Rome III Criteria Capture Higher Irritable Bowel Syndrome SNP-Heritability and Highlight a Novel Genetic Link with Cardiovascular Traits.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) shows genetic predisposition, and large-scale genome-wide association studies (GWAS) are emerging, based on heterogeneous disease definitions. We investigated the genetic architecture of IBS defined according to gold standard Rome Criteria. METHODS: We conducted GWAS meta-analyses of Rome III IBS and its subtypes in 24,735 IBS cases and 77,149 asymptomatic control subjects from 2 independent European cohorts (UK Biobank and Lifelines). Single-nucleotide polymorphism (SNP)-based heritability (h2SNP) and genetic correlations (rg) with other traits were calculated. IBS risk loci were functionally annotated to identify candidate genes. Sensitivity and conditional analyses were conducted to assess impact of confounders. Polygenic risk scores were computed and tested in independent datasets. RESULTS: Rome III IBS showed significant SNP-heritability (up to 13%) and similar genetic architecture across subtypes, including those with manifestations at the opposite ends of the symptom spectrum (rg = 0.48 between IBS-D and IBS-C). Genetic correlations with other traits highlighted commonalities with family history of heart disease and hypertension, coronary artery disease, and angina pectoris (rg = 0.20-0.45), among others. Four independent GWAS signals (P < 5×10-8) were detected, including 2 novel loci for IBS (rs2035380) and IBS-mixed (rs2048419) that had been previously associated with hypertension and coronary artery disease. Functional annotation of GWAS risk loci revealed genes implicated in circadian rhythm (BMAL1), intestinal barrier (CLDN23), immunomodulation (MFHAS1), and the cyclic adenosine monophosphate pathway (ADCY2). Polygenic risk scores allowed the identification of individuals at increased risk of IBS (odds ratio, 1.34; P = 1.1×10-3). CONCLUSIONS: Rome III Criteria capture higher SNP-heritability than previously estimated for IBS. The identified link between IBS and cardiovascular traits may contribute to the delineation of alternative therapeutic strategies, warranting further investigation.

Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes.

BACKGROUND AND AIMS: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. METHODS: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. RESULTS: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. CONCLUSION: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos.

We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (ß = -0.29, P < 2.0 × 10-16 ; ß = -0.21, P = 4.7 × 10-7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (ß = 0.10, P = 2 × 10-4 ; ß = 0.10, P = 0.01, respectively). Associations with VKORC1 (ß = -0.14, P = 2.0 × 10-16 ), CYP2C9 (ß = -0.07, P = 5.6 × 10-10 ), and CYP4F2 (ß = 0.03, P = 3 × 10-3 ), but not NQO1*2 (ß = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil.