Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
Eijsbouts C., Zheng T., Kennedy NA., Bonfiglio F., Anderson CA., Moutsianas L., Holliday J., Shi J., Shringarpure S., Agee M., Aslibekyan S., Auton A., Bell RK., Bryc K., Clark SK., Elson SL., Fletez-Brant K., Fontanillas P., Furlotte NA., Gandhi PM., Heilbron K., Hicks B., Hinds DA., Huber KE., Jewett EM., Jiang Y., Kleinman A., Lin K-H., Litterman NK., Luff MK., McCreight JC., McIntyre MH., McManus KF., Mountain JL., Mozaffari SV., Nandakumar P., Noblin ES., Northover CAM., O’Connell J., Petrakovitz AA., Pitts SJ., Poznik GD., Sathirapongsasuti JF., Shastri AJ., Shelton JF., Tian C., Tung JY., Tunney RJ., Vacic V., Wang X., Zare AS., Voda A-I., Kashyap P., Chang L., Mayer E., Heitkemper M., Sayuk GS., Ringel-Kulka T., Ringel Y., Chey WD., Eswaran S., Merchant JL., Shulman RJ., Bujanda L., Garcia-Etxebarria K., Dlugosz A., Lindberg G., Schmidt PT., Karling P., Ohlsson B., Walter S., Faresjö ÅO., Simren M., Halfvarson J., Portincasa P., Barbara G., Usai-Satta P., Neri M., Nardone G., Cuomo R., Galeazzi F., Bellini M., Latiano A., Houghton L., Jonkers D., Kurilshikov A., Weersma RK., Netea M., Tesarz J., Gauss A., Goebel-Stengel M., Andresen V., Frieling T., Pehl C., Schaefert R., Niesler B., Lieb W., Hanevik K., Langeland N., Wensaas K-A., Litleskare S., Gabrielsen ME., Thomas L., Thijs V., Lemmens R., Van Oudenhove L., Wouters M., Farrugia G., Franke A., Hübenthal M., Abecasis G., Zawistowski M., Skogholt AH., Ness-Jensen E., Hveem K., Esko T., Teder-Laving M., Zhernakova A., Camilleri M., Boeckxstaens G., Whorwell PJ., Spiller R., McVean G., D’Amato M., Jostins L., Parkes M.
AbstractIrritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS.