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Coal worker's pneumoconiosis (CWP) is a debilitating and progressive occupational lung disease resulted fromlong-term inhalation of airborne silica-containing coalmine dust. Both environmental factors and genetic variations contribute to CWP. Our previous genome-wide association study (GWAS) revealed a tiny fraction of variants with the top associations in Chinese Han population. To identify novel susceptibility loci of CWP, functional variants with suboptimal associations in the GWAS scan were further studied here. Imputation was firstly performed to access the associations between ungenotyped variants and CWP risk and suboptimal associations with p < 1.0 x 10-3 were annotated with genotype-tissue expression (GTEx) and dbNSFP. Further, expression quantitative trait loci (eQTL) and nonsynonymous variants were validated within an independent cohort with 703 CWP cases and 705 exposed controls. Comprehensively functional annotations were performed for identified single nucleotide polymorphism(SNPs) based on multiple bioinformatics databases and websites. We found 4 CWP risk-associated eQTL SNPs, including rs10797062 at 1q23.2 (p = 6.91 x 10-4, OR = 1.28), rs1667614 at 2q13.1 (p = 1.48 x 10-4, OR = 0.53), rs2540438 at 2q33.1 (p = 2.13 x 10-3, OR = 1.33) and rs2274554 at 13q31.1 (p = 9.01 x 10-5, OR = 1.35). Based on the results from GTEx, the identified variants were significantly associated with host genes in lung tissues: rs10797062- ATP1A4 (p = 8.60 x 10-11), rs1667614-FNBP1P1 (p = 1.00 x 10-20), rs2540438-ALS2CR12 (p = 1.90 x 10-7), and rs2274554-RBM26 (p = 5.00 x 10-6). Joint effect analysis showed the risk of CWP was significantly increased with the number of risk variant alleles in an allele-dosagemanner (ptrend = 2.20 x 10-12). Enrichment pathway analysis suggested coexpressed genes of ATP1A4, FNBP1P1 and RBM26 were enriched in Ubiquitin mediated proteolysis pathway simultaneously. These results may provide a deeper understanding of the genetic predisposition of CWP. [ABSTRACT FROM AUTHOR]