Loss of pod dehiscence is a key step during soybean [Glycine max (L.) Merr.] domestication. Genome-wide association analysis for soybean shattering identified loci harboring Pdh1, NST1A and SHAT1-5. Pairwise epistatic interactions were observed, and the dehiscent Pdh1 overcomes the resistance conferred by NST1A or SHAT1-5 locus, indicating that Pdh1 predominates pod dehiscence expression. Further candidate gene association analysis identified a nonsense mutation in NST1A associated with pod dehiscence. Allele composition and population differential analyses unraveled that Pdh1 and NST1A, but not SHAT1-5, underwent domestication and modern breeding selections. Geographic analysis showed that in Northeast China (NEC), indehiscence at both Pdh1 and NST1A were required by cultivated soybean; while indehiscent Pdh1 alone is capable of coping shattering in Huang-Huai-Hai (HHH) valleys where it originated; and no specific indehiscence was required in Southern China (SC). Geo-climatic investigation revealed strong correlation between relative humidity and frequency of indehiscent Pdh1 across China. This study demonstrates that the epistatic interaction between Pdh1 and NST1A fulfills a pivotal role in determining the level of resistance against pod dehiscence. Humidity shapes the distribution of indehiscent alleles. Our results also suggest that HHH valleys, not NEC, was at least one of the origin centers of cultivated soybean.