Some patients with chronic hepatitis B virus (HBV) infection failed to clear HBV, even persistently continue to produce antibodies to HBV. Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV. The first stage involved genome wide exome sequencing of 101 cases (HBsAg plus anti-HBs positive) compared with 102 control patients (anti-HBs positive, HBsAg negative). Over 80% of individual sequences displayed 20 × sequence coverage. Adapters, uncertain bases > 10% or low-quality base calls (> 50%) were filtered and compared to the human reference genome hg19. In the second stage, 579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage. Although there were no significant associated gene variants in the first stage, two significant gene associations were discovered when the two stages were assessed in a combined analysis. One association showed rs506121-“T” allele [within the dedicator of cytokinesis 8 (DOCK8) gene] was higher in chronic HBV infection group than that in clearance group (P = 0.002, OR = 0.77, 95% CI [0.65, 0.91]). The second association involved rs2071676—A allele within the Carbonic anhydrase (CA9) gene that was significantly elevated in chronic HBV infection group compared to the clearance group (P = 0.0003, OR = 1.35, 95% CI [1.15, 1.58]). Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.