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1. Skewed X-inactivation is common in the general female population

Author

Shvetsova, E, Sofronova, A, Monajemi, R, Gagalova, K, Draisma, HHM, White, SJ, Santen, GWE, Lopes, SMCDS, Heijmans, BT, Van Meurs, J, Jansen, R, Franke, L, Kielbasa, SM, Den Dunnen, JT, 't Hoen, PAC, Boomsma, DI, Pool, R, Van Dongen, J, Hottenga, JJ, Van Greevenbroek, MMJ, Da Stehouwer, C, Van der Kallen, CJH, Schalkwijk, CG, Wijmenga, C, Zhernakova, S, Tigchelaar, EF, Slagboom, PE, Beekman, M, Deelen, J, Van Heemst, D, Veldink, JH, Van den Berg, LH, Van Duijn, CM, Hofman, BA, Uitterlinden, AG, Jhamai, PM, Verbiest, M, Suchiman, HED, Verkerk, M, Van der Breggen, R, Van Rooij, J, Lakenberg, N, Mei, H, Bot, J, Zhernakova, DV, 't Hof, PV, Deelen, P, Nooren, I, Moed, M, Vermaat, M, Luijk, R, Bonder, MJ, Van Iterson, M, Van Dijk, F, Van Galen, M, Arindrarto, W, Swertz, MA, Van Zwet, EW, Isaacs, A, Francioli, LC, Menelaou, A, Pulit, SL, Palamara, PF, Elbers, CC, Neerincx, PB, Ye, K, Guryev, V, Kloosterman, WP, Abdellaoui, A, Van Leeuwen, EM, Van Oven, M, Li, M, Laros, JF, Karssen, LC, Kanterakis, A, Amin, N, Lameijer, EW, Kattenberg, M, Dijkstra, M, Byelas, H, Van Setten, J, Van Schaik, BD, Nijman, IJ, Renkens, I, Marschall, T, Schonhuth, A, Hehir-Kwa, JY, Handsaker, RE, Polak, P, Sohail, M, Vuzman, D, Hormozdiari, F, Van Enckevort, D, Koval, V, Moed, MH, Van der Velde, KJ, Rivadeneira, F, Estrada, K, Medina-Gomez, C, McCarroll, SA, De Craen, AJ, Suchiman, HE, Oostra, B, Willemsen, G, Platteel, M, Pitts, SJ, Potluri, S, Sundar, P, Cox, DR, Sunyaev, SR, Stoneking, M, De Knijff, P, Kayser, M, Li, Q, Li, Y, Du, Y, Chen, R, Cao, H, Li, N, Cao, S, Wang, J, Bovenberg, JA, Pe'er, I, Van Ommen, GJ, De Bakker, PI, Consortium, Bios, Consortium, Gonl, BIOS consortium, GoNL consortium, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology and Data Science, AII - Inflammatory diseases, APH - Methodology, Experimental Immunology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Personalized Medicine, Biological Psychology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, Interne Geneeskunde, RS: CARIM - R3 - Vascular biology, MUMC+: MA Reumatologie (9), MUMC+: MA Nefrologie (9), MUMC+: MA Medische Oncologie (9), MUMC+: MA Hematologie (9), MUMC+: MA Maag Darm Lever (9), MUMC+: MA Endocrinologie (9), MUMC+: HVC Pieken Maastricht Studie (9), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, MUMC+: MA Interne Geneeskunde (3), RS: Carim - B01 Blood proteins & engineering, RS: FHML MaCSBio, RS: CARIM - R1 - Thrombosis and haemostasis, RS: CARIM - R1.01 - Blood proteins & engineering, Biochemie, Psychiatry, VU University medical center, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Internal Medicine, Epidemiology, Genetic Identification, and Clinical Genetics

