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1. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Author

Porcu, E. (Eleonora), Rüeger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Heijmans, B.T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G.W. (Grant), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Slagboom, P.E. (Eline), Stehouwer, C.D. (Coen), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), ‘t Hoen, P.A.C. (Peter A. C.), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), van Dongen, J. (Jenny), Iterson, M. (Maarten) van, Meurs, J. (J.) van, Veldink, J.H. (Jan), Verlouw, J.A.M. (Joost), Visscher, P.M. (Peter M.), Völker, U. (Uwe), Võsa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D.I. (Dorret), Bot, J.J. (Jan), Deelen, J. (Joris), Hofman, B.A. (Bert A.), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Bonder, M.J. (Marc), Jhamai, P.M. (Mila), Kielbasa, S.M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (René), Mei, H. (Hailiang), Moed, H. (Heleen), Nooren, I. (Irene), Pool, R. (Reńe), Schalkwijk, C.G. (Casper), Stehouwer, C.D.A. (Coen D. A.), Suchiman, H.E.D. (H. Eka D.), Swertz, M.A. (Morris A.), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Berg, L.H. (Leonard) van den, Breggen, R. (Ruud) van der, Kallen, C.J. van der, Dijk, F. (Freerk) van, Dongen, J. (Jenny) van, Duijn, C.M. (Cornelia) van, Van Galen, M. (Michiel), van Greevenbroek, M.M.J. (Marleen M. J.), Heemst, D. (Diana) van, Meurs, J.B.J. (Joyce) van, van Rooij, J. (Jeroen), van’t Hof, P. (Peter), Zwet, E.W. (Erik) van, Vermaat, M. (Martijn), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Zhernakova, D.V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F.A. (Federico A.), Reymond, A. (Alexandre), Kutalik, Z. (Zoltán), Porcu, E. (Eleonora), Rüeger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Heijmans, B.T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G.W. (Grant), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B.M. (Bruce), Raitakari, O. (Olli), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Slagboom, P.E. (Eline), Stehouwer, C.D. (Coen), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), ‘t Hoen, P.A.C. (Peter A. C.), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), van Dongen, J. (Jenny), Iterson, M. (Maarten) van, Meurs, J. (J.) van, Veldink, J.H. (Jan), Verlouw, J.A.M. (Joost), Visscher, P.M. (Peter M.), Völker, U. (Uwe), Võsa, U. (Urmo), Westra, H.-J. (Harm-Jan), Wijmenga, C. (Cisca), Yaghootkar, H. (Hanieh), Yang, J. (Jian), Zeng, B. (Biao), Zhang, F. (Futao), Beekman, M. (Marian), Boomsma, D.I. (Dorret), Bot, J.J. (Jan), Deelen, J. (Joris), Hofman, B.A. (Bert A.), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Bonder, M.J. (Marc), Jhamai, P.M. (Mila), Kielbasa, S.M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (René), Mei, H. (Hailiang), Moed, H. (Heleen), Nooren, I. (Irene), Pool, R. (Reńe), Schalkwijk, C.G. (Casper), Stehouwer, C.D.A. (Coen D. A.), Suchiman, H.E.D. (H. Eka D.), Swertz, M.A. (Morris A.), Tigchelaar, E.F. (Ettje F.), Uitterlinden, A.G. (André), Berg, L.H. (Leonard) van den, Breggen, R. (Ruud) van der, Kallen, C.J. van der, Dijk, F. (Freerk) van, Dongen, J. (Jenny) van, Duijn, C.M. (Cornelia) van, Van Galen, M. (Michiel), van Greevenbroek, M.M.J. (Marleen M. J.), Heemst, D. (Diana) van, Meurs, J.B.J. (Joyce) van, van Rooij, J. (Jeroen), van’t Hof, P. (Peter), Zwet, E.W. (Erik) van, Vermaat, M. (Martijn), Verbiest, M.M.P.J. (Michael), Verkerk, M. (Marijn), Zhernakova, D.V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F.A. (Federico A.), Reymond, A. (Alexandre), and Kutalik, Z. (Zoltán)

Abstract

Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majo

Published
2019
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2. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes

Author

Xue, A. (Angli), Wu, Y. (Yang), Zhu, Z. (Zhihong), Zhang, F. (Futao), Kemper, K.E. (Kathryn E.), Zheng, Z. (Zhili), Yengo, L. (Loic), Lloyd-Jones, L.R. (Luke R.), Sidorenko, J. (Julia), Wu, Y. (Yeda), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M.J. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), McRae, A.F. (Allan F.), Visscher, P.M. (Peter), Zeng, J. (Jian), Yang, J. (Jian), Xue, A. (Angli), Wu, Y. (Yang), Zhu, Z. (Zhihong), Zhang, F. (Futao), Kemper, K.E. (Kathryn E.), Zheng, Z. (Zhili), Yengo, L. (Loic), Lloyd-Jones, L.R. (Luke R.), Sidorenko, J. (Julia), Wu, Y. (Yeda), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M.J. (Marc), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), McRae, A.F. (Allan F.), Visscher, P.M. (Peter), Zeng, J. (Jian), and Yang, J. (Jian)

Abstract

Type 2 diabetes (T2D) is a very common disease in humans. Here we conduct a meta-analysis of genome-wide association studies (GWAS) with ~16 million genetic variants in 62,892 T2D cases and 596,424 controls of European ancestry. We identify 139 common and 4 rare variants associated with T2D, 42 of which (39 common and 3 rare variants) are independent of the known variants. Integration of the gene expression data from blood (n = 14,115 and 2765) with the GWAS results identifies 33 putative functional genes for T2D, 3 of which were targeted by approved drugs. A further integration of DNA methylation (n = 1980) and epigenomic annotation data highlight 3 genes (CAMK1D, TP53INP1, and ATP5G1) with plausible regulatory mechanisms, whereby a genetic variant exerts an effect on T2D through epigenetic regulation of gene expression. Our study uncovers additional loci, proposes putative genetic regulatory mechanisms for T2D, and provides evidence of purifying selection for T2D-associated variants.

