In:
Human Molecular Genetics, Oxford University Press (OUP), Vol. 30, No. 17 ( 2021-08-12), p. 1666-1676
Kurzfassung:
Although dozens of susceptibility loci have been identified for lung cancer in genome-wide association studies (GWASs), the susceptibility genes and underlying mechanisms remain unclear. In this study, we conducted a cross-tissue transcriptome-wide association study (TWAS) with UTMOST based on summary statistics from 13 327 lung cancer cases and 13 328 controls and the genetic-expression matrix over 44 human tissues in the Genotype-Tissue Expression (GTEx) project. After further evaluating the associations in each tissue, we revealed 6 susceptibility genes in known loci and identified 12 novel ones. Among those, five novel genes, including DCAF16 (Pcross-tissue = 2.57 × 10−5, PLung = 2.89 × 10−5), CBL (Pcross-tissue = 5.08 × 10−7, PLung = 1.82 × 10−4), ATR (Pcross-tissue = 1.45 × 10−5, PLung = 9.68 × 10−5), GYPE (Pcross-tissue = 1.45 × 10−5, PLung = 2.17 × 10−3) and PARD3 (Pcross-tissue = 5.79 × 10−6, PLung = 4.05 × 10−3), were significantly associated with the risk of lung cancer in both cross-tissue and lung tissue models. Further colocalization analysis indicated that rs7667864 (C & gt; A) and rs2298650 (G & gt; T) drove the GWAS association signals at 4p15.31–32 (OR = 1.09, 95%CI: 1.04–1.12, PGWAS = 5.54 × 10−5) and 11q23.3 (OR = 1.08, 95%CI: 1.04–1.13, PGWAS = 5.55 × 10−5), as well as the expression of DCAF16 (βGTEx = 0.24, PGTEx = 9.81 × 10−15; βNJLCC = 0.29, PNJLCC = 3.84 × 10−8) and CBL (βGTEx = −0.17, PGTEx = 2.82 × 10−8; βNJLCC = −0.32, PNJLCC = 2.61 × 10−7) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.
Materialart:
Online-Ressource
ISSN:
0964-6906
,
1460-2083
Sprache:
Englisch
Verlag:
Oxford University Press (OUP)
Publikationsdatum:
2021
ZDB Id:
1474816-2
SSG:
12
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