Joint disease-specificity at the regulatory base-pair level

Pushpanathan Muthuirulan, Dewei Zhao, Mariel Young, Daniel Richard, Zun Liu, Alireza Emami, Gabriela Portilla, Shayan Hosseinzadeh, Jiaxue Cao, David Maridas, Mary Sedlak, Danilo Menghini, Liangliang Cheng, Lu Li, Xinjia Ding, Yan Ding, Vicki Rosen, Ata M. Kiapour () and Terence D. Capellini ()
Additional contact information
Pushpanathan Muthuirulan: Harvard University
Dewei Zhao: Affiliated Zhongshan Hospital of Dalian University
Mariel Young: Harvard University
Daniel Richard: Harvard University
Zun Liu: Harvard University
Alireza Emami: Boston Children’s Hospital, Harvard Medical School
Gabriela Portilla: Boston Children’s Hospital, Harvard Medical School
Shayan Hosseinzadeh: Boston Children’s Hospital, Harvard Medical School
Jiaxue Cao: Harvard University
David Maridas: Harvard School of Dental Medicine
Mary Sedlak: Harvard University
Danilo Menghini: Boston Children’s Hospital, Harvard Medical School
Liangliang Cheng: Affiliated Zhongshan Hospital of Dalian University
Lu Li: Affiliated Zhongshan Hospital of Dalian University
Xinjia Ding: the Second Affiliated Hospital of Dalian Medical University
Yan Ding: Boston Children’s Hospital, Harvard Medical School
Vicki Rosen: Harvard School of Dental Medicine
Ata M. Kiapour: Boston Children’s Hospital, Harvard Medical School
Terence D. Capellini: Harvard University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations.

Date: 2021
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DOI: 10.1038/s41467-021-24345-9

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