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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. Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression (vol 11, 810, 2020)

Author

Cuomo, ASE, Seaton, DD, McCarthy, DJ, Martinez, I, Bonder, MJ, Garcia-Bernardo, J, Amatya, S, Madrigal, P, Isaacson, A, Buettner, F, Knights, A, Natarajan, KN, Vallier, L, Marioni, JC, Chhatriwala, M, Stegle, O, Cuomo, ASE, Seaton, DD, McCarthy, DJ, Martinez, I, Bonder, MJ, Garcia-Bernardo, J, Amatya, S, Madrigal, P, Isaacson, A, Buettner, F, Knights, A, Natarajan, KN, Vallier, L, Marioni, JC, Chhatriwala, M, and Stegle, O

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

3. An epigenome-wide association study meta-analysis of educational attainment

Author

Karlsson Linnér, R, Marioni, RE, Rietveld, CA, Simpkin, AJ, Davies, NM, Watanabe, K, Armstrong, NJ, Auro, K, Baumbach, C, Bonder, MJ, Buchwald, J, Fiorito, G, Ismail, K, Iurato, S, Joensuu, A, Karell, P, Kasela, S, Lahti, J, McRae, AF, Mandaviya, PR, Seppälä, I, Wang, Y, Baglietto, L, Binder, EB, Harris, SE, Hodge, AM, Horvath, S, Hurme, M, Johannesson, M, Latvala, A, Mather, KA, Medland, SE, Metspalu, A, Milani, L, Milne, RL, Pattie, A, Pedersen, NL, Peters, A, Polidoro, S, Räikkönen, K, Severi, G, Starr, JM, Stolk, L, Waldenberger, M, BIOS Consortium, Eriksson, JG, Esko, T, Franke, L, Gieger, C, Giles, GG, Hägg, S, Jousilahti, P, Kaprio, J, Kähönen, M, Lehtimäki, T, Martin, NG, Van Meurs, JBC, Ollikainen, M, Perola, M, Posthuma, D, Raitakari, OT, Sachdev, PS, Taskesen, E, Uitterlinden, AG, Vineis, P, Wijmenga, C, Wright, MJ, Relton, C, Davey Smith, G, Deary, IJ, Koellinger, PD, and Benjamin, DJ

Subjects
17 Psychology And Cognitive Sciences, Psychiatry, BIOS Consortium, 11 Medical And Health Sciences, 06 Biological Sciences
Abstract

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.Molecular Psychiatry advance online publication, 31 October 2017; doi:10.1038/mp.2017.210.

Published
2017

4. Assembly of 43 human Y chromosomes reveals extensive complexity and variation.

Author

Hallast P, Ebert P, Loftus M, Yilmaz F, Audano PA, Logsdon GA, Bonder MJ, Zhou W, Höps W, Kim K, Li C, Hoyt SJ, Dishuck PC, Porubsky D, Tsetsos F, Kwon JY, Zhu Q, Munson KM, Hasenfeld P, Harvey WT, Lewis AP, Kordosky J, Hoekzema K, O'Neill RJ, Korbel JO, Tyler-Smith C, Eichler EE, Shi X, Beck CR, Marschall T, Konkel MK, and Lee C

Subjects
Humans, Male, Genome, Human genetics, Genomics, Mutation Rate, Phenotype, Euchromatin genetics, Pseudogenes, Genetic Variation genetics, Chromosomes, Human, X genetics, Pseudoautosomal Regions genetics, Chromosomes, Human, Y genetics, Evolution, Molecular
Abstract

The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date 1 and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes 2 . Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established 1 boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2023
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5. Hematopoietic Npc1 mutation shifts gut microbiota composition in Ldlr -/- mice on a high-fat, high-cholesterol diet.

