Study objectives were to: mine the complete exome to identify putative rare single nucleotide variants (SNVs) associated with irritable bowel syndrome-diarrhea (IBS D) phenotype; assess genes that regulate bile acids in IBS-D; explore univariate associations of SNVs with symptom phenotype and quantitative traits in independent IBS cohort. Using principal component analysis, we identified 2 groups of IBS-D (n=16) with increased fecal bile acids: rapid colonic transit or high bile acids synthesis. DNA was sequenced indepth, analyzing SNVs in bile acids genes (ASBT, FXR, OSTα/β, FGF19, FGFR4, KLB, SHP, CYP7A1, LRH-1, and FABP6). Exome findings were compared to 50 similar ethnicity controls. We assessed univariate associations of each SNV with quantitative traits and principal component analysis and associations between SNVs in KLB and FGFR4 and symptom phenotype in 405 IBS, 228 controls and colonic transit in 70 IBS-D, 71 IBS-C. Mining the complete exome did not reveal significant associations with IBS-D over controls. There were 54 SNVs in 10/11 bile acids-regulating genes, with no SNVs in FGF19; 15 non-synonymous SNVs were identified in similar proportions of IBS-D and controls. Variations in KLB (rs1015450, downstream) and FGFR4 (rs434434 [intronic], rs1966265, and rs351855 [non-synonymous]) were associated with colonic transit (rs1966265; P=.043), fecal bile acids (rs1015450; P=.064), and PCA groups (all 3 FGFR4 SNVs; P<.05). In the 633 person cohort, FGFR4 rs434434 was associated with symptom phenotype (P=.027) and rs1966265 with 24h colonic transit (P=.066). Thus, exome sequencing identified additional variants in KLB and FGFR4 associated with bile acids or colonic transit in IBS-D.