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1. Genetic analyses identify widespread sex-differential participation bias

Author

Pirastu N., Cordioli M., Nandakumar P., Mignogna G., Abdellaoui A., Hollis B., Kanai M., Rajagopal V. M., Parolo P. D. B., Baya N., Carey C. E., Karjalainen J., Als T. D., Van der Zee M. D., Day F. R., Ong K. K., Agee M., Aslibekyan S., Bell R. K., Bryc K., Clark S. K., Elson S. L., Fletez-Brant K., Fontanillas P., Furlotte N. A., Gandhi P. M., Heilbron K., Hicks B., Huber K. E., Jewett E. M., Jiang Y., Kleinman A., Lin K. -H., Litterman N. K., Luff M. K., McIntyre M. H., McManus K. F., Mountain J. L., Mozaffari S. V., Noblin E. S., Northover C. A. M., O'Connell J., Petrakovitz A. A., Pitts S. J., Poznik G. D., Sathirapongsasuti J. F., Shelton J. F., Shringarpure S., Tian C., Tung J. Y., Tunney R. J., Vacic V., Wang X., Zare A., Mortensen P. B., Mors O., Werge T., Nordentoft M., Hougaard D. M., Bybjerg-Grauholm J., Baekvad-Hansen M., Morisaki T., de Geus E., Bellocco R., Okada Y., Borglum A. D., Joshi P., Auton A., Hinds D., Neale B. M., Walters R. K., Nivard M. G., Perry J. R. B., Ganna A., Pirastu, N, Cordioli, M, Nandakumar, P, Mignogna, G, Abdellaoui, A, Hollis, B, Kanai, M, Rajagopal, V, Parolo, P, Baya, N, Carey, C, Karjalainen, J, Als, T, Van der Zee, M, Day, F, Ong, K, Agee, M, Aslibekyan, S, Bell, R, Bryc, K, Clark, S, Elson, S, Fletez-Brant, K, Fontanillas, P, Furlotte, N, Gandhi, P, Heilbron, K, Hicks, B, Huber, K, Jewett, E, Jiang, Y, Kleinman, A, Lin, K, Litterman, N, Luff, M, Mcintyre, M, Mcmanus, K, Mountain, J, Mozaffari, S, Noblin, E, Northover, C, O'Connell, J, Petrakovitz, A, Pitts, S, Poznik, G, Sathirapongsasuti, J, Shelton, J, Shringarpure, S, Tian, C, Tung, J, Tunney, R, Vacic, V, Wang, X, Zare, A, Mortensen, P, Mors, O, Werge, T, Nordentoft, M, Hougaard, D, Bybjerg-Grauholm, J, Baekvad-Hansen, M, Morisaki, T, de Geus, E, Bellocco, R, Okada, Y, Borglum, A, Joshi, P, Auton, A, Hinds, D, Neale, B, Walters, R, Nivard, M, Perry, J, Ganna, A, Biological Psychology, APH - Personalized Medicine, APH - Mental Health, and Adult Psychiatry

Subjects
Adult, Inheritance Pattern, Male, Sex Characteristics, Inheritance Patterns, Sex Characteristic, Polymorphism, Single Nucleotide, Article, United Kingdom, Bias, Genetic Loci, Sample Size, Bia, Artifact, Biological Specimen Bank, Humans, Chromosomes, Human, Female, Artifacts, Biological Specimen Banks, Genome-Wide Association Study, Human
Abstract

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10-36). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

Published
2021

2. Genetic analyses identify widespread sex-differential participation bias

Author

Pirastu, N, Cordioli, M, Nandakumar, P, Mignogna, G, Abdellaoui, A, Hollis, B, Kanai, M, Rajagopal, V, Parolo, P, Baya, N, Carey, C, Karjalainen, J, Als, T, Van der Zee, M, Day, F, Ong, K, Agee, M, Aslibekyan, S, Bell, R, Bryc, K, Clark, S, Elson, S, Fletez-Brant, K, Fontanillas, P, Furlotte, N, Gandhi, P, Heilbron, K, Hicks, B, Huber, K, Jewett, E, Jiang, Y, Kleinman, A, Lin, K, Litterman, N, Luff, M, Mcintyre, M, Mcmanus, K, Mountain, J, Mozaffari, S, Noblin, E, Northover, C, O'Connell, J, Petrakovitz, A, Pitts, S, Poznik, G, Sathirapongsasuti, J, Shelton, J, Shringarpure, S, Tian, C, Tung, J, Tunney, R, Vacic, V, Wang, X, Zare, A, Mortensen, P, Mors, O, Werge, T, Nordentoft, M, Hougaard, D, Bybjerg-Grauholm, J, Baekvad-Hansen, M, Morisaki, T, de Geus, E, Bellocco, R, Okada, Y, Borglum, A, Joshi, P, Auton, A, Hinds, D, Neale, B, Walters, R, Nivard, M, Perry, J, Ganna, A, Pirastu N., Cordioli M., Nandakumar P., Mignogna G., Abdellaoui A., Hollis B., Kanai M., Rajagopal V. M., Parolo P. D. B., Baya N., Carey C. E., Karjalainen J., Als T. D., Van der Zee M. D., Day F. R., Ong K. K., Agee M., Aslibekyan S., Bell R. K., Bryc K., Clark S. K., Elson S. L., Fletez-Brant K., Fontanillas P., Furlotte N. A., Gandhi P. M., Heilbron K., Hicks B., Huber K. E., Jewett E. M., Jiang Y., Kleinman A., Lin K. -H., Litterman N. K., Luff M. K., McIntyre M. H., McManus K. F., Mountain J. L., Mozaffari S. V., Noblin E. S., Northover C. A. M., O'Connell J., Petrakovitz A. A., Pitts S. J., Poznik G. D., Sathirapongsasuti J. F., Shelton J. F., Shringarpure S., Tian C., Tung J. Y., Tunney R. J., Vacic V., Wang X., Zare A., Mortensen P. B., Mors O., Werge T., Nordentoft M., Hougaard D. M., Bybjerg-Grauholm J., Baekvad-Hansen M., Morisaki T., de Geus E., Bellocco R., Okada Y., Borglum A. D., Joshi P., Auton A., Hinds D., Neale B. M., Walters