Abstract
Background/objectives: Genome-wide association studies identified a chromosome 4q21.1 locus
spanning FAM47E, STBD1, CCDC158, and SHROOM3, prominently associated with kidney function
markers but also with electrolytes, hematological and cardiovascular traits. Functional studies linked
SHROOM3, encoding an actin-binding protein involved in cell shaping, with kidney damage. However,
systematic explorations of functional variants of all genes at the locus are lacking. We thus conducted
phenome-wide, metabolomic and proteomic analyses of exonic haplotypes spanning the four genes.
Methods: We reconstructed haplotypes for 12,834 individuals of the Cooperative Health Research in
South Tyrol (CHRIS) study, following genotype imputation from a whole-exome sequencing reference
panel of a 3422 CHRIS sample subset. Haplotypes, including 146 exonic and intronic variants over the
four genes, were tested for association with 74 serum, urine, and anthropometric traits, 172 serum
metabolites, and 148 plasma proteins concentrations using linear models.
Results: The 11 identified haplotypes (frequency: 2% to 24%) showed both shared and specific
characteristics. Compared to the most common haplotype, most haplotypes were jointly associated with
kidney function and serum magnesium levels. The second most common haplotype (12% frequency)
was associated with better kidney function and lower dodecanoyl-, hydroxyvaleryl- and tiglyl-carnitine
concentrations. A haplotype of 4% frequency was associated with better kidney function and lower
hematological marker levels. A haplotype of 2% frequency was associated with lower magnesium,
glutamine, and putrescine levels. Cluster analysis revealed six distinct trait groups and two distinct
haplotype groups.
Conclusion: FAM47E-SHROOM3 functional haplotypes exhibit marked pleiotropic effects and identify
population subgroups with distinct biomarker profiles.