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2. Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

Author

Vogel, G.F., Mozer-Glassberg, Y., Landau, Y.E., Schlieben, L.D., Prokisch, H., Feichtinger, R.G., Mayr, J.A., Brennenstuhl, H., Schröter, J., Pechlaner, A., Alkuraya, F.S., Baker, J.J., Barcia, G., Baric, I., Braverman, N., Burnyte, B., Christodoulou, J., Ciara, E., Coman, D., Das, A.M., Darin, N., Marina, A. Della, Distelmaier, F., Eklund, E.A., Ersoy, M., Fang, W., Gaignard, P., Ganetzky, R.D., Gonzales, E., Howard, C., Hughes, J., Konstantopoulou, V., Kose, M., Kerr, M., Khan, A., Lenz, D., McFarland, R., Margolis, M.G., Morrison, K., Müller, T., Murayama, K., Nicastro, E., Pennisi, A., Peters, Heidi, Piekutowska-Abramczuk, D., Rötig, A., Santer, R., Scaglia, F., Schiff, M., Shagrani, M., Sharrard, M., Soler-Alfonso, C., Staufner, C., Storey, I., Stormon, M., Taylor, R.W., Thorburn, D.R., Teles, E.L., Wang, J.S., Weghuber, D., Wortmann, S.B., Vogel, G.F., Mozer-Glassberg, Y., Landau, Y.E., Schlieben, L.D., Prokisch, H., Feichtinger, R.G., Mayr, J.A., Brennenstuhl, H., Schröter, J., Pechlaner, A., Alkuraya, F.S., Baker, J.J., Barcia, G., Baric, I., Braverman, N., Burnyte, B., Christodoulou, J., Ciara, E., Coman, D., Das, A.M., Darin, N., Marina, A. Della, Distelmaier, F., Eklund, E.A., Ersoy, M., Fang, W., Gaignard, P., Ganetzky, R.D., Gonzales, E., Howard, C., Hughes, J., Konstantopoulou, V., Kose, M., Kerr, M., Khan, A., Lenz, D., McFarland, R., Margolis, M.G., Morrison, K., Müller, T., Murayama, K., Nicastro, E., Pennisi, A., Peters, Heidi, Piekutowska-Abramczuk, D., Rötig, A., Santer, R., Scaglia, F., Schiff, M., Shagrani, M., Sharrard, M., Soler-Alfonso, C., Staufner, C., Storey, I., Stormon, M., Taylor, R.W., Thorburn, D.R., Teles, E.L., Wang, J.S., Weghuber, D., and Wortmann, S.B.

Abstract

01 juni 2023, Item does not contain fulltext, PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Published
2023

3. Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes

Author

Zech, M., Kopajtich, R., Steinbrücker, K., Bris, C., Gueguen, N., Feichtinger, R.G., Achleitner, M.T., Duzkale, N., Périvier, M., Koch, J., Engelhardt, H., Freisinger, P., Wagner, M., Brunet, T., Berutti, R., Smirnov, D., Navaratnarajah, T., Rodenburg, R.J.T., Pais, L.S., Austin-Tse, C., O'Leary, M., Boesch, S., Jech, R., Bakhtiari, S., Jin, S.C., Wilbert, F., Kruer, M.C., Wortmann, S.B., Eckenweiler, M., Mayr, J.A., Distelmaier, F., Steinfeld, R., Winkelmann, J., Prokisch, H., Zech, M., Kopajtich, R., Steinbrücker, K., Bris, C., Gueguen, N., Feichtinger, R.G., Achleitner, M.T., Duzkale, N., Périvier, M., Koch, J., Engelhardt, H., Freisinger, P., Wagner, M., Brunet, T., Berutti, R., Smirnov, D., Navaratnarajah, T., Rodenburg, R.J.T., Pais, L.S., Austin-Tse, C., O'Leary, M., Boesch, S., Jech, R., Bakhtiari, S., Jin, S.C., Wilbert, F., Kruer, M.C., Wortmann, S.B., Eckenweiler, M., Mayr, J.A., Distelmaier, F., Steinfeld, R., Winkelmann, J., and Prokisch, H.

Abstract

Item does not contain fulltext, OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients. RESULTS: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETA

Published
2022

4. Clinical implementation of RNA sequencing for Mendelian disease diagnostics

Author

Yépez, V.A., Gusic, M., Kopajtich, R., Mertes, C., Smith, N.H., Alston, C.L., Ban, R., Beblo, S., Berutti, R., Blessing, H., Ciara, E., Distelmaier, F., Freisinger, P., Häberle, J., Hayflick, S.J., Hempel, M., Itkis, Y.S., Kishita, Y., Klopstock, T., Krylova, T.D., Lamperti, C., Lenz, D., Makowski, C., Mosegaard, S., Müller, M.F., Muñoz-Pujol, G., Nadel, A., Ohtake, A., Okazaki, Y., Procopio, E., Schwarzmayr, T., Smet, J., Staufner, C., Stenton, S.L., Strom, T.M., Terrile, C., Tort, F., Coster, R. van, Vanlander, A., Wagner, M., Xu, M., Fang, F., Ghezzi, D., Mayr, J.A., Piekutowska-Abramczuk, D., Ribes, A., Rötig, A., Taylor, R.W., Wortmann, S.B., Murayama, K., Meitinger, T., Gagneur, J., Prokisch, H., Yépez, V.A., Gusic, M., Kopajtich, R., Mertes, C., Smith, N.H., Alston, C.L., Ban, R., Beblo, S., Berutti, R., Blessing, H., Ciara, E., Distelmaier, F., Freisinger, P., Häberle, J., Hayflick, S.J., Hempel, M., Itkis, Y.S., Kishita, Y., Klopstock, T., Krylova, T.D., Lamperti, C., Lenz, D., Makowski, C., Mosegaard, S., Müller, M.F., Muñoz-Pujol, G., Nadel, A., Ohtake, A., Okazaki, Y., Procopio, E., Schwarzmayr, T., Smet, J., Staufner, C., Stenton, S.L., Strom, T.M., Terrile, C., Tort, F., Coster, R. van, Vanlander, A., Wagner, M., Xu, M., Fang, F., Ghezzi, D., Mayr, J.A., Piekutowska-Abramczuk, D., Ribes, A., Rötig, A., Taylor, R.W., Wortmann, S.B., Murayama, K., Meitinger, T., Gagneur, J., and Prokisch, H.

Abstract

Contains fulltext : 283137.pdf (Publisher’s version ) (Open Access), BACKGROUND: Lack of functional evidence hampers variant interpretation, leaving a large proportion of individuals with a suspected Mendelian disorder without genetic diagnosis after whole genome or whole exome sequencing (WES). Research studies advocate to further sequence transcriptomes to directly and systematically probe gene expression defects. However, collection of additional biopsies and establishment of lab workflows, analytical pipelines, and defined concepts in clinical interpretation of aberrant gene expression are still needed for adopting RNA sequencing (RNA-seq) in routine diagnostics. METHODS: We implemented an automated RNA-seq protocol and a computational workflow with which we analyzed skin fibroblasts of 303 individuals with a suspected mitochondrial disease that previously underwent WES. We also assessed through simulations how aberrant expression and mono-allelic expression tests depend on RNA-seq coverage. RESULTS: We detected on average 12,500 genes per sample including around 60% of all disease genes-a coverage substantially higher than with whole blood, supporting the use of skin biopsies. We prioritized genes demonstrating aberrant expression, aberrant splicing, or mono-allelic expression. The pipeline required less than 1 week from sample preparation to result reporting and provided a median of eight disease-associated genes per patient for inspection. A genetic diagnosis was established for 16% of the 205 WES-inconclusive cases. Detection of aberrant expression was a major contributor to diagnosis including instances of 50% reduction, which, together with mono-allelic expression, allowed for the diagnosis of dominant disorders caused by haploinsufficiency. Moreover, calling aberrant splicing and variants from RNA-seq data enabled detecting and validating splice-disrupting variants, of which the majority fell outside WES-covered regions. CONCLUSION: Together, these results show that streamlined experimental and computational processes can

Published
2022

5. Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier

Author

Bölsterli, B.K., Boltshauser, E., Palmieri, L., Spenger, J., Brunner-Krainz, M., Distelmaier, F., Freisinger, P., Geis, T., Gropman, A.L., Häberle, J., Hentschel, J., Jeandidier, B., Karall, D., Keren, B., Klabunde-Cherwon, A., Konstantopoulou, V., Kottke, R., Lasorsa, F.M., Makowski, C., Mignot, C., Tuura, R. O'Gorman, Porcelli, V., Santer, R., Sen, K., Steinbrücker, K., Syrbe, S., Wagner, M., Ziegler, A., Zöggeler, T., Mayr, J.A., Prokisch, H., Wortmann, S.B., Bölsterli, B.K., Boltshauser, E., Palmieri, L., Spenger, J., Brunner-Krainz, M., Distelmaier, F., Freisinger, P., Geis, T., Gropman, A.L., Häberle, J., Hentschel, J., Jeandidier, B., Karall, D., Keren, B., Klabunde-Cherwon, A., Konstantopoulou, V., Kottke, R., Lasorsa, F.M., Makowski, C., Mignot, C., Tuura, R. O'Gorman, Porcelli, V., Santer, R., Sen, K., Steinbrücker, K., Syrbe, S., Wagner, M., Ziegler, A., Zöggeler, T., Mayr, J.A., Prokisch, H., and Wortmann, S.B.

Abstract

Contains fulltext : 283140.pdf (Publisher’s version ) (Open Access), The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

Published
2022

6. Bi-allelic LETM1 variants perturb mitochondrial ion homeostasis leading to a clinical spectrum with predominant nervous system involvement

Author

Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., Houlden, H., Kaiyrzhanov, R., Mohammed, S.E.M., Maroofian, R., Husain, R.A., Catania, A., Torraco, A., Alahmad, A., Dutra-Clarke, M., Grønborg, S., Sudarsanam, A., Vogt, J., Arrigoni, F., Baptista, J., Haider, S., Feichtinger, R.G., Bernardi, P., Zulian, A., Gusic, M., Efthymiou, S., Bai, R., Bibi, F., Horga, A., Martinez-Agosto, J.A., Lam, A., Manole, A, Rodriguez, D.P., Durigon, R., Pyle, A., Albash, B., Dionisi-Vici, C., Murphy, D., Martinelli, D., Bugiardini, E., Allis, K., Lamperti, C., Reipert, S., Risom, L., Laugwitz, L., Nottia, M. Di, McFarland, R., Vilarinho, L., Hanna, M., Prokisch, H., Mayr, J.A., Bertini, E.S., Ghezzi, D., Østergaard, E., Wortmann, S.B., Carrozzo, R., Haack, T.B., Taylor, R.W., Spinazzola, A., Nowikovsky, K., and Houlden, H.

Abstract

Contains fulltext : 283148.pdf (Publisher’s version ) (Open Access), Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K(+)/H(+) exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic LETM1 variants are associated with defective mitochondrial K(+) efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial patholog

Published
2022

7. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Scala, M., Wortmann, S.B., Kaya, N., Stellingwerff, M.D., Pistorio, A., Glamuzina, E., Karnebeek, C.D. van, Skrypnyk, C., Iwanicka-Pronicka, K., Piekutowska-Abramczuk, D., Ciara, E., Tort, F., Sheidley, B., Poduri, A., Jayakar, P., Jayakar, A., Upadia, J., Walano, N., Haack, T.B., Prokisch, H., Aldhalaan, H., Karimiani, E.G., Yildiz, Y., Ceylan, A.C., Santiago-Sim, T., Dameron, A., Yang, H., Toosi, M.B., Ashrafzadeh, F., Akhondian, J., Imannezhad, S., Mirzadeh, H.S., Maqbool, S., Farid, A., Al-Muhaizea, M.A., Alshwameen, M.O., Aldowsari, L., Alsagob, M., Alyousef, A., Almass, R., AlHargan, A., Alwadei, A.H., AlRasheed, M.M., Colak, D., Alqudairy, H., Khan, S., Lines, M.A., Cazorla, M., Ribes, A., Morava, E., Bibi, F., Haider, S., Ferla, M.P., Taylor, J.C., Alsaif, H.S., Firdous, A., Hashem, M., Shashkin, C., Koneev, K., Kaiyrzhanov, R., Efthymiou, S., Genomics, Q.S., Schmitt-Mechelke, T., Ziegler, A., Issa, M.Y., Elbendary, H.M., Striano, P., Alkuraya, F.S., Zaki, M.S., Gleeson, J.G., Barakat, T.S., Bierau, J., Knaap, M.S. van der, Maroofian, R., Houlden, H., Scala, M., Wortmann, S.B., Kaya, N., Stellingwerff, M.D., Pistorio, A., Glamuzina, E., Karnebeek, C.D. van, Skrypnyk, C., Iwanicka-Pronicka, K., Piekutowska-Abramczuk, D., Ciara, E., Tort, F., Sheidley, B., Poduri, A., Jayakar, P., Jayakar, A., Upadia, J., Walano, N., Haack, T.B., Prokisch, H., Aldhalaan, H., Karimiani, E.G., Yildiz, Y., Ceylan, A.C., Santiago-Sim, T., Dameron, A., Yang, H., Toosi, M.B., Ashrafzadeh, F., Akhondian, J., Imannezhad, S., Mirzadeh, H.S., Maqbool, S., Farid, A., Al-Muhaizea, M.A., Alshwameen, M.O., Aldowsari, L., Alsagob, M., Alyousef, A., Almass, R., AlHargan, A., Alwadei, A.H., AlRasheed, M.M., Colak, D., Alqudairy, H., Khan, S., Lines, M.A., Cazorla, M., Ribes, A., Morava, E., Bibi, F., Haider, S., Ferla, M.P., Taylor, J.C., Alsaif, H.S., Firdous, A., Hashem, M., Shashkin, C., Koneev, K., Kaiyrzhanov, R., Efthymiou, S., Genomics, Q.S., Schmitt-Mechelke, T., Ziegler, A., Issa, M.Y., Elbendary, H.M., Striano, P., Alkuraya, F.S., Zaki, M.S., Gleeson, J.G., Barakat, T.S., Bierau, J., Knaap, M.S. van der, Maroofian, R., and Houlden, H.

Abstract

Contains fulltext : 283128.pdf (Publisher’s version ) (Open Access), Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan-Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Published
2022

8. How to proceed after 'negative' exome: A review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques

Author

Wortmann, S.B., Oud, M.M., Alders, M., Coene, K.L.M., Crabben, S.N. van der, Feichtinger, R.G., Garanto, A., Hoischen, A., Langeveld, M., Lefeber, D.J., Mayr, J.A., Ockeloen, C.W., Prokisch, H., Rodenburg, R.J., Waterham, H.R., Wevers, R.A., Warrenburg, B.P.C. van de, Willemsen, M.A.A.P., Wolf, N.I., Vissers, L.E.L.M., Karnebeek, C.D. van, Wortmann, S.B., Oud, M.M., Alders, M., Coene, K.L.M., Crabben, S.N. van der, Feichtinger, R.G., Garanto, A., Hoischen, A., Langeveld, M., Lefeber, D.J., Mayr, J.A., Ockeloen, C.W., Prokisch, H., Rodenburg, R.J., Waterham, H.R., Wevers, R.A., Warrenburg, B.P.C. van de, Willemsen, M.A.A.P., Wolf, N.I., Vissers, L.E.L.M., and Karnebeek, C.D. van

Abstract

Contains fulltext : 282561.pdf (Publisher’s version ) (Open Access), Exome sequencing (ES) in the clinical setting of inborn metabolic diseases (IMDs) has created tremendous improvement in achieving an accurate and timely molecular diagnosis for a greater number of patients, but it still leaves the majority of patients without a diagnosis. In parallel, (personalized) treatment strategies are increasingly available, but this requires the availability of a molecular diagnosis. IMDs comprise an expanding field with the ongoing identification of novel disease genes and the recognition of multiple inheritance patterns, mosaicism, variable penetrance, and expressivity for known disease genes. The analysis of trio ES is preferred over singleton ES as information on the allelic origin (paternal, maternal, "de novo") reduces the number of variants that require interpretation. All ES data and interpretation strategies should be exploited including CNV and mitochondrial DNA analysis. The constant advancements in available techniques and knowledge necessitate the close exchange of clinicians and molecular geneticists about genotypes and phenotypes, as well as knowledge of the challenges and pitfalls of ES to initiate proper further diagnostic steps. Functional analyses (transcriptomics, proteomics, and metabolomics) can be applied to characterize and validate the impact of identified variants, or to guide the genomic search for a diagnosis in unsolved cases. Future diagnostic techniques (genome sequencing [GS], optical genome mapping, long-read sequencing, and epigenetic profiling) will further enhance the diagnostic yield. We provide an overview of the challenges and limitations inherent to ES followed by an outline of solutions and a clinical checklist, focused on establishing a diagnosis to eventually achieve (personalized) treatment.