R. K., Nivard M. G., Perry J. R. B., Ganna A., Pirastu, N, Cordioli, M, Nandakumar, P, Mignogna, G, Abdellaoui, A, Hollis, B, Kanai, M, Rajagopal, V, Parolo, P, Baya, N, Carey, C, Karjalainen, J, Als, T, Van der Zee, M, Day, F, Ong, K, Agee, M, Aslibekyan, S, Bell, R, Bryc, K, Clark, S, Elson, S, Fletez-Brant, K, Fontanillas, P, Furlotte, N, Gandhi, P, Heilbron, K, Hicks, B, Huber, K, Jewett, E, Jiang, Y, Kleinman, A, Lin, K, Litterman, N, Luff, M, Mcintyre, M, Mcmanus, K, Mountain, J, Mozaffari, S, Noblin, E, Northover, C, O'Connell, J, Petrakovitz, A, Pitts, S, Poznik, G, Sathirapongsasuti, J, Shelton, J, Shringarpure, S, Tian, C, Tung, J, Tunney, R, Vacic, V, Wang, X, Zare, A, Mortensen, P, Mors, O, Werge, T, Nordentoft, M, Hougaard, D, Bybjerg-Grauholm, J, Baekvad-Hansen, M, Morisaki, T, de Geus, E, Bellocco, R, Okada, Y, Borglum, A, Joshi, P, Auton, A, Hinds, D, Neale, B, Walters, R, Nivard, M, Perry, J, Ganna, A, Pirastu N., Cordioli M., Nandakumar P., Mignogna G., Abdellaoui A., Hollis B., Kanai M., Rajagopal V. M., Parolo P. D. B., Baya N., Carey C. E., Karjalainen J., Als T. D., Van der Zee M. D., Day F. R., Ong K. K., Agee M., Aslibekyan S., Bell R. K., Bryc K., Clark S. K., Elson S. L., Fletez-Brant K., Fontanillas P., Furlotte N. A., Gandhi P. M., Heilbron K., Hicks B., Huber K. E., Jewett E. M., Jiang Y., Kleinman A., Lin K. -H., Litterman N. K., Luff M. K., McIntyre M. H., McManus K. F., Mountain J. L., Mozaffari S. V., Noblin E. S., Northover C. A. M., O'Connell J., Petrakovitz A. A., Pitts S. J., Poznik G. D., Sathirapongsasuti J. F., Shelton J. F., Shringarpure S., Tian C., Tung J. Y., Tunney R. J., Vacic V., Wang X., Zare A., Mortensen P. B., Mors O., Werge T., Nordentoft M., Hougaard D. M., Bybjerg-Grauholm J., Baekvad-Hansen M., Morisaki T., de Geus E., Bellocco R., Okada Y., Borglum A. D., Joshi P., Auton A., Hinds D., Neale B. M., Walters R. K., Nivard M. G., Perry J. R. B., and Ganna A.

