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

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. ### Competing Interest Statement CP is consultant for Quotient Therapeutics. DA is employed by AstraZeneca. The other authors declare no competing financial interests. ### Funding Statement The CHRIS study was funded by the Department of Innovation, Research and University of the Autonomous Province of Bolzano-South Tyrol and supported by the European Regional Development Fund (FESR1157). This work was carried out within the TrainCKDis project, funded by the European Union Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement H2020-MSCA-ITN-2019 ID:860977 (TrainCKDis). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of the Eurac Research Institute for Biomedicine gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used in the current study can be requested with an application to access.request.biomedicine{at}eurac.edu at the Eurac Research Institute for Biomedicine.