Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample

Dariush Ghasemi-Semeskandeh; Eva König; Luisa Foco; Nikola Dordevic; Martin Gögele; Johannes Rainer; Markus Ralser; Dianne Acoba; Francisco S. Domingues; Dorien J.M. Peters; Peter P. Pramstaller; Cristian Pattaro

doi:10.1016/j.ekir.2025.02.018

Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample

Dariush Ghasemi-Semeskandeh, Eva König, Luisa Foco, Nikola Dordevic, Martin Gögele, Johannes Rainer, Markus Ralser, Dianne Acoba, Francisco S. Domingues, Dorien J.M. Peters, Peter P. Pramstaller, Cristian Pattaro

Research output: Contribution to journal › Article › peer-review

Abstract

Introduction: Genome-wide association studies (GWAS) identified a locus on chromosome 4q21.1, spanning the Family With Sequence Similarity 47 Member E (FAM47E), Starch Binding Domain 1 (STBD1), Coiled-Coil Domain Containing 158 (CCDC158), and Shroom Family Member 3 (SHROOM3) genes, to be associated with kidney function markers. Functional studies implicated SHROOM3 as the effector gene, demonstrating its developmental role to guarantee podocyte barrier integrity. However, the locus has also been associated with other clinical traits, including electrolytes, hematological, cardiovascular, and neurological traits, not all of which can be easily traced to the regulation of kidney function. We therefore conducted a systematic analysis of the whole locus’ genetic profiles (haplotypes) to assess which phenotypic profiles they were associated with.

Methods: For the 4 genes, we reconstructed haplotypes spanning 71 exonic and intronic variants for 12,834 participants in the Cooperative Health Research in South Tyrol (CHRIS) study based on genotypes imputed on a local whole-exome sequencing (WES) reference panel. Haplotypes were tested for associations with 72 clinical traits, 170 serum metabolites, and 148 plasma protein concentrations, using linear regression models.

Results: We identified 11 haplotypes with a population frequency between 2% and 24%. Compared with the most common haplotype, most haplotypes were associated with higher creatinine-based estimated glomerular filtration rate (eGFR) and lower serum magnesium levels. In addition, specific haplotypes were also associated with biologically diverse groups of traits, including albuminuria, blood pressure, red blood cell traits, carnitines, and amino acids. Cluster analysis highlighted the existence of distinct genetic profiles in which individuals with specific haplotypes presented with specific phenotypic and metabolic signatures.

Conclusion: The genetic variability of the FAM47E–SHROOM3 locus indicates the existence of population subgroups with distinct biomarker profiles.

Original language	English
Pages (from-to)	1495-1508
Journal	Kidney International Reports
Volume	10
Issue number	5
Early online date	2025
DOIs	https://doi.org/10.1016/j.ekir.2025.02.018
Publication status	Published - 2025 May
Externally published	Yes

Free keywords

CCDC158
FAM47E
haplotype
kidney
SHROOM3
STBD1

Access to Document

10.1016/j.ekir.2025.02.018Licence: CC BY

Cite this

Ghasemi-Semeskandeh, D., König, E., Foco, L., Dordevic, N., Gögele, M., Rainer, J., Ralser, M., Acoba, D., Domingues, F. S., Peters, D. J. M., Pramstaller, P. P., & Pattaro, C. (2025). Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample. Kidney International Reports, 10(5), 1495-1508. https://doi.org/10.1016/j.ekir.2025.02.018

@article{b4992a0fe7314394be2c87da3d596184,

title = "Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample",

abstract = "Introduction: Genome-wide association studies (GWAS) identified a locus on chromosome 4q21.1, spanning the Family With Sequence Similarity 47 Member E (FAM47E), Starch Binding Domain 1 (STBD1), Coiled-Coil Domain Containing 158 (CCDC158), and Shroom Family Member 3 (SHROOM3) genes, to be associated with kidney function markers. Functional studies implicated SHROOM3 as the effector gene, demonstrating its developmental role to guarantee podocyte barrier integrity. However, the locus has also been associated with other clinical traits, including electrolytes, hematological, cardiovascular, and neurological traits, not all of which can be easily traced to the regulation of kidney function. We therefore conducted a systematic analysis of the whole locus{\textquoteright} genetic profiles (haplotypes) to assess which phenotypic profiles they were associated with. Methods: For the 4 genes, we reconstructed haplotypes spanning 71 exonic and intronic variants for 12,834 participants in the Cooperative Health Research in South Tyrol (CHRIS) study based on genotypes imputed on a local whole-exome sequencing (WES) reference panel. Haplotypes were tested for associations with 72 clinical traits, 170 serum metabolites, and 148 plasma protein concentrations, using linear regression models. Results: We identified 11 haplotypes with a population frequency between 2\% and 24\%. Compared with the most common haplotype, most haplotypes were associated with higher creatinine-based estimated glomerular filtration rate (eGFR) and lower serum magnesium levels. In addition, specific haplotypes were also associated with biologically diverse groups of traits, including albuminuria, blood pressure, red blood cell traits, carnitines, and amino acids. Cluster analysis highlighted the existence of distinct genetic profiles in which individuals with specific haplotypes presented with specific phenotypic and metabolic signatures. Conclusion: The genetic variability of the FAM47E–SHROOM3 locus indicates the existence of population subgroups with distinct biomarker profiles.",