Abstract

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index–increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10−36). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

Published
2021

3. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease

Author

Wightman, D. P., Jansen, I. E., Savage, J. E., Shadrin, A. A., Bahrami, S., Holland, D., Rongve, A., Børte, S., Winsvold, B. S., Drange, O. K., Martinsen, A. E., Skogholt, A. H., Willer, C., Bråthen, G., Bosnes, I., Nielsen, J. B., Fritsche, L. G., Thomas, L. F., Pedersen, L. M., Gabrielsen, M. E., Johnsen, M. B., Meisingset, T. W., Zhou, W., Proitsi, P., Hodges, A., Dobson, R., Velayudhan, L., Agee, M., Aslibekyan, S., Babalola, E., Bell, R. K., Bielenberg, J., Bryc, K., Bullis, E., Cameron, B., Coker, D., Partida, G. C., Dhamija, D., Das, S., Elson, S. L., Filshtein, T., Fletez-Brant, K., Fontanillas, P., Freyman, W., Gandhi, P. M., Hicks, B., Hinds, D. A., Huber, K. E., Jewett, E. M., Jiang, Y., Kleinman, A., Kukar, K., Lane, V., Lin, K. -H, Lowe, M., Luff, M. K., McCreight, J. C., McIntyre, M. H., McManus, K. F., Micheletti, S. J., Moreno, M. E., Mountain, J. L., Mozaffari, S. V., Nandakumar, P., Noblin, E. S., O’Connell, J., Petrakovitz, A. A., Poznik, G. D., Schumacher, M., Shastri, A. J., Shelton, J. F., Shi, J., Shringarpure, S., Tian, C., Tran, V., Tung, J. Y., Wang, X., Wang, W., Weldon, C. H., Wilton, P., Sealock, J. M., Davis, L. K., Pedersen, N. L., Reynolds, C. A., Karlsson, Ida K., Magnusson, S., Stefansson, H., Thordardottir, S., Jonsson, P. V., Snaedal, J., Zettergren, A., Skoog, I., Kern, S., Waern, M., Zetterberg, H., Blennow, K., Stordal, E., Hveem, K., Zwart, J. -A, Athanasiu, L., Selnes, P., Saltvedt, I., Sando, S. B., Ulstein, I., Djurovic, S., Fladby, T., Aarsland, D., Selbæk, G., Ripke, S., Stefansson, K., Andreassen, O. A., Posthuma, D., Team, 23andMe Research, Wightman, D. P., Jansen, I. E., Savage, J. E., Shadrin, A. A., Bahrami, S., Holland, D., Rongve, A., Børte, S., Winsvold, B. S., Drange, O. K., Martinsen, A. E., Skogholt, A. H., Willer, C., Bråthen, G., Bosnes, I., Nielsen, J. B., Fritsche, L. G., Thomas, L. F., Pedersen, L. M., Gabrielsen, M. E., Johnsen, M. B., Meisingset, T. W., Zhou, W., Proitsi, P., Hodges, A., Dobson, R., Velayudhan, L., Agee, M., Aslibekyan, S., Babalola, E., Bell, R. K., Bielenberg, J., Bryc, K., Bullis, E., Cameron, B., Coker, D., Partida, G. C., Dhamija, D., Das, S., Elson, S. L., Filshtein, T., Fletez-Brant, K., Fontanillas, P., Freyman, W., Gandhi, P. M., Hicks, B., Hinds, D. A., Huber, K. E., Jewett, E. M., Jiang, Y., Kleinman, A., Kukar, K., Lane, V., Lin, K. -H, Lowe, M., Luff, M. K., McCreight, J. C., McIntyre, M. H., McManus, K. F., Micheletti, S. J., Moreno, M. E., Mountain, J. L., Mozaffari, S. V., Nandakumar, P., Noblin, E. S., O’Connell, J., Petrakovitz, A. A., Poznik, G. D., Schumacher, M., Shastri, A. J., Shelton, J. F., Shi, J., Shringarpure, S., Tian, C., Tran, V., Tung, J. Y., Wang, X., Wang, W., Weldon, C. H., Wilton, P., Sealock, J. M., Davis, L. K., Pedersen, N. L., Reynolds, C. A., Karlsson, Ida K., Magnusson, S., Stefansson, H., Thordardottir, S., Jonsson, P. V., Snaedal, J., Zettergren, A., Skoog, I., Kern, S., Waern, M., Zetterberg, H., Blennow, K., Stordal, E., Hveem, K., Zwart, J. -A, Athanasiu, L., Selnes, P., Saltvedt, I., Sando, S. B., Ulstein, I., Djurovic, S., Fladby, T., Aarsland, D., Selbæk, G., Ripke, S., Stefansson, K., Andreassen, O. A., Posthuma, D., and Team, 23andMe Research