Author

Houben T, Penders J, Oligschlaeger Y, Dos Reis IAM, Bonder MJ, Koonen DP, Fu J, Hofker MH, and Shiri-Sverdlov R

Subjects
Animals, Bone Marrow Transplantation, Cholesterol, Dietary, Diet, High-Fat, Female, Granuloma metabolism, Hepatocytes metabolism, Inflammation, Kupffer Cells, Lipid Metabolism, Liver metabolism, Lysosomes metabolism, Male, Mice, Mice, Knockout, Mutation, Niemann-Pick C1 Protein, Phenotype, Polymorphism, Single Nucleotide, RNA, Ribosomal, 16S metabolism, Receptors, LDL genetics, Gastrointestinal Microbiome, Hematopoietic Stem Cells cytology, Intracellular Signaling Peptides and Proteins genetics, Metabolic Syndrome microbiology
Abstract

While the link between diet-induced changes in gut microbiota and lipid metabolism in metabolic syndrome (MetS) has been established, the contribution of host genetics is rather unexplored. As several findings suggested a role for the lysosomal lipid transporter Niemann-Pick type C1 (NPC1) in macrophages during MetS, we here explored whether a hematopoietic Npc1 mutation, induced via bone marrow transplantation, influences gut microbiota composition in low-density lipoprotein receptor knockout (Ldlr -/- ) mice fed a high-fat, high-cholesterol (HFC) diet for 12 weeks. Ldlr -/- mice fed a HFC diet mimic a human plasma lipoprotein profile and show features of MetS, providing a model to explore the role of host genetics on gut microbiota under MetS conditions. Fecal samples were used to profile the microbial composition by 16 s ribosomal RNA gene sequencing. The hematopoietic Npc1 mutation shifted the gut microbiota composition and increased microbial richness and diversity. Variations in plasma lipid levels correlated with microbial diversity and richness as well as with several bacterial genera. This study suggests that host genetic influences on lipid metabolism affect the gut microbiome under MetS conditions. Future research investigating the role of host genetics on gut microbiota might therefore lead to identification of diagnostic and therapeutic targets for MetS.

Published
2019
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6. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Author

Wahl S, Drong A, Lehne B, Loh M, Scott WR, Kunze S, Tsai PC, Ried JS, Zhang W, Yang Y, Tan S, Fiorito G, Franke L, Guarrera S, Kasela S, Kriebel J, Richmond RC, Adamo M, Afzal U, Ala-Korpela M, Albetti B, Ammerpohl O, Apperley JF, Beekman M, Bertazzi PA, Black SL, Blancher C, Bonder MJ, Brosch M, Carstensen-Kirberg M, de Craen AJ, de Lusignan S, Dehghan A, Elkalaawy M, Fischer K, Franco OH, Gaunt TR, Hampe J, Hashemi M, Isaacs A, Jenkinson A, Jha S, Kato N, Krogh V, Laffan M, Meisinger C, Meitinger T, Mok ZY, Motta V, Ng HK, Nikolakopoulou Z, Nteliopoulos G, Panico S, Pervjakova N, Prokisch H, Rathmann W, Roden M, Rota F, Rozario MA, Sandling JK, Schafmayer C, Schramm K, Siebert R, Slagboom PE, Soininen P, Stolk L, Strauch K, Tai ES, Tarantini L, Thorand B, Tigchelaar EF, Tumino R, Uitterlinden AG, van Duijn C, van Meurs JB, Vineis P, Wickremasinghe AR, Wijmenga C, Yang TP, Yuan W, Zhernakova A, Batterham RL, Smith GD, Deloukas P, Heijmans BT, Herder C, Hofman A, Lindgren CM, Milani L, van der Harst P, Peters A, Illig T, Relton CL, Waldenberger M, Järvelin MR, Bollati V, Soong R, Spector TD, Scott J, McCarthy MI, Elliott P, Bell JT, Matullo G, Gieger C, Kooner JS, Grallert H, and Chambers JC

Subjects
Adipose Tissue metabolism, Asian People genetics, Blood metabolism, Cohort Studies, Diabetes Mellitus, Type 2 complications, Europe ethnology, Female, Genetic Markers, Genetic Predisposition to Disease, Humans, India ethnology, Male, Obesity blood, Obesity complications, Overweight blood, Overweight complications, Overweight genetics, White People genetics, Adiposity genetics, Body Mass Index, DNA Methylation genetics, Diabetes Mellitus, Type 2 genetics, Epigenesis, Genetic, Epigenomics, Genome-Wide Association Study, Obesity genetics
Abstract

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10 -7 , range P = 9.2 × 10 -8 to 6.0 × 10 -46 ; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10 -6 , range P = 5.5 × 10 -6 to 6.1 × 10 -35 , n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10 -54 ). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

Published
2017
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