Subjects
Netherlands Twin Register (NTR), Male, 0301 basic medicine, Receptors, Cytoplasmic and Nuclear/genetics, CHROMOSOME-INACTIVATION, BIOS consortium, Receptors, Cytoplasmic and Nuclear, Septins/genetics, Population genetics, GoNL consortium, Population/genetics, Negative selection, 0302 clinical medicine, X Chromosome Inactivation, Receptors, Non-U.S. Gov't, Genetics (clinical), Netherlands, Genetics & Heredity, Genetics, education.field_of_study, Membrane Glycoproteins, Dosage compensation, DMD LOCUS, Research Support, Non-U.S. Gov't, Receptors, Peptide/genetics, Intracellular Signaling Peptides and Proteins, Peptide/genetics, Single Nucleotide, CARRIERS, TRANSLOCATION, VARIABILITY, Female, Life Sciences & Biomedicine, EXPRESSION, Biochemistry & Molecular Biology, Receptors, Peptide, Population, ADRENOLEUKODYSTROPHY, Biology, Research Support, Polymorphism, Single Nucleotide, Article, X-inactivation, DUCHENNE MUSCULAR-DYSTROPHY, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Journal Article, Humans, Polymorphism, Allele, education, Skewed X-inactivation, Gene, 0604 Genetics, Calcium-Binding Proteins/genetics, Science & Technology, CONSEQUENCES, Calcium-Binding Proteins, Membrane Glycoproteins/genetics, 030104 developmental biology, Cytoplasmic and Nuclear/genetics, PATTERNS, Intracellular Signaling Peptides and Proteins/genetics, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Septins, 030217 neurology & neurosurgery
Abstract

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.

Published
2019
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2. Mendelian randomization while jointly modeling cis genetics identifies causal relationships between gene expression and lipids

Author

Graaf, A, Claringbould, A, Rimbert, A, Heijmans, BT, 't Hoen, PAC, van Meurs, Joyce, Jansen, R, Franke, L, Westra, HJ, Li, Y, Wijmenga, C, Sanna, S, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, CiiM, Zentrum für individualisierte Infektionsmedizin, Feodor-Lynen-Str.7, 30625 Hannover., Internal Medicine, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
Proteomics, 0301 basic medicine, Apolipoprotein E, Multifactorial Inheritance, Linkage disequilibrium, Statistical methods, Science, Nectins, Quantitative Trait Loci, Datasets as Topic, General Physics and Astronomy, Genomics, Locus (genetics), Quantitative trait locus, Biology, Linkage Disequilibrium, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Apolipoproteins E, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Mendelian randomization, Humans, Computer Simulation, Genetic Predisposition to Disease, RNA-Seq, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Netherlands, Genetics, Multidisciplinary, Models, Genetic, Genetic Pleiotropy, Cholesterol, LDL, General Chemistry, Mendelian Randomization Analysis, Lipid Metabolism, Adaptor Proteins, Vesicular Transport, 030104 developmental biology, Gene Expression Regulation, Causal inference, Expression quantitative trait loci, lcsh:Q, Gene expression, Metabolic Networks and Pathways, 030217 neurology & neurosurgery
Abstract

Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc. Application of MR-link to low-density lipoprotein cholesterol (LDL-C) measurements in 12,449 individuals with expression and protein QTL summary statistics from blood and liver identifies 25 genes causally linked to LDL-C. These include the known SORT1 and ApoE genes as well as PVRL2, located in the APOE locus, for which a causal role in liver was not known. Our results showcase the strength of MR-link for transcriptome-wide causal inferences., Mendelian randomization is a useful tool to infer causal relationships between traits, but can be confounded by the presence of pleiotropy. Here, the authors have developed MR-link, a Mendelian randomization method which accounts for unobserved pleiotropy and linkage disequilibrium between instrumental variables.

Published
2020
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3. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression

Author

Mahmoud Elansary, Knut Krohn, Eleonora Porcu, Julia Dmitrieva, Michel Georges, Harm-Jan Westra, Isabel Alves, Matthias Nauck, Jan H. Veldink, Joost Verlouw, Anette Kalnapenkis, Silva Kasela, Alex W. Hewitt, Roy Oelen, Willem H. Ouwehand, Frank Beutner, Ilkka Seppälä, Yukihide Momozawa, Samuli Ripatti, Brenda W.J.H. Penninx, Patrick Deelen, Michael Stumvoll, Jenny van Dongen, Jonathan K. Pritchard, Roman Kreuzhuber, Marie-Julie Favé, Bernett Lee, Hailang Mei, Biao Zeng, Philip Awadalla, Shuang Li, Kate Downes, Gibran Hemani, Urko M. Marigorta, Anke Tönjes, Morris Swertz, Robert Warmerdam, Joseph E. Powell, Mika Kähönen, Urmo Võsa, Brandon L. Pierce, Benjamin P. Fairfax, Anand Kumar Andiappan, Bastiaan T. Heijmans, Martina Müller-Nurasyid, Sven Bergmann, Katharina Schramm, Hanieh Yaghootkar, Sina Rüeger, Monique G. P. van der Wijst, Lude Franke, Ting Qi, Rick Jansen, Greg Gibson, Cisca Wijmenga, Marc Jan Bonder, Yungil Kim, Viktorija Kukushkina, Johannes Kettunen, Joachim Thiery, Peter A C 't Hoen, Zoltán Kutalik, Jian Yang, Dylan H. de Vries, Olaf Rötzschke, Maarten van Iterson, Peter Kovacs, Peter M. Visscher, Wibowo Arindrarto, Oliver Stegle, Natalia Pervjakova, Julian C. Knight, Tõnu Esko, Annique Claringbould, Lili Milani, Patrick F. Sullivan, Habibul Ahsan, Timothy M. Frayling, Lin Tong, Uwe Völker, Reyhan Sönmez Flitman, Eline Slagboom, Dorret I. Boomsma, Holger Prokisch, Michel G. Nivard, Mawusse Agbessi, Joyce B. J. van Meurs, Alexis Battle, Futao Zhang, Emmanouil T. Dermitzakis, Morris A. Swertz, Grant W. Montgomery, Terho Lehtimäki, Coen D.A. Stehouwer, Jaanika Kronberg, Holger Kirsten, Olli T. Raitakari, Sina A. Gharib, Bruce M. Psaty, Seyhan Yazar, Markus Loeffler, Harm Brugge, Jose Alquicira Hernandez, Mark W. Christiansen, Andrew A. Brown, Markus Perola, Markus Scholz, Ashis Saha, Alexander Teumer, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), BIOS Consortium, i2QTL Consortium, 't Hoen, PAC, van Meurs, J., van Dongen, J., van Iterson, M., Swertz, M.A., Jan Bonder, M., Biological Psychology, APH - Personalized Medicine, APH - Methodology, Internal Medicine, Interne Geneeskunde, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), and RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome

Subjects
DISORDER, Multifactorial Inheritance, Quantitative Trait Loci, Genome-wide association study, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Gene Expression Regulation/genetics, DISEASE, LINKS, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, RELEVANCE, Blood Proteins/genetics, Gene expression, Genetics, Humans, GENOME-WIDE ASSOCIATION, Polymorphism, Gene, Multifactorial Inheritance/genetics, 030304 developmental biology, Regulation of gene expression, RISK, 0303 health sciences, ARCHITECTURE, Blood Proteins, Transcriptome/genetics, Polymorphism, Single Nucleotide/genetics, Phenotype, SERINE BIOSYNTHESIS, HUMAN TRANSCRIPTOME, DEFICIENCY, Gene Expression Regulation, Expression quantitative trait loci, genome-wide association studies, gene expression, gene regulation, Quantitative Trait Loci/genetics, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Single Nucleotide/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants.

Published
2021
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4. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits

Author

Porcu, E., Rueger, S., Lepik, K., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Arindrarto, W., Awadalla, P., Battle, A., Beutner, F., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., Esko, T., Fave, M.J., Franke, L., Frayling, T., Gharib, S.A., Gibson, G., Heijmans, B.T., Hemani, G., Jansen, R., Kahonen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Lee, B., Lehtimaki, T., Loeffler, M., Marigorta, U.M., Mei, H.L., Milani, L., Montgomery, G.W., Muller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B.L., Powell, J., Prokisch, H., Psaty, B.M., Raitakari, O.T., Ripatti, S., Rotzschke, O., Saha, A., Scholz, M., Schramm, K., Seppala, I., Slagboom, E.P., Stehouwer, C.D.A., Stumvoll, M., Sullivan, P., Hoen, P.A.C. 't, Teumer, A., Thiery, J., Tong, L., Tonjes, A., Dongen, J. van, Iterson, M. van, Meurs, J. van, Veldink, J.H., Verlouw, J., Visscher, P.M., Volker, U., Vosa, U., Westra, H.J., Wijmenga, C., Yaghootkar, H., Yang, J., Zeng, B., Zhang, F.T., Beekman, M., Boomsma, D.I., Bot, J., Deelen, J., Hofman, B.A., Hottenga, J.J., Isaacs, A., Jhamai, P.M., Kielbasa, S.M., Lakenberg, N., Luijk, R., Mei, H., Moed, M., Nooren, I., Pool, R., Schalkwijk, C.G., Slagboom, P.E., Suchiman, H.E.D., Swertz, M.A., Tigchelaar, E.F., Uitterlinden, A.G., Berg, L.H. van den, Breggen, R. van der, Kallen, C.J.H. van der, Dijk, F. van, Duijn, C.M. van, Galen, M. van, Greevenbroek, M.M.J. van, Heemst, D. van, Rooij, J. van, Van't Hof, P., Zwet, E.W. van, Vermaat, M., Verbiest, M., Verkerk, M., Zhernakova, D.V., Zhernakova, S., Santoni, F.A., Reymond, A., Kutalik, Z., eQTLGen Consortium, BIOS Consortium, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), APH - Methodology, APH - Mental Health, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Laboratory Medicine, Human genetics, VU University medical center, APH - Digital Health, eQTLGen Consortium, BIOS Consortium, Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Arindrarto, W., Awadalla, P., Battle, A., Beutner, F., Jan Bonder, M., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., Esko, T., Favé, M.J., Franke, L., Frayling, T., Gharib, S.A., Gibson, G., Heijmans, B.T., Hemani, G., Jansen, R., Kähönen, M., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U.M., Mei, H., Milani, L., Montgomery, G.W., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B.L., Powell, J., Prokisch, H., Psaty, B.M., Raitakari, O.T., Ripatti, S., Rotzschke, O., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Slagboom, E.P., Stehouwer, CDA, Stumvoll, M., Sullivan, P., 't Hoen, PAC, Teumer, A., Thiery, J., Tong, L., Tönjes, A., van Dongen, J., van Iterson, M., van Meurs, J., Veldink, J.H., Verlouw, J., Visscher, P.M., Völker, U., Võsa, U., Westra, H.J., Wijmenga, C., Yaghootkar, H., Yang, J., Zeng, B., Zhang, F., Beekman, M., Boomsma, D.I., Bot, J., Deelen, J., Hofman, B.A., Hottenga, J.J., Isaacs, A., Bonder, M.J., Jhamai, P.M., Kielbasa, S.M., Lakenberg, N., Luijk, R., Moed, M., Nooren, I., Pool, R., Schalkwijk, C.G., Slagboom, P.E., Suchiman, HED, Swertz, M.A., Tigchelaar, E.F., Uitterlinden, A.G., van den Berg, L.H., van der Breggen, R., van der Kallen, CJH, van Dijk, F., van Duijn, C.M., van Galen, M., van Greevenbroek, MMJ, van Heemst, D., van Rooij, J., Van't Hof, P., van Zwet, E.W., Vermaat, M., Verbiest, M., Verkerk, M., Zhernakova, D.V., Zhernakova, S., Epidemiology, University Management, Department of Public Health, Centre of Excellence in Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Institute for Molecular Medicine Finland, Complex Disease Genetics, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), Interne Geneeskunde, RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, RS: CARIM - R3 - Vascular biology, MUMC+: MA Endocrinologie (9), MUMC+: MA Maag Darm Lever (9), MUMC+: MA Hematologie (9), MUMC+: MA Medische Oncologie (9), RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), MUMC+: MA Nefrologie (9), MUMC+: MA Reumatologie (9), RS: CARIM - R1 - Thrombosis and haemostasis, Biochemie, RS: Carim - B01 Blood proteins & engineering, and RS: FHML MaCSBio

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Statistical methods, General Physics and Astronomy, Genome-wide association study, 02 engineering and technology, VARIANTS, Quantitative trait, DISEASE, 0302 clinical medicine, Pleiotropy, GTP-Binding Protein gamma Subunits, lcsh:Science, MUTATION, 0303 health sciences, Brain Diseases, Multidisciplinary, 1184 Genetics, developmental biology, physiology, Mendelian Randomization Analysis, ASSOCIATION, 021001 nanoscience & nanotechnology, Phenotype, STATISTICS, ddc, FAMILY, OBESITY, symbols, 0210 nano-technology, EXPRESSION, Science, Quantitative Trait Loci, Single-nucleotide polymorphism, Computational biology, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, symbols.namesake, Mendelian randomization, Brain Diseases/genetics, Gene Expression Profiling, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Transcriptome, INSTRUMENTAL VARIABLES, SNP, 030304 developmental biology, Genetic association, General Chemistry, 030104 developmental biology, Expression quantitative trait loci, Mendelian inheritance, PLEIOTROPY, lcsh:Q, Gene expression, 030217 neurology & neurosurgery
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 majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits., Many genetic variants identified in genome-wide association studies are associated with gene expression. Here, Porcu et al. propose a transcriptome-wide summary statistics-based Mendelian randomization approach (TWMR) that, applied to 43 human traits, uncovers hundreds of previously unreported gene–trait associations.

Published
2019
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