Abstract

Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.

Published
2021
Full Text
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4. Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Author

Eijsbouts, Chris, Zheng, Tenghao, Kennedy, Nicholas A., Bonfiglio, Ferdinando, Anderson, Carl A., Moutsianas, Loukas, Holliday, Joanne, Shi, Jingchunzi, Shringarpure, Suyash, Voda, Alexandru-Ioan, Farrugia, Gianrico, Franke, Andre, H��benthal, Matthias, Abecasis, Gon��alo, Zawistowski, Matthew, Skogholt, Anne Heidi, Ness-Jensen, Eivind, Hveem, Kristian, Esko, T��nu, Teder-Laving, Maris, Zhernakova, Alexandra, Camilleri, Michael, Boeckxstaens, Guy, Whorwell, Peter J., Spiller, Robin, McVean, Gil, D���Amato, Mauro, Jostins, Luke, Parkes, Miles, Agee, Michelle, Aslibekyan, Stella, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Clark, Sarah K., Elson, Sarah L., Fletez-Brant, Kipper, Fontanillas, Pierre, Furlotte, Nicholas A., Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Hinds, David A., Huber, Karen E., Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., Luff, Marie K., McCreight, Jey C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Mozaffari, Sahar V., Nandakumar, Priyanka, Noblin, Elizabeth S., Northover, Carrie A. M., O���Connell, Jared, Petrakovitz, Aaron A., Pitts, Steven J., Poznik, G. David, Sathirapongsasuti, J. Fah, Shastri, Anjali J., Shelton, Janie F., Tian, Chao, Tung, Joyce Y., Tunney, Robert J., Vacic, Vladimir, Wang, Xin, Zare, Amir S., Kashyap, Purna, Chang, Lin, Mayer, Emeran, Heitkemper, Margaret, Sayuk, Gregory S., Ringel-Kulka, Tamar, Ringel, Yehuda, Chey, William D., Eswaran, Shanti, Merchant, Juanita L., Shulman, Robert J., Bujanda, Luis, Garcia-Etxebarria, Koldo, Dlugosz, Aldona, Lindberg, Greger, Schmidt, Peter T., Karling, Pontus, Ohlsson, Bodil, Walter, Susanna, Faresj��, ��shild O., Simren, Magnus, Halfvarson, Jonas, Portincasa, Piero, Barbara, Giovanni, Usai-Satta, Paolo, Neri, Matteo, Nardone, Gerardo, Cuomo, Rosario, Galeazzi, Francesca, Bellini, Massimo, Latiano, Anna, Houghton, Lesley, Jonkers, Daisy, Kurilshikov, Alexander, Weersma, Rinse K., Netea, Mihai, Tesarz, Jonas, Gauss, Annika, Goebel-Stengel, Miriam, Andresen, Viola, Frieling, Thomas, Pehl, Christian, Schaefert, Rainer, Niesler, Beate, Lieb, Wolfgang, Hanevik, Kurt, Langeland, Nina, Wensaas, Knut-Arne, Litleskare, Sverre, Gabrielsen, Maiken E., Thomas, Laurent, Thijs, Vincent, Lemmens, Robin, Van Oudenhove, Lukas, Wouters, Mira, Eijsbouts C., Zheng T., Kennedy N.A., Bonfiglio F., Anderson C.A., Moutsianas L., Holliday J., Shi J., Shringarpure S., Agee M., Aslibekyan S., Auton A., Bell R.K., Bryc K., Clark S.K., Elson S.L., Fletez-Brant K., Fontanillas P., Furlotte N.A., Gandhi P.M., Heilbron K., Hicks B., Hinds D.A., Huber K.E., Jewett E.M., Jiang Y., Kleinman A., Lin K.-H., Litterman N.K., Luff M.K., McCreight J.C., McIntyre M.H., McManus K.F., Mountain J.L., Mozaffari S.V., Nandakumar P., Noblin E.S., Northover C.A.M., O'Connell J., Petrakovitz A.A., Pitts S.J., Poznik G.D., Sathirapongsasuti J.F., Shastri A.J., Shelton J.F., Tian C., Tung J.Y., Tunney R.J., Vacic V., Wang X., Zare A.S., Voda A.-I., Kashyap P., Chang L., Mayer E., Heitkemper M., Sayuk G.S., Ringel-Kulka T., Ringel Y., Chey W.D., Eswaran S., Merchant J.L., Shulman R.J., Bujanda L., Garcia-Etxebarria K., Dlugosz A., Lindberg G., Schmidt P.T., Karling P., Ohlsson B., Walter S., Faresjo A.O., 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 R.K., 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 M.E., Thomas L., Thijs V., Lemmens R., Van Oudenhove L., Wouters M., Farrugia G., Franke A., Hubenthal M., Abecasis G., Zawistowski M., Skogholt A.H., Ness-Jensen E., Hveem K., Esko T., Teder-Laving M., Zhernakova A., Camilleri M., Boeckxstaens G., Whorwell P.J., Spiller