IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

Behaviour difficulties and cognitive function in children born very prematurely

Children born very prematurely are at risk of low average IQ and behaviour difficulties throughout childhood and adolescence. Associations among preterm birth, IQ and behaviour have been reported; however, the nature of the relationship among these outcomes is not fully understood. Some studies have proposed that the consequences of preterm birth, such as low average IQ, mediate the association between preterm birth and later behaviour difficulties. The aim of this study was to investigate the relationship among preterm birth, IQ and childhood behaviour problems, by testing mediation and moderation models. We assessed a UK sample of 69 very preterm (< 32 weeks gestational age) and 70 term born children aged between 6 and 12 years on an abbreviated IQ test. Parental behaviour ratings were obtained using the Strengths and Difficulties Questionnaire. Mediation and moderation models were tested using hierarchical regression analyses. The findings indicate that IQ mediates the relationship between birth status and emotional behaviour problems. Furthermore, the results indicate that birth status moderates the relationship between IQ and behavioural difficulties, i.e., that the relationship between low IQ and behaviour problems is most pronounced for the preterm children. The findings highlight the importance of considering indirect effects in the study of outcome after very preterm birth