Abstract
Pituitary adenoma is one of the most common intracranial neoplasms, and its genetic basis remains largely unknown. To identify genetic susceptibility loci for sporadic pituitary adenoma, we performed a three-stage genome-wide association study (GWAS) in the Han Chinese population. We first analyzed genome-wide SNP data in 771 pituitary adenoma cases and 2,788 controls and then carried forward the promising variants for replication in another 2 independent sets (2,542 cases and 3,620 controls in total). We identified three new susceptibility loci below the genome-wide significance threshold (P < 5 × 10−8) in the combined analyses: 10p12.31 (rs2359536, Pmeta = 2.25 × 10−10 and rs10828088, Pmeta = 6.27 × 10−10), 10q21.1 (rs10763170, Pmeta = 6.88 × 10−10) and 13q12.13 (rs17083838, Pmeta = 1.89 × 10−8). This study is the first GWAS to our knowledge on sporadic pituitary adenoma, and our results provide insight into the genetic basis of this disease.
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Acknowledgements
We thank and acknowledge all of the participants in the study. We gratefully thank Y. Wang, Q. Song, Y. Zhang and Q. Zhu for sample collection. The research was supported by the China Pituitary Adenoma Specialist Council (CPASC) and has received funding from the National High-Technology Research and Development Program of China (2014AA020611), the 973 Program (2015CB559100), the National Program for Support of Top-Notch Young Professionals, the National Natural Science Foundation of China (81172391, 31325014, 81130022 and 81272302), the Program for New-Century Excellent Talents in University (NCET-10-0356), the Shanghai Rising-Star Tracking Program (12QH1400400), the National 863 Program (2012AA02A515), the Shanghai Jiao Tong University Liberal Arts and Sciences Cross-Disciplinary Project (13JCRZ02), the Shanghai Key Laboratory of Psychotic Disorders (13dz2260500), the 'Shu Guang' project supported by the Shanghai Municipal Education Commission and the Shanghai Education Development Foundation (12SG17).
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Y. Zhao and Y.S. were the overall principal investigators for the study who conceived the study and obtained financial support, and they were responsible for study design and oversaw the entire study. Z. Ye, Z.L., Q.Z. and C.H. participated in the study design. Y. Zhao, L.Z., S.L., Y.M., Yongfei Wang, M.S., D.G., Z.Z. and Y.L. supervised the diagnosis of patients and subject recruitment. Y.S. and Z.L. supervised the experiments and data analyses. Y.S., Z.L., Z. Song and J.S. performed biostatistics and bioinformatics analyses, and the results were interpreted by Y.S., Y. Zhao and Z.L. L.P., W.B., J.W., X.S., K.Z., Yi Zhang, R.X., Z.M., N.Q., H.Q., W.H., Yichao Zhang, S.H., T.W., Z. Shi, Y. Zhu, H.Y., B.L., Z. Yao, W.T., Yin Wang, H. Chen and H. Cheng coordinated and provided samples. J.C., J.J., M.W., Z.W., W.L., K.L., J.Z. and L.W. performed the experiments. The manuscript was drafted by Z.L., Z. Ye and Q.Z. under the supervision of Y. Zhao and Y.S., who synthesized the manuscript. All authors critically reviewed the article and approved the final manuscript.
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Integrated supplementary information
Supplementary Figure 1 PCA plot of the first two components of our sample in the discovery stage.
The first principal component (C1; x axis) was plotted against the second principal component (C2; y axis). Controls are orange circles, and cases are blue circles.
Supplementary Figure 2 Quantile-quantile plot for the discovery stage.
The quantile-quantile plot presents the observed (y axis) versus expected (x axis) SNP distribution. The plot was generated on PCA-adjusted data. The λ value was 1.0157, calculated from the bottom 90% of SNPs. The red line denotes the 90th percentile.
Supplementary Figure 3 Manhattan plot of the GWAS of the discovery cohort comprising 771 cases of sporadic pituitary adenoma and 2,788 controls.
Genome-wide P values (–log10 (P); y axis) plotted against their respective chromosomal positions (x axis). The blue line is the significance level used for follow-up (1 × 10−4).
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Supplementary Figures 1–3 and Supplementary Tables 1–9. (PDF 1154 kb)
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Ye, Z., Li, Z., Wang, Y. et al. Common variants at 10p12.31, 10q21.1 and 13q12.13 are associated with sporadic pituitary adenoma. Nat Genet 47, 793–797 (2015). https://doi.org/10.1038/ng.3322
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DOI: https://doi.org/10.1038/ng.3322
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