TY - JOUR
T1 - Human rs75776403 polymorphism links differential phenotypic and clinical outcomes to a CLEC18A p.T151M-driven multiomics
AU - Hsu, Yu Wen
AU - Wong, Henry Sung Ching
AU - Huang, Wan Chen
AU - Yeh, Yi Hung
AU - Hsiao, Chwan Deng
AU - Chang, Wei Chiao
AU - Hsieh, Shie Liang
N1 - Funding Information:
This work was supported by Academia Sinica (107-2101-01-18-03, AS-IA-109-L02), Translational Medical Research Program (AS-TM-108-02-10), and Biotechnology Research Park Translational Project (AS-BRPT-110-02). The other supports are from Academia Sinica Investigator Award (AS-IA-109-L02), Summit Research Projects and grant 109-2101-01-19-20 (Academia Sinica), Ministry of Science and Technology (MOST 107-2321-B-001-015, MOST110-2628-B-038-020), Establishing A Translational Female Cancer Biomedical Big Data Bank and Developing Precision Medicine Healthcare System (MOST 110-2321-B-038-002), and VGH, TSGH, AS Joint Research Program (VTA109-A-3-1).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Background: Human traits, diseases susceptibility, and clinical outcomes vary hugely among individuals. Despite a fundamental understanding of genetic (or environmental) contributions, the detailed mechanisms of how genetic variation impacts molecular or cellular behaviours of a gene, and subsequently leads to such variability remain poorly understood. Methods: Here, in addition to phenome-wide correlations, we leveraged multiomics to exploit mechanistic links, from genetic polymorphism to protein structural or functional changes and a cross-omics perturbation landscape of a germline variant. Results: We identified a missense cis-acting expression quantitative trait locus in CLEC18A (rs75776403) in which the altered residue (T151→M151) disrupts the lipid-binding ability of the protein domain. The altered allele carriage led to a metabolic and proliferative shift, as well as immune deactivation, therefore determines human anthropometrics (body height), kidney, and hematological traits. Conclusions: Collectively, we uncovered genetic pleiotropy in human complex traits and diseases via CLEC18A rs75776403-regulated pathways.
AB - Background: Human traits, diseases susceptibility, and clinical outcomes vary hugely among individuals. Despite a fundamental understanding of genetic (or environmental) contributions, the detailed mechanisms of how genetic variation impacts molecular or cellular behaviours of a gene, and subsequently leads to such variability remain poorly understood. Methods: Here, in addition to phenome-wide correlations, we leveraged multiomics to exploit mechanistic links, from genetic polymorphism to protein structural or functional changes and a cross-omics perturbation landscape of a germline variant. Results: We identified a missense cis-acting expression quantitative trait locus in CLEC18A (rs75776403) in which the altered residue (T151→M151) disrupts the lipid-binding ability of the protein domain. The altered allele carriage led to a metabolic and proliferative shift, as well as immune deactivation, therefore determines human anthropometrics (body height), kidney, and hematological traits. Conclusions: Collectively, we uncovered genetic pleiotropy in human complex traits and diseases via CLEC18A rs75776403-regulated pathways.
KW - Body height
KW - CLEC18A
KW - CLEC18A p.T151M
KW - Phosphatidic acid (PA)
KW - Phosphatidylserine (PS)
KW - rs75776403
KW - Thyroid hormone
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U2 - 10.1186/s12929-022-00822-1
DO - 10.1186/s12929-022-00822-1
M3 - Article
C2 - 35717171
AN - SCOPUS:85132311355
SN - 1021-7770
VL - 29
JO - Journal of Biomedical Science
JF - Journal of Biomedical Science
IS - 1
M1 - 43
ER -