Published
2022

9. Mitochondrial diseases mimicking autoimmune diseases of the CNS and good response to steroids initially

Author

Marina, A. Della, Bertolini, A., Wegener-Panzer, A., Flotats-Bastardas, M., Reinhardt, T., Naggar, I. El, Distelmaier, F., Blaschek, A., Schara-Schmidt, U., Brunet, T., Wagner, M., Smirnov, D., Prokisch, H., Wortmann, S.B., Rostasy, K., Marina, A. Della, Bertolini, A., Wegener-Panzer, A., Flotats-Bastardas, M., Reinhardt, T., Naggar, I. El, Distelmaier, F., Blaschek, A., Schara-Schmidt, U., Brunet, T., Wagner, M., Smirnov, D., Prokisch, H., Wortmann, S.B., and Rostasy, K.

Abstract

Item does not contain fulltext, INTRODUCTION: Neuroimmunological diseases such as autoimmune encephalitis (AE) or acquired demyelinating syndromes (ADS), can present with neurological symptoms and imaging features that are indistinguishable from mitochondrial diseases (MD) in particular at initial presentation. METHODS: Retrospective analysis of the clinical, laboratory and neuroimaging features of five patients who presented with signs of a neuroimmunological disease but all had pathological pathogenic variants in genes related to mitochondrial energy metabolism. RESULTS: Four patients presented with an acute neurological episode reminiscent of a possible AE and one patient with a suspected ADS at initial presentation. MRI findings were compatible with neuroimmunological diseases in all patients. In two children cerebrospinal fluid (CSF) studies revealed a mildly elevated cell count, two had elevated CSF lactate, none had oligoclonal bands (OCBs). All patients improved rapidly with intravenous steroids or immunoglobulins. Four patients had one or more relapses. Three patients showed worsening of their neurological symptoms with subsequent episodes and one patient died. Relapses in conjunction with new and progressive neurological symptoms, led to additional work-up which finally resulted in different genetic diagnosis of MD in all patients (MT-TL1, MT-ND5, APOA1-BP, HPDL, POLG). DISCUSSION: We would like to draw attention to a subset of patients with MD initially presenting with signs and symptoms mimicking neuroimmunological. Absence of CSF pleocytosis, elevated CSF lactate and progressive, relapsing course should trigger further (genetic) investigations in search of a MD even in patients with good response initially to immunomodulating therapies.

Published
2022

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

Author

Vosa, U. (Urmo), Claringbould, A. (Annique), Westra, H.-J. (Harm-Jan), Bonder, M. J. (Marc Jan), Deelen, P. (Patrick), Zeng, B. (Biao), Kirsten, H. (Holger), Saha, A. (Ashis), Kreuzhuber, R. (Roman), Yazar, S. (Seyhan), Brugge, H. (Harm), Oelen, R. (Roy), de Vries, D. H. (Dylan H.), van der Wijst, M. G. (Monique G. P.), Kasela, S. (Silva), Pervjakova, N. (Natalia), Alves, I. (Isabel), Fave, M.-J. (Marie-Julie), Agbessi, M. (Mawusse), Christiansen, M. W. (Mark W.), Jansen, R. (Rick), Seppala, I. (Ilkka), Tong, L. (Lin), Teumer, A. (Alexander), Schramm, K. (Katharina), Hemani, G. (Gibran), Verlouw, J. (Joost), Yaghootkar, H. (Hanieh), Flitman, R. S. (Reyhan Sonmez), Brown, A. (Andrew), Kukushkina, V. (Viktorija), Kalnapenkis, A. (Anette), Rueger, S. (Sina), Porcu, E. (Eleonora), Kronberg, J. (Jaanika), Kettunen, J. (Johannes), Lee, B. (Bernett), Zhang, F. (Futao), Qi, T. (Ting), Hernandez, J. A. (Jose Alquicira), Arindrarto, W. (Wibowo), Beutner, F. (Frank), Dmitrieva, J. (Julia), Elansary, M. (Mahmoud), Fairfax, B. P. (Benjamin P.), Georges, M. (Michel), Heijmans, B. T. (Bastiaan T.), Hewitt, A. W. (Alex W.), Kahonen, M. (Mika), Kim, Y. (Yungil), Knight, J. C. (Julian C.), Kovacs, P. (Peter), Krohn, K. (Knut), Li, S. (Shuang), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Momozawa, Y. (Yukihide), Mueller-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. G. (Michel G.), Penninx, B. W. (Brenda W. J. H.), Pritchard, J. K. (Jonathan K.), Raitakari, O. T. (Olli T.), Rotzschke, O. (Olaf), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Thiery, J. (Joachim), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), Veldink, J. H. (Jan H.), Voelker, U. (Uwe), Warmerdam, R. (Robert), Wijmenga, C. (Cisca), Swertz, M. (Morris), Andiappan, A. (Anand), Montgomery, G. W. (Grant W.), Ripatti, S. (Samuli), Perola, M. (Markus), Kutalik, Z. (Zoltan), Dermitzakis, E. (Emmanouil), Bergmann, S. (Sven), Frayling, T. (Timothy), van Meurs, J. (Joyce), Prokisch, H. (Holger), Ahsan, H. (Habibul), Pierce, B. L. (Brandon L.), Lehtimaki, T. (Terho), Boomsma, D. I. (Dorret, I), Psaty, B. M. (Bruce M.), Gharib, S. A. (Sina A.), Awadalla, P. (Philip), Milani, L. (Lili), Ouwehand, W. H. (Willem H.), Downes, K. (Kate), Stegle, O. (Oliver), Battle, A. (Alexis), Visscher, P. M. (Peter M.), Yang, J. (Jian), Scholz, M. (Markus), Powell, J. (Joseph), Gibson, G. (Greg), Esko, T. (Tonu), and Franke, L. (Lude)

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.

