Final Report, ECCO Grant for Ho-Su Lee

Methodology used in the research

We included 55 multiplex families with IBD, encompassing 157 CD, 29 UC and 138 unaffected relatives. Genotyping was performed using Immunochip, and further imputation was done using the Michigan imputation server to increase the coverage of the genotyping data. Polygenic risk score (PRS) analysis was used to assess the burden of known common genetic risk variants in the studied families. Additionally, association analysis using SAIGE was conducted to identify potentially novel underlying genetic factors that contribute to the familial aggregation of IBD.

Main findings/results of the research

We found that, in general, unaffected relatives in IBD multiplex families have a lower PRS than affected relatives, though the PRS is still higher than that in unrelated controls. Importantly, while we observed that almost half of the families have a familial PRS (i.e. the mean PRS of all relatives in a family) that is higher than the mean PRS of sporadic cases, there were seven families with a familial PRS lower than the mean PRS of unrelated controls.

SAIGE analysis identified several novel genetic loci associated with IBD in multiplex families, including two independently associated variants in the IL18RAP locus, rs2241130 in IL1RL2 and rs144641193 in IL1RL1, and a variant in PRKCQ, rs72781786.

Conclusions and perceived impact of the findings

These findings suggest that common risk variants play an important role in familial aggregation of disease in many multiplex families. However, it is important to note that not all multiplex families have the same genetic architecture or cause. Some families have a very low polygenic risk, indicating that shared environmental factors may be relatively more important, or the presence of genetic factors not captured by the score, such as rare variants. Further WGS/WES data analysis is ongoing to identify the genetic variant(s) that can explain familial aggregation in these low PRS families.