In this study, we systematically evaluated the correlations between UC PRS, CD PRS, UC + CD PRS, IBS PRS and addiction-related traits including “ever addicted to any substance or behavior” and “ever addicted to alcohol” in UK Biobank cohort. And based on another published GWAS summary datasets, we conducted LDSC analysis to evaluate the genetic correlation of UC, CD and alcohol addiction again. The two analyses results suggested a notable genetic correlation relationship between alcohol addiction and CD rather than UC. Further GWGIS study identified several genetic variations with interactive effect with CD in the association of alcohol addiction.
UC, CD and IBS are all chronic bowel disorders. But there are several differences in their pathology and mechanism. UC and CD both have inflammatory changes, whereas IBS is a collective term for a group of symptoms that are not accompanied by inflammatory changes and organic lesions of the intestines. CD demonstrates patchy lesions that are potentially scattered anywhere in the gastrointestinal tract, and UC is characterized by mucosal inflammation initiating in the rectum and extending proximally in the colon in a continuous fashion [32]. The inflammation in UC is typically limited to the mucosal layer, causing superficial damage of the bowel wall, whereas CD is characterized by transmural inflammation (involving all layers of the bowel wall) that leads to fibrosis, stricture and fistulas. Some factors, including a dysregulated immune response, altered gut microbiota, genetic susceptibility and environmental factors, are related to the developments of them [32]. Although both of them have genetic component in etiology, our results suggested that each of them owned distinct genetic architecture and CD shared more common features with alcohol addiction genetically. However, the exact genetic architecture and mechanism is complex, and multi-scale studies including in vivo and in vitro are needed to clarify this issue.
According to the results of GWGIS study in CD PRS and alcohol addiction, a number of SNPs, such as rs12063422, rs72664149, rs113604198, rs4937609, rs11222510, showed suggestive interactive effect with P < 1×10− 5 although they didn’t reach the strict threshold of 5×10− 8. These results suggested that the interactive effect was from a group of SNPs with minor effect and eventually formed an accumulated effect in the association with alcohol addiction. Those SNPs exist in the LD block in chromosome 1, 3, 11, 18. This suggested that the true causal effective SNPs may just exist in this block. One SNPs lies in the gene of NMD3, which is a ribosome export adaptor, mapped to chromosome 3, and the protein encoded by this gene is involved in the passage of the 60S subunit through the nuclear pore complex and into the cytoplasm. It can express in the small intestine, colon and rectum. Previous studies found NMD3 was significantly associated with a neurodegenerative disorder, Parkinson's disease [33]. But the exact mechanism still remains unclear. Our results assumed this gene might also be involved in the alcohol addiction by interaction with CD. However, this still need further population, animal and cellular studies to clarify.
In addition, there are also some limitations in this study. Firstly, the phenotypical data of addiction were from public platform, UK Biobank, which were measured by questionnaire. Although UK Biobank provides a large cohort for research, there are a lack of more detailed information about the addiction traits like the amount, frequency and duration of addictive substance exposure, which might lead to potential confounding factors for the study. A more exact design with detailed information about alcohol addiction is still needed to confirm our results. Secondly, we used PRS of chronic bowel disorders rather than direct prevalence information to conduct the regression analysis since the limitation in data availability. That causes a lack of the direct evidence about the correlation of the two. To make the results more reliable, we conducted LDSC analysis using another study population. Lastly, the study is basically an observational one and we should be cautious to conclude a causal relationship of the two.