Published
2021

15. Meta-analyses identify DNA methylation associated with kidney function and damage

Author

Schlosser, P. (Pascal), Tin, A. (Adrienne), Matias-Garcia, P. R. (Pamela R.), Thio, C. H. (Chris H. L.), Joehanes, R. (Roby), Liu, H. (Hongbo), Weihs, A. (Antoine), Yu, Z. (Zhi), Hoppmann, A. (Anselm), Grundner-Culemann, F. (Franziska), Min, J. L. (Josine L.), Adeyemo, A. A. (Adebowale A.), Agyemang, C. (Charles), Arnlov, J. (Johan), Aziz, N. A. (Nasir A.), Baccarelli, A. (Andrea), Bochud, M. (Murielle), Brenner, H. (Hermann), Breteler, M. M. (Monique M. B.), Carmeli, C. (Cristian), Chaker, L. (Layal), Chambers, J. C. (John C.), Cole, S. A. (Shelley A.), Coresh, J. (Josef), Corre, T. (Tanguy), Correa, A. (Adolfo), Cox, S. R. (Simon R.), de Klein, N. (Niek), Delgado, G. E. (Graciela E.), Domingo-Relloso, A. (Arce), Eckardt, K.-U. (Kai-Uwe), Ekici, A. B. (Arif B.), Endlich, K. (Karlhans), Evans, K. L. (Kathryn L.), Floyd, J. S. (James S.), Fornage, M. (Myriam), Franke, L. (Lude), Fraszczyk, E. (Eliza), Gao, X. (Xu), Gao, X. (Xin), Ghanbari, M. (Mohsen), Ghasemi, S. (Sahar), Gieger, C. (Christian), Greenland, P. (Philip), Grove, M. L. (Megan L.), Harris, S. E. (Sarah E.), Hemani, G. (Gibran), Henneman, P. (Peter), Herder, C. (Christian), Horvath, S. (Steve), Hou, L. (Lifang), Hurme, M. A. (Mikko A.), Hwang, S.-J. (Shih-Jen), Järvelin, M.-R. (Marjo-Riitta), Kardia, S. L. (Sharon L. R.), Kasela, S. (Silva), Kleber, M. E. (Marcus E.), Koenig, W. (Wolfgang), Kooner, J. S. (Jaspal S.), Kramer, H. (Holly), Kronenberg, F. (Florian), Kuhnel, B. (Brigitte), Lehtimaki, T. (Terho), Lind, L. (Lars), Liu, D. (Dan), Liu, Y. (Yongmei), Lloyd-Jones, D. M. (Donald M.), Lohman, K. (Kurt), Lorkowski, S. (Stefan), Lu, A. T. (Ake T.), Marioni, R. E. (Riccardo E.), Marz, W. (Winfried), McCartney, D. L. (Daniel L.), Meeks, K. A. (Karlijn A. C.), Milani, L. (Lili), Mishra, P. P. (Pashupati P.), Nauck, M. (Matthias), Navas-Acien, A. (Ana), Nowak, C. (Christoph), Peters, A. (Annette), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ratliff, S. M. (Scott M.), Reiner, A. P. (Alex P.), Rosas, S. E. (Sylvia E.), Schottker, B. (Ben), Schwartz, J. (Joel), Sedaghat, S. (Sanaz), Smith, J. A. (Jennifer A.), Sotoodehnia, N. (Nona), Stocker, H. R. (Hannah R.), Stringhini, S. (Silvia), Sundstrom, J. (Johan), Swenson, B. R. (Brenton R.), Tellez-Plaza, M. (Maria), van Meurs, J. B. (Joyce B. J.), van Vliet-Ostaptchouk, J. V. (Jana V.), Venema, A. (Andrea), Verweij, N. (Niek), Walker, R. M. (Rosie M.), Wielscher, M. (Matthias), Winkelmann, J. (Juliane), Wolffenbuttel, B. H. (Bruce H. R.), Zhao, W. (Wei), Zheng, Y. (Yinan), Loh, M. (Marie), Snieder, H. (Harold), Levy, D. (Daniel), Waldenberger, M. (Melanie), Susztak, K. (Katalin), Kottgen, A. (Anna), Teumer, A. (Alexander), Schlosser, P. (Pascal), Tin, A. (Adrienne), Matias-Garcia, P. R. (Pamela R.), Thio, C. H. (Chris H. L.), Joehanes, R. (Roby), Liu, H. (Hongbo), Weihs, A. (Antoine), Yu, Z. (Zhi), Hoppmann, A. (Anselm), Grundner-Culemann, F. (Franziska), Min, J. L. (Josine L.), Adeyemo, A. A. (Adebowale A.), Agyemang, C. (Charles), Arnlov, J. (Johan), Aziz, N. A. (Nasir A.), Baccarelli, A. (Andrea), Bochud, M. (Murielle), Brenner, H. (Hermann), Breteler, M. M. (Monique M. B.), Carmeli, C. (Cristian), Chaker, L. (Layal), Chambers, J. C. (John C.), Cole, S. A. (Shelley A.), Coresh, J. (Josef), Corre, T. (Tanguy), Correa, A. (Adolfo), Cox, S. R. (Simon R.), de Klein, N. (Niek), Delgado, G. E. (Graciela E.), Domingo-Relloso, A. (Arce), Eckardt, K.-U. (Kai-Uwe), Ekici, A. B. (Arif B.), Endlich, K. (Karlhans), Evans, K. L. (Kathryn L.), Floyd, J. S. (James S.), Fornage, M. (Myriam), Franke, L. (Lude), Fraszczyk, E. (Eliza), Gao, X. (Xu), Gao, X. (Xin), Ghanbari, M. (Mohsen), Ghasemi, S. (Sahar), Gieger, C. (Christian), Greenland, P. (Philip), Grove, M. L. (Megan L.), Harris, S. E. (Sarah E.), Hemani, G. (Gibran), Henneman, P. (Peter), Herder, C. (Christian), Horvath, S. (Steve), Hou, L. (Lifang), Hurme, M. A. (Mikko A.), Hwang, S.-J. (Shih-Jen), Järvelin, M.-R. (Marjo-Riitta), Kardia, S. L. (Sharon L. R.), Kasela, S. (Silva), Kleber, M. E. (Marcus E.), Koenig, W. (Wolfgang), Kooner, J. S. (Jaspal S.), Kramer, H. (Holly), Kronenberg, F. (Florian), Kuhnel, B. (Brigitte), Lehtimaki, T. (Terho), Lind, L. (Lars), Liu, D. (Dan), Liu, Y. (Yongmei), Lloyd-Jones, D. M. (Donald M.), Lohman, K. (Kurt), Lorkowski, S. (Stefan), Lu, A. T. (Ake T.), Marioni, R. E. (Riccardo E.), Marz, W. (Winfried), McCartney, D. L. (Daniel L.), Meeks, K. A. (Karlijn A. C.), Milani, L. (Lili), Mishra, P. P. (Pashupati P.), Nauck, M. (Matthias), Navas-Acien, A. (Ana), Nowak, C. (Christoph), Peters, A. (Annette), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ratliff, S. M. (Scott M.), Reiner, A. P. (Alex P.), Rosas, S. E. (Sylvia E.), Schottker, B. (Ben), Schwartz, J. (Joel), Sedaghat, S. (Sanaz), Smith, J. A. (Jennifer A.), Sotoodehnia, N. (Nona), Stocker, H. R. (Hannah R.), Stringhini, S. (Silvia), Sundstrom, J. (Johan), Swenson, B. R. (Brenton R.), Tellez-Plaza, M. (Maria), van Meurs, J. B. (Joyce B. J.), van Vliet-Ostaptchouk, J. V. (Jana V.), Venema, A. (Andrea), Verweij, N. (Niek), Walker, R. M. (Rosie M.), Wielscher, M. (Matthias), Winkelmann, J. (Juliane), Wolffenbuttel, B. H. (Bruce H. R.), Zhao, W. (Wei), Zheng, Y. (Yinan), Loh, M. (Marie), Snieder, H. (Harold), Levy, D. (Daniel), Waldenberger, M. (Melanie), Susztak, K. (Katalin), Kottgen, A. (Anna), and Teumer, A. (Alexander)

Abstract

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

Published
2021

16. DNA methylation and lipid metabolism:an EWAS of 226 metabolic measures

Author

Gomez-Alonso, M. d. (Monica del C.), Kretschmer, A. (Anja), Wilson, R. (Rory), Pfeiffer, L. (Liliane), Karhunen, V. (Ville), Seppala, I. (Ilkka), Zhang, W. (Weihua), Mittelstrass, K. (Kirstin), Wahl, S. (Simone), Matias-Garcia, P. R. (Pamela R.), Prokisch, H. (Holger), Horn, S. (Sacha), Meitinger, T. (Thomas), Serrano-Garcia, L. R. (Luis R.), Sebert, S. (Sylvain), Raitakari, O. (Olli), Loh, M. (Marie), Rathmann, W. (Wolfgang), Mueller-Nurasyid, M. (Martina), Herder, C. (Christian), Roden, M. (Michael), Hurme, M. (Mikko), Jarvelin, M.-R. (Marjo-Riitta), Ala-Korpela, M. (Mika), Kooner, J. S. (Jaspal S.), Peters, A. (Annette), Lehtimaki, T. (Terho), Chambers, J. C. (John C.), Gieger, C. (Christian), Kettunen, J. (Johannes), Waldenberger, M. (Melanie), Gomez-Alonso, M. d. (Monica del C.), Kretschmer, A. (Anja), Wilson, R. (Rory), Pfeiffer, L. (Liliane), Karhunen, V. (Ville), Seppala, I. (Ilkka), Zhang, W. (Weihua), Mittelstrass, K. (Kirstin), Wahl, S. (Simone), Matias-Garcia, P. R. (Pamela R.), Prokisch, H. (Holger), Horn, S. (Sacha), Meitinger, T. (Thomas), Serrano-Garcia, L. R. (Luis R.), Sebert, S. (Sylvain), Raitakari, O. (Olli), Loh, M. (Marie), Rathmann, W. (Wolfgang), Mueller-Nurasyid, M. (Martina), Herder, C. (Christian), Roden, M. (Michael), Hurme, M. (Mikko), Jarvelin, M.-R. (Marjo-Riitta), Ala-Korpela, M. (Mika), Kooner, J. S. (Jaspal S.), Peters, A. (Annette), Lehtimaki, T. (Terho), Chambers, J. C. (John C.), Gieger, C. (Christian), Kettunen, J. (Johannes), and Waldenberger, M. (Melanie)

Abstract

Background: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. Results: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10⁻¹⁰), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures

Published
2021

18. Das Deutsche Netzwerk für mitochondriale Erkrankungen (mitoNET)

Author

Büchner, B., Gallenmüller, C., Lautenschläger, R., Kuhn, K., Wittig, I., Schöls, L., Rapaport, D., Seelow, D., Freisinger, P., Prokisch, H., Sperl, W., Wenz, T., Behl, C., Deschauer, M., Kornblum, C., Schneiderat, P., Abicht, A., Schuelke, M., Meitinger, T., Klopstock, T., and und das mitoNET-Consortium

Published
2012
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22. Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies

Author

Feichtinger R. G., Olahova M., Kishita Y., Garone C., Kremer L. S., Yagi M., Uchiumi T., Jourdain A. A., Thompson K., D'Souza A. R., Kopajtich R., Alston C. L., Koch J., Sperl W., Mastantuono E., Strom T. M., Wortmann S. B., Meitinger T., Pierre G., Chinnery P. F., Chrzanowska-Lightowlers Z. M., Lightowlers R. N., DiMauro S., Calvo S. E., Mootha V. K., Moggio M., Sciacco M., Comi G. P., Ronchi D., Murayama K., Ohtake A., Rebelo-Guiomar P., Kohda M., Kang D., Mayr J. A., Taylor R. W., Okazaki Y., Minczuk M., Prokisch H., Garone, Caterina [0000-0003-4928-1037], Chinnery, Patrick [0000-0002-7065-6617], Minczuk, Michal [0000-0001-8242-1420], Apollo - University of Cambridge Repository, Feichtinger R.G., Olahova M., Kishita Y., Garone C., Kremer L.S., Yagi M., Uchiumi T., Jourdain A.A., Thompson K., D'Souza A.R., Kopajtich R., Alston C.L., Koch J., Sperl W., Mastantuono E., Strom T.M., Wortmann S.B., Meitinger T., Pierre G., Chinnery P.F., Chrzanowska-Lightowlers Z.M., Lightowlers R.N., DiMauro S., Calvo S.E., Mootha V.K., Moggio M., Sciacco M., Comi G.P., Ronchi D., Murayama K., Ohtake A., Rebelo-Guiomar P., Kohda M., Kang D., Mayr J.A., Taylor R.W., Okazaki Y., Minczuk M., and Prokisch H.

