Phenotypic spectrum of FAM47E-SHROOM3 haplotype composition in a general population sample

Abstract

Genome-wide association studies identified a locus on chromosome 4q21.1, spanning the FAM47E, STBD1, CCDC158, and SHROOM3 genes, as associated with kidney function markers. Functional studies implicated SHROOM3, encoding an actin-binding protein involved in cell shaping, into podocyte barrier damage. Despite the locus was also found associated with electrolytes, hematological and cardiovascular traits, systematic explorations of functional variants across all the genes in the locus are lacking. We reconstructed haplotypes covering the whole locus on 12,834 participants to the Cooperative Health Research in South Tyrol (CHRIS) study, using genotypes imputed on a whole-exome sequencing reference panel of a subsample of 3,422 participants. Haplotypes included 146 exonic and intronic variants over the four genes and were tested for association with 73 serum, urine and anthropometric traits, 172 serum metabolite and 148 plasma protein concentrations using linear regression models. We identified 11 haplotypes with 2% to 24% frequency. Compared to the most common haplotype, most haplotypes were associated with higher levels of the creatinine-based estimated glomerular filtration rate and lower serum magnesium levels. The second most common haplotype (12% frequency) was additionally associated with lower dodecanoyl-, hydroxyvaleryl- and tiglyl-carnitine serum concentrations. A haplotype of 4% frequency was also associated with lower red blood cell count, hemoglobin, and hematocrit levels. A haplotype of 2% frequency was associated with serum glutamine and putrescine concentrations. Cluster analysis revealed distinct groups of traits and of haplotypes. The FAM47E-SHROOM3 locus exhibits haplotype variability that corresponds to marked pleiotropic effects, implicating the existence of population subgroups with distinct biomarker profiles.