X chromosome contribution to the genetic architecture of primary biliary cholangitis.
588 auth.
R. Asselta,
E. Paraboschi,
A. Gerussi,
H. Cordell,
G. Mells,
R. Sandford,
Dave E. Jones,
Minoru Nakamura,
Kazuko Ueno,
Y. Hitomi,
Minae Kawashima,
N. Nishida,
K. Tokunaga,
M. Nagasaki,
A. Tanaka,
...
R. Tang,
Zhiqiang Li,
Yongyong Shi,
Xiangdong Liu,
M. Xiong,
G. Hirschfield,
K. Siminovitch,
M. Carbone,
Giulia Cardamone,
S. Duga,
M. Gershwin,
M. Seldin,
P. Invernizzi,
E. Walker,
G. Xie,
A. Mason,
R. Myers,
K. Peltekian,
C. Ghent,
Elizabeth G. Atkinson,
B. Juran,
Kostas Lazaridis,
Yue Lu,
X. Gu,
Kaiyan Jing,
C. Amos,
A. Affronti,
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V. Cardinale,
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F. Rosina,
A. Ciaccio,
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F. Malinverno,
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S. Massironi,
C. Milani,
S. O’Donnell,
V. Ronca,
D. Barisani,
P. Lampertico,
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S. Fagiuoli,
P. Almasio,
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M. Colombo,
Luca Valenti,
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Y. Takeyama,
M. Harada,
M. Senju,
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Y. Miyake,
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Kazuhide Yamamoto,
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Tomohiro Tanaka,
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N. Kokudo
BACKGROUND & AIMS
Genome-wide association studies (GWAS) in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually-dimorp…
BACKGROUND & AIMS
Genome-wide association studies (GWAS) in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually-dimorphic complex autoimmune disease.
METHODS
We performed a chrX-wide association study (XWAS), including genotype data from five GWAS (from Italy, UK, Canada, China, Japan; 5,244 cases, 11,875 controls).
RESULTS
Single-marker association analyses found ∼100 loci displaying P<5*10-4, with the most significant being a signal within the OTUD5 gene (rs3027490, P=4.80*10-6; OR=1.39 CI=1.028-1.88; Japanese cohort). While the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR=1.17, 95%CI=1.09-1.26; P=9.93*10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asians pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P=6.2*10-9, OR=1.33, CI=1.21-1.46). Indeed, rs7059064 tags a unique LD block including seven genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a super-enhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is predicted to target also FOXP3, the main T regulatory cell lineage-specification factor. Consistently, OTUD5 and FOXP3 RNA levels were upregulated in PBC cases (1.75- and 1.64-fold, respectively).
CONCLUSION
This work represents the first comprehensive study of the chrX contribution to the genetics of an autoimmune liver disease and revealed a novel PBC-related genome-wide significant locus.
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5
2021
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