Subjects
Male, Mitochondrial Diseases, Protein Conformation, Sequence Homology, Severity of Illness Index, Cohort Studies, Mice, Mitochondrial Disease, Age of Onset, Cells, Cultured, Allele, multiple mtDNA deletions, Middle Aged, Pedigree, mitochondria, Child, Preschool, Adult, Aged, Alleles, Amino Acid Sequence, Animals, Cardiomyopathies/complications, Cardiomyopathies/genetics, Cardiomyopathies/pathology, Carrier Proteins/chemistry, Carrier Proteins/genetics, Carrier Proteins/metabolism, DNA, Mitochondrial, Electron Transport/physiology, Embryo, Mammalian/metabolism, Embryo, Mammalian/pathology, Female, Fibroblasts/metabolism, Fibroblasts/pathology, Humans, Infant, Newborn, Mitochondrial Diseases/complications, Mitochondrial Diseases/genetics, Mitochondrial Diseases/pathology, Mitochondrial Proteins/chemistry, Mitochondrial Proteins/genetics, Mitochondrial Proteins/metabolism, Mutation, Oxidative Phosphorylation, Young Adult, MAM33, PEO, lactate, myopathy, oxidative phosphorylation, p32, progressive external ophthalmoplegia, multiple mtDNA deletion, Fibroblast, Cardiomyopathies, Human, Article, Electron Transport, Mitochondrial Proteins, Mitochondrial Protein, Cardiomyopathie, Animal, Fibroblasts, Embryo, Mammalian, Cohort Studie, Carrier Protein, Carrier Proteins
Abstract

Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals' samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp -/- mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp -/- MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.

Published
2017

23. A common atopy-associated variant in the Th2 cytokine locus control region impacts transcriptional regulation and alters SMAD3 and SP1 binding

Author

Kretschmer, A., Möller, G., Lee, H., Laumen, H., von Toerne, C., Schramm, K., Prokisch, H., Eyerich, S., Wahl, S., Baurecht, H., Franke, A., Claussnitzer, M., Eyerich, K., Teumer, A., Milani, L., Klopp, N., Hauck, S. M., Illig, T., Peters, A., Waldenberger, M., Adamski, J., Reischl, E., and Weidinger, S.

Published
2014
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28. Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis

Author

Gusic, Mirjana, Schottmann, G., Feichtinger, R.G., Du, Chen, Scholz, Caroline, Wagner, Matias, Panneman, D.M., Rodenburg, R.J., Prokisch, H., Schuelke, M., Gusic, Mirjana, Schottmann, G., Feichtinger, R.G., Du, Chen, Scholz, Caroline, Wagner, Matias, Panneman, D.M., Rodenburg, R.J., Prokisch, H., and Schuelke, M.

Abstract

Contains fulltext : 215007.pdf (publisher's version ) (Closed access)

Published
2020

29. Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits

Author

Maas, S.C.E., Mens, M.M.J., Kuhnel, B. (Brigitte), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Peters, A. (Annette), Prokisch, H. (Holger), Herder, C. (Christian), Grallert, H. (Harald), Kunze, S., Waldenberger, M. (Melanie), Kavousi, M. (Maryam), Kayser, M.H. (Manfred), Ghanbari, M. (Mohsen), Maas, S.C.E., Mens, M.M.J., Kuhnel, B. (Brigitte), Meurs, J.B.J. (Joyce) van, Uitterlinden, A.G. (André), Peters, A. (Annette), Prokisch, H. (Holger), Herder, C. (Christian), Grallert, H. (Harald), Kunze, S., Waldenberger, M. (Melanie), Kavousi, M. (Maryam), Kayser, M.H. (Manfred), and Ghanbari, M. (Mohsen)

Abstract

Background: Tobacco smoking is a well-known modifable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifcations, which could afect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits. Results: We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our fndings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identifed both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifcally, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identifed a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation efect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. Conclusions: Our study indicates that smoking

Published
2020
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30. Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits

Author

Maas, Silvana, Mens, Michelle, Kuhnel, B, van Meurs, Joyce, Uitterlinden, André, Peters, A, Prokisch, H, Herder, C, Grallert, H, Kunze, S, Waldenberger, M, Kavousi, Maryam, Kayser, Manfred, Ghanbari, Mohsen, Maas, Silvana, Mens, Michelle, Kuhnel, B, van Meurs, Joyce, Uitterlinden, André, Peters, A, Prokisch, H, Herder, C, Grallert, H, Kunze, S, Waldenberger, M, Kavousi, Maryam, Kayser, Manfred, and Ghanbari, Mohsen

Published
2020

37. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Couto Alves, A, De Silva, NMG, Karhunen, V, Sovio, U, Das, S, Taal, HR, Warrington, NM, Lewin, AM, Kaakinen, M, Cousminer, DL, Thiering, E, Timpson, NJ, Bond, TA, Lowry, E, Brown, CD, Estivill, X, Lindi, V, Bradfield, JP, Geller, F, Speed, D, Coin, LJM, Loh, M, Barton, SJ, Beilin, LJ, Bisgaard, H, Bønnelykke, K, Alili, R, Hatoum, IJ, Schramm, K, Cartwright, R, Charles, M, Salerno, V, Clément, K, Claringbould, AAJ, BIOS Consortium, van Duijn, CM, Moltchanova, E, Eriksson, JG, Elks, C, Feenstra, B, Flexeder, C, Franks, S, Frayling, TM, Freathy, RM, Elliott, P, Widén, E, Hakonarson, H, Hattersley, AT, Rodriguez, A, Banterle, M, Heinrich, J, Heude, B, Holloway, JW, Hofman, A, Hyppönen, E, Inskip, H, Kaplan, LM, Hedman, AK, Läärä, E, Prokisch, H, Grallert, H, Lakka, TA, Lawlor, DA, Melbye, M, Ahluwalia, TS, Marinelli, M, Millwood, IY, Palmer, LJ, Pennell, CE, Perry, JR, Ring, SM, Savolainen, MJ, Rivadeneira, F, Standl, M, Sunyer, J, Tiesler, CMT, Uitterlinden, AG, Schierding, W, O’Sullivan, JM, Prokopenko, I, Herzig, K, Smith, GD, O'Reilly, P, Felix, JF, Buxton, JL, Blakemore, AIF, Ong, KK, Jaddoe, VWV, Grant, SFA, Sebert, S, McCarthy, MI, Järvelin, M., and Early Growth Genetics (EGG) Consortium

Abstract

Copyright © 2019 The Authors. Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

38. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances

Author

Timmers, P.R., Mounier, N., Lall, K., Fischer, K., Ning, Z., Feng, X., Bretherick, A.D., Clark, D.W., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., van Dongen, J., Esko, T., Favé, M., Franke, L., Frayling, T., Gharib, S.A., Gibson, G., Hemani, G., Jansen, R., Kalnapenkis, A., Kasela, S., Kettunen, J., Kim, Y., Kirsten, H., Kovacs, P., Krohn, K., Kronberg-Guzman, J., Kukushkina, V., Kutalik, Z., Kähönen, M., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U., Metspalu, A., van Meurs, J., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B.M., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., Verlouw, J., Visscher, P.M., Võsa, U., Völker, U., Yaghootkar, H., Yang, J., Zeng, B., Zhang, F., Shen, X., Wilson, J.F., Joshi, P.K., eQTLGen Consortium, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, and APH - Digital Health

