of pica within a cohort of volunteer blood donors implicates the gene encoding neuropeptide VF

Abstract Background: Pica is an eating disorder characterized by the persistent craving and consumption of non-food substances such as ice, chalk, starch, earth, or raw pasta. Pica symptoms are more common in people with iron deficiency, but fewer than 10% of people with iron deficiency develop pica symptoms, suggesting there may be associated genetic factors. Volunteer blood donors become iron deficient after repeated donations, making them an ideal population to study pica. Our previous analysis of over 13,000 genetically diverse volunteer blood donors in the U.S. Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) found that pica prevalence varied with race, age, restless leg syndrome status, ferritin, and several other biomarkers associated with iron deficiency anemia. Given these associations, we hypothesized that the genetic architecture of pica overlaps that of iron homeostasis. Study design and methods: A genome-wide association study (GWAS) was conducted with 12,157 volunteer blood donors within the REDS-III RBC-Omics study. Three pica outcomes of interest were evaluated via a questionnaire, including ice-only consumption, non-ice consumption, or both. Genotyping used a high-density single nucleotide polymorphisms (SNPs) array, followed by imputation and quality control, with analyses adjusted for key covariates including plasma ferritin, age, and restless leg syndrome. Population stratification was addressed using principal components analysis, and GWAS were performed using logistic regression. Candidate SNPs were tested for replication using a cohort from All of Us (AoU). Results: In the full REDS-III cohort (N=12,157), pica was reported in 2.3% of donors (N=289 donors with N=174 reporting ice and N=127 reporting non-ice, non-food consumption). Pica was observed more often in donors who were women, younger, non-Hispanic, reported RLS symptoms, and had lower ferritin. Within the 2.3% of donors who reported pica symptoms, nine genome-wide significant SNPs were identified by the GWAS to be associated with pica. Stratified analysis of the European population of 7,493 REDS-III donors confirmed associations with age and ferritin. GWAS within this group identified seven genome-wide significant SNPs. Of these, one SNP, rs73277282, near the gene encoding the neuropeptide VF (NPVF) was replicated in the AoU dataset (REDS-III p = 1.53x10-8; AoU p = 0.02). Discussion: Neuropeptide VF is expressed almost exclusively in the brain in regions important for regulating energy homeostasis. It has been previously shown to regulate food intake and energy balance in animal models, suggesting that polymorphisms associated with its expression may synergize with iron deficiency to produce pica behaviors.