Published
2018
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3. Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood

Author

Qi, T. (Ting), Wu, Y. (Yang), Zeng, J. (Jian), Zhang, F. (Futao), Xue, A. (Angli), Jiang, L. (Longda), Zhu, Z. (Zhihong), Kemper, K. (Kathryn), Yengo, L. (Loic), Zheng, Z. (Zhili), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D.I. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), Marioni, R.E. (Riccardo), Montgomery, G.W. (Grant W.), Deary, I.J. (Ian), Wray, N.R. (Naomi R.), Visscher, P.M. (Peter), McRae, A.F. (Allan F.), Yang, J. (Jian), Qi, T. (Ting), Wu, Y. (Yang), Zeng, J. (Jian), Zhang, F. (Futao), Xue, A. (Angli), Jiang, L. (Longda), Zhu, Z. (Zhihong), Kemper, K. (Kathryn), Yengo, L. (Loic), Zheng, Z. (Zhili), Agbessi, M. (Mawussé), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A.K. (Anand Kumar), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Jan Bonder, M. (Marc), Boomsma, D.I. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tõnu), Favé, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T.M. (Timothy), Gharib, S.A. (Sina), Gibson, G. (Gregory), Hemani, G., Jansen, R. (Rick), Kähönen, M. (Mika), Kalnapenkis, A. (Anette), Kasela, S. (Silva), Kettunen, J. (Johannes), Kim, Y. (Yungil), Kirsten, H. (Holger), Kovacs, P. (Peter), Krohn, K. (Knut), Kronberg-Guzman, J. (Jaanika), Kukushkina, V. (Viktorija), Kutalik, Z. (Zoltán), Lee, B. (Bernett), Lehtimäki, T. (Terho), Loeffler, M. (Markus), Marigorta, U.M. (Urko), Metspalu, A. (Andres), Milani, L. (Lili), Müller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, A. (Andrew), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. (Bruce), Raitakari, O. (Olli), Ring, S.M. (Susan), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Ruëger, S. (Sina), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppälä, I. (Ilkka), Stumvoll, M. (Michael), Sullivan, P.F. (Patrick), Teumer, A. (Alexander), Thiery, J.P. (Joachim), Tong, L. (Lin), Tönjes, A. (Anke), Dongen, J. (Jenny) van, Meurs, J.B.J. (Joyce) van, Verlouw, J.A.M. (Joost), Völker, U. (Uwe), Võsa, U. (Urmo), Yaghootkar, H. (Hanieh), Zeng, B. (Biao), Marioni, R.E. (Riccardo), Montgomery, G.W. (Grant W.), Deary, I.J. (Ian), Wray, N.R. (Naomi R.), Visscher, P.M. (Peter), McRae, A.F. (Allan F.), and Yang, J. (Jian)

Abstract

Understanding the difference in genetic regulation of gene expression between brain and blood is important for discovering genes for brain-related traits and disorders. Here, we estimate the correlation of genetic effects at the top-associated cis-expression or -DNA methylation (DNAm) quantitative trait loci (cis-eQTLs or cis-mQTLs) between brain and blood (r b ). Using publicly available data, we find that genetic effects at the top cis-eQTLs or mQTLs are highly correlated between independent brain and blood samples (r b = 0.70 for cis-eQTLs and r ^ b = 0.78 for cis-mQTLs). Using meta-analyzed brain cis-eQTL/mQTL data (n = 526 to 1194), we identify 61 genes and 167 DNAm sites associated with four brain-related phenotypes, most of which are a subset of the discoveries (97 genes and 295 DNAm sites) using data from blood with larger sample sizes (n = 1980 to 14,115). Our results demonstrate the gain of power in gene discovery for brain-related phenotypes using blood cis-eQTL/mQTL data with large sample sizes.

Published
2018
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4. Recent human evolution has shaped geographical differences in susceptibility to disease

Author

Marigorta, U.M. (Urko), Lao Grueso, O. (Oscar), Casals, F. (Ferran), Calafell, F. (Francesc), Morcillo-Suárez, C. (Carlos), Faria, R. (Rui), Bosch, E. (Elena), Serra, F. (François), Bertranpetit, J. (Jaume), Dopazo, H. (Hernán), Navarro, A. (Arcadi), Marigorta, U.M. (Urko), Lao Grueso, O. (Oscar), Casals, F. (Ferran), Calafell, F. (Francesc), Morcillo-Suárez, C. (Carlos), Faria, R. (Rui), Bosch, E. (Elena), Serra, F. (François), Bertranpetit, J. (Jaume), Dopazo, H. (Hernán), and Navarro, A. (Arcadi)

Abstract

Background: Searching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.Results: We report three main findings. First, contrary to previous results, genes associated to complex diseases present lower degrees of genetic differentiation among human populations than average genome-wide levels. Second, also contrary to previous results, the differences in replicability of disease associated-loci between Europeans and East Asians are highly correlated with genetic differentiation between these populations. Finally, highly replicated genes present increased levels of high-frequency derived alleles in European and Asian populations when compared to African populations.Conclusions: Our findings highlight the heterogeneous nature of the genetic etiology of complex disease, confirm the importance of the recent evolutionary history of our species in current patterns of disease susceptibility and could cast doubts on the status as false positives of some associations that have failed to replicate across populations.

Published
2011
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