1. UK IBD twin and multiplex registry: Concordance and environmental risk factors of twins with IBD Dr Hannah Gordon, Prof Timothy Orchard, Dr Alan Steel, Dr Marcus Harbord ECCO 2015 Barcelona

2. Declarations: The authors have no competing interests Funded by an unrestricted grant from the Jesse and Thomas Tam Family Foundation

3. Introduction: Background IBD twin studies Methods UK IBD Twin and Multiplex Registry Concordance and environmental risk factors Results Conclusion

4. Background: First twin study 1876: ”Nature is far stronger than nurture” (Galton 1876) Classical twin design Compares MZ and DZ concordance CD and UC both heritable (Tysk 1988, Halfvarson 2007, Brant 2011, Chen 2014) Rate of increase in IBD incidence outweighs genetic drift (Molodecky 2012) Twin studies provide control for genetic factors Environmental factors Microbiota and epigenome (Dongen 2012)

5. Method 1: Recruitment into UK IBD Twin and Multiplex Registry UK research registry Twins Multiplex (at least 3 first degree) Recruitment IBD charities (including Royal Free cohort) Clinician referral

6. Method 2: Inclusion into this analysis Twins Monozygotic and Dizygotic Concordant and Discordant Crohn’s Disease and Ulcerative Colitis

7. Method 3: Collecting Information QUESTIONNAIRE Demographics Zygosity Concordance Disease history (IBD sufferers only) Environmental factors Smoking (including cannabis) Diet Stress Early Environment MEDICAL RECORDS Primary care physicians Gastroenterologist Disease history Montreal (CD) Disease extent (UC) Medication Surgical History

8. Method 4: Data Analysis Pair concordance of MZ and DZ pairs Analysis of environmental factors After adjusting for correlated data due to comparisons of twins, multivariable mixed-effects logistic regression analysis was performed invoking the GEE method using PROC GENMOD using the repeated statement for twins with logit link

9. Results 1: Demographics and pair concordance Mean age 57 years (range 21-83) 31 MZ:69 DZ UC 52: CD 48 Pair Concordance: Crohn’s DiseaseUlcerative Colitis Monozygotic53.3% (8:7)25% (4:12) Dizygotic9.1% (3:30)19.4% (7:29)

10. Results 2: Concordance compared with other twin cohorts Pair concordance (UK IBD TAM 2014) Previous twin cohorts (Tysk et al 1988, Halfvarson 2007, Brant 2011) Crohn’s DiseaseUlcerative Colitis Monozygotic20-55%3.6-17% Dizygotic0-3.6%0-6.3%

11. Results 3: Environmental Factors – smoking history In line with the literature, multivariate analysis suggests VariableNo.% CD N=58 % Non CD N=38 Odds Ratio 95% CIP Value Smoking history before diagnosis - CD No Yes Not Known 58 24 14 34/58 (58.6%) 22/24 (91.7%) 2/14 (14.3%) 24/58 (41.4%) 2/24 (8.3%) 12/14 (85.7%) Ref 4.11(1.60 to 10.54) 0.003 VariableNo.% UC N=62 % Non UC N=42 Odds Ratio 95% CIP Value Smoking history before diagnosis - UC No Yes Not Known 84 10 53/84 (63.1%) 7/10 (70%) 3/10 (30%) 31/84 (36.9%) 3/10 (30%) 7/10 (70%) Ref 0.39(0.14 to 1.07) 0.067

12. Results 4: Environmental Factors – Childhood Illness Variable N%IBD % Non IBD Odds ratio 95% CI p- value Childhood illness Equal to peers More than peers Less than peers Not Known 115 17 44 24 75(65.2%) 16(94.1%) 26(59.1%) 5(20.8%) 40(34.7%) 1 (5.89%) 18(40.9%) 19(79.2%) Ref 7.27 0.79 (1.34 to 39.5) (0.47 to 1.35) 0.022 0.388 Gastroenteritis prior to diagnosis Equal to peers More than peers Less than peers Not Known 124 11 41 24 83(66.9%) 10(90.0%) 24(58.5%) 5(20.8%) 41(33.1%) 1(10%) 15(41.5%) 19(79.2%) Ref 2.54 0.83 (0.92 to 7.05) (0.49 to 1.43) 0.194 More self reports of frequent childhood illness amongst IBD cohort Non significant increase in childhood gastroenteritis

13. Results 5: Environmental Factors - Diet Variable Odds ratio95% CIp-value CD “ready made meals” at least weekly Yes4.23 (1.58 to 11.34) 0.017 Univariate analysis significant for CD Significance lost with correction for multiple comparisons

14. Results 6: Environmental Factors – Infant Feeding

15. Limitations: Recall bias Pair not proband concordance Sample size

16. Conclusion: Support heritability CD UC less heritable than other cohorts (Bengtson 2010) Smoking Childhood health

17. Future Direction: Resource to study interface between genes and environment Epigenome Microbiota and metabolome Biobank International Collaboration Denmark Scotland

18. Questions? hannah.gordon@chelwest.nhs.uk

19. References: 1.Galton, F. The history of twins, as a criterion of the relative powers of nature and nurture. J. Anthropol. Institute Great Britain Ireland 5, 391–406 (1876) 2.Molodecky et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review Gastroenterology. 2012 Jan;142(1):46-54.e42 3.Dongen J, Slagboom P, Draisma H, Martin N, Boomsana DL. The continuing value of twin studies in the omics era. Nat Rev Genet. 2012 Sep;13(9):640-53 4.Tysk C, Lindberg E, Jarnerot G, et al. Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut. 1988; 29: 990–996 5.Halfvarson J, Jess T, Bodin L, et al. Longitudinal concordance for clinical characteristics in a Swedish-Danish twin population with inflammatory bowel disease. Inflamm Bowel Dis. 2007; 13: 1536–1544 6.Brant S. Update on the heritability of IBD: The importance of twin studies. Inflammatory Bowel Disease Vol 17, Issue 1, Pg 1-5 Jan 2011 7.Chen GB, Lee SH et al. Estimation and partitioning of (co)heritability of inflammatory bowel disease from GWAS and immunochip data. Hum Mol Genet. 2014 May 2 HERITABILITY CALCULATIONS FROM POOLED TWIN DATA WITHIN SUPPLEMENTARY MATERIAL 8.Bengtson MB, Aamodt G, Vatn MH, Harris JR. Concordance for IBD among twins compared to ordinary siblings – a Nowegian population based study. J Crohns Colitis. 2010 Sep;4(3):312- 8