keywords = "CCDC158, FAM47E, haplotype, kidney, SHROOM3, STBD1",

author = "Dariush Ghasemi-Semeskandeh and Eva K{\"o}nig and Luisa Foco and Nikola Dordevic and Martin G{\"o}gele and Johannes Rainer and Markus Ralser and Dianne Acoba and Domingues, \{Francisco S.\} and Peters, \{Dorien J.M.\} and Pramstaller, \{Peter P.\} and Cristian Pattaro",

note = "Publisher Copyright: {\textcopyright} 2025 International Society of Nephrology",

year = "2025",

month = may,

doi = "10.1016/j.ekir.2025.02.018",

language = "English",

volume = "10",

pages = "1495--1508",

journal = "Kidney International Reports",

issn = "2468-0249",

publisher = "Elsevier",

number = "5",

}

TY - JOUR

T1 - Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample

AU - Ghasemi-Semeskandeh, Dariush

AU - König, Eva

AU - Foco, Luisa

AU - Dordevic, Nikola

AU - Gögele, Martin

AU - Rainer, Johannes

AU - Ralser, Markus

AU - Acoba, Dianne

AU - Domingues, Francisco S.

AU - Peters, Dorien J.M.

AU - Pramstaller, Peter P.

AU - Pattaro, Cristian

PY - 2025/5

Y1 - 2025/5

N2 - Introduction: Genome-wide association studies (GWAS) identified a locus on chromosome 4q21.1, spanning the Family With Sequence Similarity 47 Member E (FAM47E), Starch Binding Domain 1 (STBD1), Coiled-Coil Domain Containing 158 (CCDC158), and Shroom Family Member 3 (SHROOM3) genes, to be associated with kidney function markers. Functional studies implicated SHROOM3 as the effector gene, demonstrating its developmental role to guarantee podocyte barrier integrity. However, the locus has also been associated with other clinical traits, including electrolytes, hematological, cardiovascular, and neurological traits, not all of which can be easily traced to the regulation of kidney function. We therefore conducted a systematic analysis of the whole locus’ genetic profiles (haplotypes) to assess which phenotypic profiles they were associated with. Methods: For the 4 genes, we reconstructed haplotypes spanning 71 exonic and intronic variants for 12,834 participants in the Cooperative Health Research in South Tyrol (CHRIS) study based on genotypes imputed on a local whole-exome sequencing (WES) reference panel. Haplotypes were tested for associations with 72 clinical traits, 170 serum metabolites, and 148 plasma protein concentrations, using linear regression models. Results: We identified 11 haplotypes with a population frequency between 2% and 24%. Compared with the most common haplotype, most haplotypes were associated with higher creatinine-based estimated glomerular filtration rate (eGFR) and lower serum magnesium levels. In addition, specific haplotypes were also associated with biologically diverse groups of traits, including albuminuria, blood pressure, red blood cell traits, carnitines, and amino acids. Cluster analysis highlighted the existence of distinct genetic profiles in which individuals with specific haplotypes presented with specific phenotypic and metabolic signatures. Conclusion: The genetic variability of the FAM47E–SHROOM3 locus indicates the existence of population subgroups with distinct biomarker profiles.

AB - Introduction: Genome-wide association studies (GWAS) identified a locus on chromosome 4q21.1, spanning the Family With Sequence Similarity 47 Member E (FAM47E), Starch Binding Domain 1 (STBD1), Coiled-Coil Domain Containing 158 (CCDC158), and Shroom Family Member 3 (SHROOM3) genes, to be associated with kidney function markers. Functional studies implicated SHROOM3 as the effector gene, demonstrating its developmental role to guarantee podocyte barrier integrity. However, the locus has also been associated with other clinical traits, including electrolytes, hematological, cardiovascular, and neurological traits, not all of which can be easily traced to the regulation of kidney function. We therefore conducted a systematic analysis of the whole locus’ genetic profiles (haplotypes) to assess which phenotypic profiles they were associated with. Methods: For the 4 genes, we reconstructed haplotypes spanning 71 exonic and intronic variants for 12,834 participants in the Cooperative Health Research in South Tyrol (CHRIS) study based on genotypes imputed on a local whole-exome sequencing (WES) reference panel. Haplotypes were tested for associations with 72 clinical traits, 170 serum metabolites, and 148 plasma protein concentrations, using linear regression models. Results: We identified 11 haplotypes with a population frequency between 2% and 24%. Compared with the most common haplotype, most haplotypes were associated with higher creatinine-based estimated glomerular filtration rate (eGFR) and lower serum magnesium levels. In addition, specific haplotypes were also associated with biologically diverse groups of traits, including albuminuria, blood pressure, red blood cell traits, carnitines, and amino acids. Cluster analysis highlighted the existence of distinct genetic profiles in which individuals with specific haplotypes presented with specific phenotypic and metabolic signatures. Conclusion: The genetic variability of the FAM47E–SHROOM3 locus indicates the existence of population subgroups with distinct biomarker profiles.

KW - CCDC158

KW - FAM47E

KW - haplotype

KW - kidney

KW - SHROOM3

KW - STBD1

UR - https://www.scopus.com/pages/publications/105000779298

U2 - 10.1016/j.ekir.2025.02.018

DO - 10.1016/j.ekir.2025.02.018

M3 - Article

C2 - 40485680

AN - SCOPUS:105000779298

SN - 2468-0249

VL - 10

SP - 1495

EP - 1508

JO - Kidney International Reports

JF - Kidney International Reports

IS - 5

ER -

Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample

Abstract

Free keywords

Access to Document

Other files and links

Fingerprint

Cite this