R., McVean G., D'Amato M., Jostins L., Parkes M., Eijsbouts, Chris [0000-0001-5179-0653], Anderson, Carl A. [0000-0003-1719-7009], Moutsianas, Loukas [0000-0001-5453-345X], Holliday, Joanne [0000-0003-4568-7320], Shringarpure, Suyash [0000-0001-6464-2668], Voda, Alexandru-Ioan [0000-0003-2974-6992], Farrugia, Gianrico [0000-0003-3473-5235], Hübenthal, Matthias [0000-0002-5956-3006], Abecasis, Gonçalo [0000-0003-1509-1825], Zawistowski, Matthew [0000-0002-3005-083X], Ness-Jensen, Eivind [0000-0001-6005-0729], Teder-Laving, Maris [0000-0002-5872-1850], Camilleri, Michael [0000-0001-6472-7514], Whorwell, Peter J. [0000-0002-5220-8474], Spiller, Robin [0000-0001-6371-4500], McVean, Gil [0000-0002-5012-4162], D’Amato, Mauro [0000-0003-2743-5197], Jostins, Luke [0000-0002-2475-3969], Parkes, Miles [0000-0002-6467-0631], Apollo - University of Cambridge Repository, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Eijsbouts, C., Zheng, T., Kennedy, N. A., Bonfiglio, F., Anderson, C. A., Moutsianas, L., Holliday, J., Shi, J., Shringarpure, S., Agee, M., Aslibekyan, S., Auton, A., Bell, R. K., Bryc, K., Clark, S. K., Elson, S. L., Fletez-Brant, K., Fontanillas, P., Furlotte, N. A., Gandhi, P. M., Heilbron, K., Hicks, B., Hinds, D. A., Huber, K. E., Jewett, E. M., Jiang, Y., Kleinman, A., Lin, K. -H., Litterman, N. K., Luff, M. K., Mccreight, J. C., Mcintyre, M. H., Mcmanus, K. F., Mountain, J. L., Mozaffari, S. V., Nandakumar, P., Noblin, E. S., Northover, C. A. M., O'Connell, J., Petrakovitz, A. A., Pitts, S. J., Poznik, G. D., Sathirapongsasuti, J. F., Shastri, A. J., Shelton, J. F., Tian, C., Tung, J. Y., Tunney, R. J., Vacic, V., Wang, X., Zare, A. S., Voda, A. -I., Kashyap, P., Chang, L., Mayer, E., Heitkemper, M., Sayuk, G. S., Ringel-Kulka, T., Ringel, Y., Chey, W. D., Eswaran, S., Merchant, J. L., Shulman, R. J., Bujanda, L., Garcia-Etxebarria, K., Dlugosz, A., Lindberg, G., Schmidt, P. T., Karling, P., Ohlsson, B., Walter, S., Faresjo, A. O., 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, R. K., 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, M. E., Thomas, L., Thijs, V., Lemmens, R., Van Oudenhove, L., Wouters, M., Farrugia, G., Franke, A., Hubenthal, M., Abecasis, G., Zawistowski, M., Skogholt, A. H., Ness-Jensen, E., Hveem, K., Esko, T., Teder-Laving, M., Zhernakova, A., Camilleri, M., Boeckxstaens, G., Whorwell, P. J., Spiller, R., Mcvean, G., D'Amato, M., Jostins, L., and Parkes, M.

Subjects
Male, Molecular Chaperone, Mood Disorder, 631/208/205/2138, Biology, 692/699/1503/1502/2071, Bioinformatics, Polymorphism, Single Nucleotide, Genetic pathways, 38/43, Irritable Bowel Syndrome, Cytoskeletal Protein, Genetics, medicine, Genetic predisposition, Aged, Anxiety Disorders, CD56 Antigen, Cell Adhesion Molecules, Cytoskeletal Proteins, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors, Homeodomain Proteins, Humans, Middle Aged, Molecular Chaperones, Mood Disorders, United Kingdom, Polymorphism, 692/699/476, Irritable bowel syndrome, Depression (differential diagnoses), article, Homeodomain Protein, Single Nucleotide, Guanine Nucleotide Exchange Factor, medicine.disease, Neuroticism, Biobank, Mood, Cell Adhesion Molecule, Anxiety, medicine.symptom, Anxiety Disorder, Human
Abstract

Funder: Kennedy Trust Rheumatology Research Prize Studentship, Funder: DFG Cluster of Excellence ���Precision Medicine in Chronic In-flammation��� (PMI; ID: EXC2167), Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: ���Ideas��� Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772, Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNL, Funder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421, Irritable 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.

Published
2021

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