Kidney Week

Abstract: TH-PO0633

Genome-Wide Association Study (GWAS) of Serum Galactose-Deficient IgA1 Uncovers Shared Genetic Determinants with IgAN

Session Information

• Genetic Diseases of the Kidneys: Complex Kidney Traits
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits

Authors

• Liu, Lili, Columbia University, New York, New York, United States

Lili Liu, PhD

• Shen, Aubrey, Columbia University, New York, New York, United States

Aubrey Shen

• Taylor, Alexandria D, Columbia University, New York, New York, United States

Alexandria D Taylor, MS

• Khan, Atlas, Columbia University, New York, New York, United States

Atlas Khan, MS, PhD, FASN

• Reily, Colin, The University of Alabama at Birmingham Department of Microbiology, Birmingham, Alabama, United States

Colin Reily, PhD

• Hall, Stacy D., Juntendo Daigaku, Bunkyo, Tokyo, Japan

Stacy D. Hall, MPH

• Green, Todd J., The University of Alabama at Birmingham Department of Microbiology, Birmingham, Alabama, United States

Todd J. Green, PhD

• Julian, Bruce A., The University of Alabama at Birmingham Department of Microbiology, Birmingham, Alabama, United States

Bruce A. Julian, MD

• Suzuki, Hitoshi, Juntendo Daigaku, Bunkyo, Tokyo, Japan

Hitoshi Suzuki, MD, PhD

• Floege, Jürgen, RWTH University of Aachen, Aachen, Germany

Jürgen Floege, MD

• Rauen, Thomas, RWTH University of Aachen, Aachen, Germany

Thomas Rauen, MD

• Gale, Daniel P., University College London, London, England, United Kingdom

Daniel P. Gale, MA, MBChB, PhD

• Barratt, Jonathan, University of Leicester, Leicester, England, United Kingdom

Jonathan Barratt, MBChB, PhD

• Xie, Jingyuan, Shanghai Jiao Tong University, Shanghai, China

Jingyuan Xie, MD, PhD

• Wang, Yan-Na, Peking University, Beijing, China

Yan-Na Wang, PhD

• Zhou, Xu-jie, Peking University, Beijing, China

Xu-jie Zhou, MD

• Zhang, Hong, Peking University, Beijing, China

Hong Zhang, MD, PhD

• Gharavi, Ali G., Columbia University, New York, New York, United States

Ali G. Gharavi, MD

• Novak, Jan, The University of Alabama at Birmingham Department of Microbiology, Birmingham, Alabama, United States

Jan Novak, PhD

• Kiryluk, Krzysztof, Columbia University, New York, New York, United States

Krzysztof Kiryluk, MD

Background

Galactose-deficient IgA1 (Gd-IgA1) is a critical pathogenic factor in IgA nephropathy (IgAN). Gd-IgA1 glycoforms are recognized by IgG autoantibodies to form pathogenic immune complexes. Some of these complexes enter glomeruli, activate mesangial cells, and induce kidney injury.

Methods

We conducted a GWAS for serum Gd-IgA1 levels in 10,228 participants across 15 international cohorts, including 1,438 IgAN patients and 8,790 population controls. GWAS for each cohort was conducted independently with dense imputation and adjustments for total serum IgA1 levels, age, and sex, followed by a fixed-effect meta-analysis and fine-mapping of the GWAS loci. Shared genetic determinants between Gd-IgA1 and other traits were examined by colocalization analyses. Phenome-wide association studies (PheWAS) were performed across major biobanks to assess pleiotropic effects for identified loci.

Results

The serum Gd-IgA1 levels were consistently higher in IgAN patients compared to healthy controls. The population controls of African ancestry exhibited substantially lower serum Gd-IgA1 levels compared to other ancestries, which is consistent with lower IgAN prevalence in this population. GWAS of serum Gd-IgA1 levels in 10,228 individuals identified five genome-wide significant loci. These include two previously reported loci: C1GALT1 and C1GALT1C1, and three newly discovered loci: OVOL1, IGH, and SMARCB1/DERL3. All three novel loci exhibited significant heterogeneity in their associations between IgAN cases and controls: OVOL1 and IGH loci showed stronger effects in IgAN patients, while SMARCB1/DERL3 locus demonstrated a more pronounced effect in controls. By colocalization analysis, the OVOL1 locus represented a shared genetic determinant of serum Gd-IgA1 levels, total serum IgA level, serum IgG galactosylation, and IgAN risk. By PheWAS, we demonstrated that the alleles associated with increased serum Gd-IgA1 levels were also associated with higher risks of systemic lupus erythematosus (OVOL1) and hypertension (C1GALT1).

Conclusion

Our findings provide new insights into the genetic regulation of serum Gd-IgA1 levels and its role in genetic susceptibility to complex traits, including IgAN.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025pyp4sfbe