Subjects
Male, Parents, Multifactorial Inheritance, QH301-705.5, Science, Longevity, Complex Trait, Genetics, Genomics, Human, Lifespan, Age Factors, Aged, Bayes Theorem, DNA Methylation/genetics, Disease/genetics, Female, Genetic Loci, Genome-Wide Association Study, Humans, Longevity/genetics, Middle Aged, Multifactorial Inheritance/genetics, Polymorphism, Single Nucleotide/genetics, Risk Factors, Sex Characteristics, Signal Transduction/genetics, Survival Analysis, complex trait, genetics, genomics, human, lifespan, longevity, Polymorphism, Single Nucleotide, Research Communication, Disease, Biology (General), Genetics and Genomics, DNA Methylation, Medicine, Signal Transduction
Abstract

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer – but not other cancers – explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)., eLife digest Ageing happens to us all, and as the cabaret singer Maurice Chevalier pointed out, "old age is not that bad when you consider the alternative". Yet, the growing ageing population of most developed countries presents challenges to healthcare systems and government finances. For many older people, long periods of ill health are part of the end of life, and so a better understanding of ageing could offer the opportunity to prolong healthy living into old age. Ageing is complex and takes a long time to study – a lifetime in fact. This makes it difficult to discern its causes, among the countless possibilities based on an individual’s genes, behaviour or environment. While thousands of regions in an individual’s genetic makeup are known to influence their risk of different diseases, those that affect how long they will live have proved harder to disentangle. Timmers et al. sought to pinpoint such regions, and then use this information to predict, based on their DNA, whether someone had a better or worse chance of living longer than average. The DNA of over 500,000 people was read to reveal the specific ‘genetic fingerprints’ of each participant. Then, after asking each of the participants how long both of their parents had lived, Timmers et al. pinpointed 12 DNA regions that affect lifespan. Five of these regions were new and had not been linked to lifespan before. Across the twelve as a whole several were known to be involved in Alzheimer’s disease, smoking-related cancer or heart disease. Looking at the entire genome, Timmers et al. could then predict a lifespan score for each individual, and when they sorted participants into ten groups based on these scores they found that top group lived five years longer than the bottom, on average. Many factors beside genetics influence how long a person will live and our lifespan cannot be read from our DNA alone. Nevertheless, Timmers et al. had hoped to narrow down their search and discover specific genes that directly influence how quickly people age, beyond diseases. If such genes exist, their effects were too small to be detected in this study. The next step will be to expand the study to include more participants, which will hopefully pinpoint further genomic regions and help disentangle the biology of ageing and disease.

Published
2019

39. Quantification and discovery of sequence determinants of protein-per-mRNA amount in 29 human tissues

Author

Eraslan, B., Wang, D., Gusic, M., Prokisch, H., Hallström, B.M., Uhlén, M., Asplund, A., Pontén, F., Wieland, T., Hopf, T., Hahne, H., Kuster, B., and Gagneur, J.

Subjects
Proteomics, Proteome, codon usage, Genome, Human, Sequence Analysis, RNA, Biochemistry and Molecular Biology, Proteins, translational control, Articles, Methods & Resources, Codon Usage, Mrna Sequence Motifs, Transcriptomics, Translational Control, RNA Biology, Mass Spectrometry, Article, transcriptomics, proteomics, Gene Expression Regulation, mRNA sequence motifs, Genome-Scale & Integrative Biology, Humans, Tissue Distribution, RNA, Messenger, Transcriptome, Biokemi och molekylärbiologi
Abstract

Despite their importance in determining protein abundance, a comprehensive catalogue of sequence features controlling protein‐to‐mRNA (PTR) ratios and a quantification of their effects are still lacking. Here, we quantified PTR ratios for 11,575 proteins across 29 human tissues using matched transcriptomes and proteomes. We estimated by regression the contribution of known sequence determinants of protein synthesis and degradation in addition to 45 mRNA and 3 protein sequence motifs that we found by association testing. While PTR ratios span more than 2 orders of magnitude, our integrative model predicts PTR ratios at a median precision of 3.2‐fold. A reporter assay provided functional support for two novel UTR motifs, and an immobilized mRNA affinity competition‐binding assay identified motif‐specific bound proteins for one motif. Moreover, our integrative model led to a new metric of codon optimality that captures the effects of codon frequency on protein synthesis and degradation. Altogether, this study shows that a large fraction of PTR ratio variation in human tissues can be predicted from sequence, and it identifies many new candidate post‐transcriptional regulatory elements.

Published
2019

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

Author

Porcu, E. (Eleonora), Rueger, S. (Sina), Lepik, K. (Kaido), Agbessi, M. (Mawusse), Ahsan, H. (Habibul), Alves, I. (Isabel), Andiappan, A. (Anand), Arindrarto, W. (Wibowo), Awadalla, P. (Philip), Battle, A. (Alexis), Beutner, F. (Frank), Bonder, M. J. (Marc Jan), Boomsma, D. (Dorret), Christiansen, M. (Mark), Claringbould, A. (Annique), Deelen, P. (Patrick), Esko, T. (Tonu), Fave, M.-J. (Marie-Julie), Franke, L. (Lude), Frayling, T. (Timothy), Gharib, S. A. (Sina A.), Gibson, G. (Gregory), Heijmans, B. T. (Bastiaan T.), Hemani, G. (Gibran), Jansen, R. (Rick), Kahonen, 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), Lehtimaki, T. (Terho), Loeffler, M. (Markus), Marigorta, U. M. (Urko M.), Mei, H. (Hailang), Milani, L. (Lili), Montgomery, G. W. (Grant W.), Mueler-Nurasyid, M. (Martina), Nauck, M. (Matthias), Nivard, M. (Michel), Penninx, B. (Brenda), Perola, M. (Markus), Pervjakova, N. (Natalia), Pierce, B. L. (Brandon L.), Powell, J. (Joseph), Prokisch, H. (Holger), Psaty, B. M. (Bruce M.), Raitakari, O. T. (Olli T.), Ripatti, S. (Samuli), Rotzschke, O. (Olaf), Saha, A. (Ashis), Scholz, M. (Markus), Schramm, K. (Katharina), Seppala, I. (Ilkka), Slagboom, E. P. (Eline P.), Stehouwer, C. D. (Coen D. A.), Stumvoll, M. (Michael), Sullivan, P. (Patrick), Teumer, A. (Alexander), Thiery, J. (Joachim), Tong, L. (Lin), Tonjes, A. (Anke), van Dongen, J. (Jenny), van Iterson, M. (Maarten), van Meurs, J. (Joyce), Veldink, J. H. (Jan H.), Verlouw, J. (Joost), Visscher, P. M. (Peter M.), Volker, U. (Uwe), Vosa, 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 I.), Bot, J. (Jan), Deelen, J. (Joris), Hofman, B. A. (Bert A.), Hottenga, J. J. (Jouke J.), Isaacs, A. (Aaron), Jhamai, P. M. (P. Mila), Kielbasa, S. M. (Szymon M.), Lakenberg, N. (Nico), Luijk, R. (Rene), Mei, H. (Hailiang), Moed, M. (Matthijs), Nooren, I. (Irene), Pool, R. (Rene), Schalkwijk, C. G. (Casper G.), Slagboom, P. E. (P. Eline), Suchiman, H. E. (H. Eka D.), Swertz, M. A. (Morris A.), Tigchelaar, E. F. (Ettje F.), Uitterlinden, A. G. (Andre G.), van den Berg, L. H. (Leonard H.), van der Breggen, R. (Ruud), van der Kallen, C. J. (Carla J. H.), van Dijk, F. (Freerk), van Duijn, C. M. (Cornelia M.), van Galen, M. (Michiel), van Greevenbroek, M. M. (Marleen M. J.), van Heemst, D. (Diana), van Rooij, J. (Jeroen), Van't Hof, P. (Peter), van Zwet, E. W. (Erik. W.), Vermaat, M. (Martijn), Verbiest, M. (Michael), Verkerk, M. (Marijn), Zhernakova, D. V. (Dasha V.), Zhernakova, S. (Sasha), Santoni, F. A. (Federico A.), Reymond, A. (Alexandre), and Kutalik, Z. (Zoltan)

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.

