Abstract
SHROOM3 encodes an actin-binding protein involved in cell shaping. Genome-wide association studies (GWAS) identified common variants at SHROOM3 associated with chronic kidney disease, creatinine-based estimated glomerular filtration rate (eGFRcrea), and serum magnesium (Mg). To understand underlying physiological mechanisms of SHROOM3, we conducted a phenome-wide, metabolomic, and proteomic analysis of SHROOM3 haplotypes in the Cooperative Health Research in South Tyrol (CHRIS) study.
We performed genotype imputation of the whole cohort of 13,389 participants based on whole-exome sequencing data from 3,840 of the sample. We reconstructed haplotypes of 146 functional variants in FAM47E, STBD1, CCDC158, and SHROOM3, bounded by the recombination hotspots. The analysis
encompassed 74 serum, urine, and anthropometric traits, 172 serum metabolites, and 148 plasma proteins concentrations on 3,423 individuals. We fitted linear models on the inverse normal transformation of each trait, adjusted for age, sex, the first 10 genetic principal components, and expectation-maximization-
based haplotype frequencies.
We identified 11 haplotypes (H1 to H11; frequency from 24.36% to 2.03%). H8 (frequency 2.67%) was associated with eGFRcrea (P=2.7e-4), the urinary albumin-to-creatinine ratio (p=3.3e-3) and multiple phosphatidylcholines. H6 (11.61%) was associated with serum creatinine and several carnitines. H4 (2.81%) was associated with Mg (P=6.7e-4), eGFRcrea and basophils. H10 (2.32%) was associated with Mg, glutamine, putrescine, and afamin. H3 (2.32%) and H9 (3.99%) were associated with thyroid-related traits, carnitines, and immunoglobulins.
Our multiomic, haplotype association analysis highlighted strong pleiotropy at SHROOM3, associated with kidney function and other traits. Identification of haplotypes jointly associated with complex traits, metabolites, and proteins highlights molecular pathways warranting further investigations.