Neonatal and Perinatal Medicine Fellow Children's Hospital of Philadelphia Children's Hospital of Philadelphia Media, Pennsylvania, United States
Background: Genetic associations link hematopoietic traits and disease end-points, but causal variants and related genes are largely unknown. Genome-wide significant signals for human traits sometimes directly overlap.
Objective: We hypothesized that such ‘genetic colocalization’ sites and related genes could explain shared genetic bases for blood traits and human phenotypes, including birth weight and gestational duration.
Design/Methods: Using genome wide association study (GWAS) summary statistics and a recently described colocalization algorithm, we determined multi-trait overlap sites for hematopoietic, cardiovascular, autoimmune, neuropsychiatric, cancer, birth weight, and gestational duration phenotypes (false discovery rate <5%). We then identified quantitative trait loci (QTLs) among these sites to highlight related genes.
Results: From 2706 genome-wide significant loci for ≥1 blood trait, we identified 1779 sites (66%) where ≥2 trait signals colocalized. We could assign genetic effects of some sites to developmental cell types. For example, SH2B3- and ATM-related sites affected white cell, erythroid and platelet traits, consistent with known impacts on hematopoietic progenitor cells. Among erythroid trait-restricted sites were QTLs for genes that impact red cell stability and development.
Expanded analysis of 10,258 genome-wide significant sites for >70 human traits defined 2325 loci (23%) where ≥2 traits colocalized. These results identified known and novel trait relationships, and colocalizations at clinically relevant coding mutations (e.g., PTPN22 with white blood cell traits and Crohn’s disease).
Targeted analysis revealed that blood traits, birth weight, and gestational duration colocalized at sites that impact inflammation and preterm birth. For example, gestational duration and eosinophil percentage colocalized at a QTL for NFATC3, which impacts innate immunity, lung maturation and preterm birth-related biology. Birth weight, eosinophil, and erythroid trait signals colocalized at QTLs for PPARgamma, a gene linked with preterm birth risk. Conclusion(s): Our findings provide a road map for gene validation experiments and offer a rationale for pleiotropic interactions between hematopoietic loci and disease traits. Application of our pipeline to pediatric disease-specific data may help pinpoint causal genes underlying pediatric disease phenotypes and anticipate off-target effects on blood traits in the pediatric population.
Authors/Institutions: Christopher Thom, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania, United States; Benjamin F. Voight, University of Pennsylvania, Philadelphia, Pennsylvania, United States
