Strength of Genetic Associations with Thyrotropin Values Differs Between Populations with Similarity to African and European Reference Populations

Abstract

Background: Epidemiological data suggest the population distribution of thyrotropin (TSH) values is shifted toward lower values in self-identified Black non-Hispanic individuals compared with self-identified White non-Hispanic individuals. It is unknown whether genetic differences between individuals with genetic similarities to African reference populations (GSA) and those with similarities to European reference populations (GSE) contribute to these observed differences. We aimed to compare genome-wide associations with TSH and putative causal TSH-associated variants between GSA and GSE groups. Methods: We performed genome-wide association studies (GWAS) in 9827 GSA individuals and 9827 GSE individuals with TSH values between 0.45 and 4.5 mU/L. We compared effect sizes and allele frequencies of previously reported putative causal TSH-associated variants and our power to detect associations with these variants between the two groups. We additionally focused on variants in PDE8B and PDE10A, loci that have been most strongly associated with TSH in previous GWAS in GSE populations. Results: Four loci attained genome-wide significance in the GSA group compared with seven in the GSE group. PDE8B was not significantly associated with TSH in the GSA group, despite its strong association in the GSE group. Eight putative causal variants had significantly different effect sizes between groups. There was ≥80% power in the GSA group to detect significant associations with variants in PDE8B, PDE10A, NFIA, and LOC105377480, with higher expected power than in the GSE group for variants in PDE8B, NFIA, and LOC105377480 and similar power for other variants in PDE8B and PDE10A. No additional putative causal variants in PDE8B and PDE10A had effect sizes that differed significantly between the groups; power to identify associations with additional putative causal variants in PDE8B and PDE10A was similar between the groups. Conclusions: Patterns of genetic associations with TSH differed between identically sized GSA and GSE groups. Failure to replicate the strongest associations previously reported in GSE individuals in our GSA population was not fully explained by differences in allele frequencies or power, assuming similar effect sizes. Larger GSA population GWAS are necessary to confirm our findings and further investigate the contribution of genetic factors to population differences in the distribution of TSH values.

Keywords: genome-wide association study; population ancestry; thyrotropin.