Published
2019

43. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Alves, AC, De Silva, NMG, Karhunen, V, Sovio, U, Das, S, Taal, HR, Warrington, NM, Lewin, AM, Kaakinen, M, Cousminer, DL, Thiering, E, Timpson, NJ, Bond, TA, Lowry, E, Brown, CD, Estivill, X, Lindi, V, Bradfield, JP, Geller, F, Speed, D, Coin, LJM, Loh, M, Barton, SJ, Beilin, LJ, Bisgaard, H, Bonnelykke, K, Alili, R, Hatoum, IJ, Schramm, K, Cartwright, R, Charles, M-A, Salerno, V, Clement, K, Claringbould, AAJ, van Duijn, CM, Moltchanova, E, Eriksson, JG, Elks, C, Feenstra, B, Flexeder, C, Franks, S, Frayling, TM, Freathy, RM, Elliott, P, Widen, E, Hakonarson, H, Hattersley, AT, Rodriguez, A, Banterle, M, Heinrich, J, Heude, B, Holloway, JW, Hofman, A, Hypponen, E, Inskip, H, Kaplan, LM, Hedman, AK, Laara, E, Prokisch, H, Grallert, H, Lakka, TA, Lawlor, DA, Melbye, M, Ahluwalia, TS, Marinelli, M, Millwood, IY, Palmer, LJ, Pennell, CE, Perry, JR, Ring, SM, Savolainen, MJ, Rivadeneira, F, Standl, M, Sunyer, J, Tiesler, CMT, Uitterlinden, AG, Schierding, W, O'Sullivan, JM, Prokopenko, I, Herzig, K-H, Smith, GD, O'Reilly, P, Felix, JF, Buxton, JL, Blakemore, AIF, Ong, KK, Jaddoe, VWV, Grant, SFA, Sebert, S, McCarthy, MI, Jarvelin, M-R, Alves, AC, De Silva, NMG, Karhunen, V, Sovio, U, Das, S, Taal, HR, Warrington, NM, Lewin, AM, Kaakinen, M, Cousminer, DL, Thiering, E, Timpson, NJ, Bond, TA, Lowry, E, Brown, CD, Estivill, X, Lindi, V, Bradfield, JP, Geller, F, Speed, D, Coin, LJM, Loh, M, Barton, SJ, Beilin, LJ, Bisgaard, H, Bonnelykke, K, Alili, R, Hatoum, IJ, Schramm, K, Cartwright, R, Charles, M-A, Salerno, V, Clement, K, Claringbould, AAJ, van Duijn, CM, Moltchanova, E, Eriksson, JG, Elks, C, Feenstra, B, Flexeder, C, Franks, S, Frayling, TM, Freathy, RM, Elliott, P, Widen, E, Hakonarson, H, Hattersley, AT, Rodriguez, A, Banterle, M, Heinrich, J, Heude, B, Holloway, JW, Hofman, A, Hypponen, E, Inskip, H, Kaplan, LM, Hedman, AK, Laara, E, Prokisch, H, Grallert, H, Lakka, TA, Lawlor, DA, Melbye, M, Ahluwalia, TS, Marinelli, M, Millwood, IY, Palmer, LJ, Pennell, CE, Perry, JR, Ring, SM, Savolainen, MJ, Rivadeneira, F, Standl, M, Sunyer, J, Tiesler, CMT, Uitterlinden, AG, Schierding, W, O'Sullivan, JM, Prokopenko, I, Herzig, K-H, Smith, GD, O'Reilly, P, Felix, JF, Buxton, JL, Blakemore, AIF, Ong, KK, Jaddoe, VWV, Grant, SFA, Sebert, S, McCarthy, MI, and Jarvelin, M-R

Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

44. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Alves, A. C. (Alexessander Couto), De Silva, N. M. (N. Maneka G.), Karhunen, V. (Ville), Sovio, U. (Ulla), Das, S. (Shikta), Taal, H. R. (H. Rob), Warrington, N. M. (Nicole M.), Lewin, A. M. (Alexandra M.), Kaakinen, M. (Marika), Cousminer, D. L. (Diana L.), Thiering, E. (Elisabeth), Timpson, N. J. (Nicholas J.), Bond, T. A. (Tom A.), Lowry, E. (Estelle), Brown, C. D. (Christopher D.), Estivill, X. (Xavier), Lindi, V. (Virpi), Bradfield, J. P. (Jonathan P.), Geller, F. (Frank), Speed, D. (Doug), Coin, L. J. (Lachlan J. M.), Loh, M. (Marie), Barton, S. J. (Sheila J.), Beilin, L. J. (Lawrence J.), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Alili, R. (Rohia), Hatoum, I. J. (Ida J.), Schramm, K. (Katharina), Cartwright, R. (Rufus), Charles, M.-A. (Marie-Aline), Salerno, V. (Vincenzo), Clement, K. (Karine), Claringbould, A. A. (Annique A. J.), van Duijn, C. M. (Cornelia M.), Moltchanova, E. (Elena), Eriksson, J. G. (Johan G.), Elks, C. (Cathy), Feenstra, B. (Bjarke), Flexeder, C. (Claudia), Franks, S. (Stephen), Frayling, T. M. (Timothy M.), Freathy, R. M. (Rachel M.), Elliott, P. (Paul), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Hattersley, A. T. (Andrew T.), Rodriguez, A. (Alina), Banterle, M. (Marco), Heinrich, J. (Joachim), Heude, B. (Barbara), Holloway, J. W. (John W.), Hofman, A. (Albert), Hypponen, E. (Elina), Inskip, H. (Hazel), Kaplan, L. M. (Lee M.), Hedman, A. K. (Asa K.), Läärä, E. (Esa), Prokisch, H. (Holger), Grallert, H. (Harald), Lakka, T. A. (Timo A.), Lawlor, D. A. (Debbie A.), Melbye, M. (Mads), Ahluwalia, T. S. (Tarunveer S.), Marinelli, M. (Marcella), Millwood, I. Y. (Iona Y.), Palmer, L. J. (Lyle J.), Pennell, C. E. (Craig E.), Perry, J. R. (John R.), Ring, S. M. (Susan M.), Savolainen, M. J. (Markku J.), Rivadeneira, F. (Fernando), Standl, M. (Marie), Sunyer, J. (Jordi), Tiesler, C. M. (Carla M. T.), Uitterlinden, A. G. (Andre G.), Schierding, W. (William), O'Sullivan, J. M. (Justin M.), Prokopenko, I. (Inga), Herzig, K.-H. (Karl-Heinz), Smith, G. D. (George Davey), O'Reilly, P. (Paul), Felix, J. F. (Janine F.), Buxton, J. L. (Jessica L.), Blakemore, A. I. (Alexandra I. F.), Ong, K. K. (Ken K.), Jaddoe, V. W. (Vincent W. V.), Grant, S. F. (Struan F. A.), Sebert, S. (Sylvain), McCarthy, M. I. (Mark I.), Jarvelin, M.-R. (Marjo-Riitta), Alves, A. C. (Alexessander Couto), De Silva, N. M. (N. Maneka G.), Karhunen, V. (Ville), Sovio, U. (Ulla), Das, S. (Shikta), Taal, H. R. (H. Rob), Warrington, N. M. (Nicole M.), Lewin, A. M. (Alexandra M.), Kaakinen, M. (Marika), Cousminer, D. L. (Diana L.), Thiering, E. (Elisabeth), Timpson, N. J. (Nicholas J.), Bond, T. A. (Tom A.), Lowry, E. (Estelle), Brown, C. D. (Christopher D.), Estivill, X. (Xavier), Lindi, V. (Virpi), Bradfield, J. P. (Jonathan P.), Geller, F. (Frank), Speed, D. (Doug), Coin, L. J. (Lachlan J. M.), Loh, M. (Marie), Barton, S. J. (Sheila J.), Beilin, L. J. (Lawrence J.), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Alili, R. (Rohia), Hatoum, I. J. (Ida J.), Schramm, K. (Katharina), Cartwright, R. (Rufus), Charles, M.-A. (Marie-Aline), Salerno, V. (Vincenzo), Clement, K. (Karine), Claringbould, A. A. (Annique A. J.), van Duijn, C. M. (Cornelia M.), Moltchanova, E. (Elena), Eriksson, J. G. (Johan G.), Elks, C. (Cathy), Feenstra, B. (Bjarke), Flexeder, C. (Claudia), Franks, S. (Stephen), Frayling, T. M. (Timothy M.), Freathy, R. M. (Rachel M.), Elliott, P. (Paul), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Hattersley, A. T. (Andrew T.), Rodriguez, A. (Alina), Banterle, M. (Marco), Heinrich, J. (Joachim), Heude, B. (Barbara), Holloway, J. W. (John W.), Hofman, A. (Albert), Hypponen, E. (Elina), Inskip, H. (Hazel), Kaplan, L. M. (Lee M.), Hedman, A. K. (Asa K.), Läärä, E. (Esa), Prokisch, H. (Holger), Grallert, H. (Harald), Lakka, T. A. (Timo A.), Lawlor, D. A. (Debbie A.), Melbye, M. (Mads), Ahluwalia, T. S. (Tarunveer S.), Marinelli, M. (Marcella), Millwood, I. Y. (Iona Y.), Palmer, L. J. (Lyle J.), Pennell, C. E. (Craig E.), Perry, J. R. (John R.), Ring, S. M. (Susan M.), Savolainen, M. J. (Markku J.), Rivadeneira, F. (Fernando), Standl, M. (Marie), Sunyer, J. (Jordi), Tiesler, C. M. (Carla M. T.), Uitterlinden, A. G. (Andre G.), Schierding, W. (William), O'Sullivan, J. M. (Justin M.), Prokopenko, I. (Inga), Herzig, K.-H. (Karl-Heinz), Smith, G. D. (George Davey), O'Reilly, P. (Paul), Felix, J. F. (Janine F.), Buxton, J. L. (Jessica L.), Blakemore, A. I. (Alexandra I. F.), Ong, K. K. (Ken K.), Jaddoe, V. W. (Vincent W. V.), Grant, S. F. (Struan F. A.), Sebert, S. (Sylvain), McCarthy, M. I. (Mark I.), and Jarvelin, M.-R. (Marjo-Riitta)

Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

46. Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency

Author

Alston, CL, Heidler, J, Dibley, MG, Kremer, LS, Taylor, LS, Fratter, C, French, CE, Glasgow, RIC, Feichtinger, RG, Delon, I, Pagnamenta, AT, Dolling, H, Lemonde, H, Aiton, N, Bjørnstad, A, Henneke, L, Gärtner, J, Thiele, H, Tauchmannova, K, Quaghebeur, G, Houstek, J, Sperl, W, Raymond, FL, Prokisch, H, Mayr, JA, McFarland, R, Poulton, J, Ryan, MT, Wittig, I, Henneke, M, Taylor, RW, French, Courtney [0000-0001-7620-1544], Dolling, Helen [0000-0001-6279-3622], Raymond, Lucy [0000-0003-2652-3355], and Apollo - University of Cambridge Repository

Subjects
Male, Electron Transport Complex I, Mitochondrial Diseases, complex I, complexome profiling, Infant, Fibroblasts, Mitochondria, Mitochondrial Proteins, Complex I, Complexome Profiling, Mitochondrial Disease, Ndufa6, mitochondrial disease, Genetic Heterogeneity, NDUFA6, Phenotype, Report, Mutation, Humans, Female, ddc:610, Amino Acid Sequence, Sequence Alignment, Alleles
Abstract

Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the similar to 65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects' fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the similar to 830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.

Published
2018

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

Author

Xue, A., Wu, Y., Zhu, Z., Zhang, F., Kemper, K.E., Zheng, Z., Yengo, L., Lloyd-Jones, L.R., Sidorenko, J., Agbessi, M., Ahsan, H., Alves, I., Andiappan, A., Awadalla, P., Battle, A., Beutner, F., Bonder, M.J., Boomsma, D., Christiansen, M., Claringbould, A., Deelen, P., Esko, T., Favé, M.-J., Franke, L., Frayling, T., Gharib, S., Gibson, G., 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., Kutalik, Z., Lee, B., Lehtimäki, T., Loeffler, M., Marigorta, U.M., Metspalu, A., Milani, L., Müller-Nurasyid, M., Nauck, M., Nivard, M., Penninx, B., Perola, M., Pervjakova, N., Pierce, B., Powell, J., Prokisch, H., Psaty, B., Raitakari, O., Ring, S., Ripatti, S., Rotzschke, O., Ruëger, S., Saha, A., Scholz, M., Schramm, K., Seppälä, I., Stumvoll, M., Sullivan, P., Teumer, A., Thiery, J., Tong, L., Tönjes, A., van Dongen, J., van Meurs, J., Verlouw, J., Völker, U., Võsa, U., Yaghootkar, H., Zeng, B., McRae, A.F., Visscher, P.M., Zeng, J., Yang, J., Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Clinicum, Complex Disease Genetics, Psychiatry, APH - Digital Health, and Internal Medicine

Subjects
0301 basic medicine, Epigenomics, Netherlands Twin Register (NTR), endocrine system diseases, General Physics and Astronomy, Genome-wide association study, Epigenesis, Genetic, Genotype, lcsh:Science, Heat-Shock Proteins, Genetics, Multidisciplinary, Mitochondrial Proton-Translocating ATPases, 3. Good health, DNA methylation, Risk, endocrine system, Science, education, Biology, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, Humans, Genetic Predisposition to Disease, Epigenetics, Gene, Genetic association, Genetic Variation, nutritional and metabolic diseases, General Chemistry, DNA Methylation, 030104 developmental biology, Calcium-Calmodulin-Dependent Protein Kinase Type 1, Diabetes Mellitus, Type 2, Gene Expression Regulation, 3121 General medicine, internal medicine and other clinical medicine, lcsh:Q, 3111 Biomedicine, Carrier Proteins, human activities, Genome-Wide Association Study
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., GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.

Published
2018

48. A DNA methylation biomarker of alcohol consumption

Author

Liu, C, Marioni, R E, Hedman, Åsa K, Pfeiffer, L, Tsai, P-C, Reynolds, L M, Just, A C, Duan, Q, Boer, C G, Tanaka, T, Elks, C E, Aslibekyan, S, Brody, J A, Kühnel, B, Herder, C, Almli, L M, Zhi, D, Wang, Y, Huan, T, Yao, C, Mendelson, M M, Joehanes, R, Liang, L, Love, S-A, Guan, W, Shah, S, McRae, A F, Kretschmer, A, Prokisch, H, Strauch, K, Peters, A, Visscher, P M, Wray, N R, Guo, X, Wiggins, K L, Smith, A K, Binder, E B, Ressler, K J, Irvin, M R, Absher, D M, Hernandez, D, Ferrucci, L, Bandinelli, S, Lohman, K, Ding, J, Trevisi, L, Gustafsson, Stefan, Sandling, Johanna K., Stolk, L, Uitterlinden, A G, Yet, I, Castillo-Fernandez, J E, Spector, T D, Schwartz, J D, Vokonas, P, Lind, Lars, Li, Y, Fornage, M, Arnett, D K, Wareham, N J, Sotoodehnia, N, Ong, K K, van Meurs, J B J, Conneely, K N, Baccarelli, A A, Deary, I J, Bell, J T, North, K E, Liu, Y, Waldenberger, M, London, S J, Ingelsson, Erik, Levy, D, Wareham, Nicholas [0000-0003-1422-2993], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Erasmus MC other, Internal Medicine, and Epidemiology

Subjects
Adult, Male, Alcohol Drinking, Ethanol, Black People, DNA Methylation, Middle Aged, White People, Epigenesis, Genetic, Annan medicinsk grundvetenskap, Genetics, Humans, CpG Islands, Female, Other Basic Medicine, Alcohol-Related Disorders, Biomarkers, Aged, Genome-Wide Association Study
Abstract

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted PDe tio första författarna delar på förstaförfattarskapet. De sex sista författarna delar på sistaförfattarskapet.

Published
2018
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49. Association of methylation signals with incident coronary heart disease in an epigenome-wide assessment of circulating tumor necrosis factor α

Author

Aslibekyan, S. (Stella), Agha, G. (Golareh), Colicino, E. (Elena), Do, A. N. (Anh N.), Lahti, J. (Jari), Ligthart, S. (Symen), Marioni, R. E. (Riccardo E.), Marzi, C. (Carola), Mendelson, M. M. (Michael M.), Tanaka, T. (Toshiko), Wielscher, M. (Matthias), Absher, D. M. (Devin M.), Ferrucci, L. (Luigi), Franco, O. H. (Oscar H.), Gieger, C. (Christian), Grallert, H. (Harald), Hernandez, D. (Dena), Huan, T. (Tianxiao), Iurato, S. (Stella), Joehanes, R. (Roby), Just, A. C. (Allan C.), Kunze, S. (Sonja), Lin, H. (Honghuang), Liu, C. (Chunyu), Meigs, J. B. (James B.), van Meurs, J. B. (Joyce B.J.), Moore, A. Z. (Ann Zenobia), Peters, A. (Annette), Prokisch, H. (Holger), Räikkönen, K. (Katri), Rathmann, W. (Wolfgang), Roden, M. (Michael), Schramm, K. (Katharina), Schwartz, J. D. (Joel D.), Starr, J. M. (John M.), Uitterlinden, A. G. (André G.), Vokonas, P. (Pantel), Waldenberger, M. (Melanie), Yao, C. (Chen), Zhi, D. (Degui), Baccarelli, A. A. (Andrea A.), Bandinelli, S. (Stefania), Deary, I. J. (Ian J.), Dehghan, A. (Abbas), Eriksson, J. (Johan), Herder, C. (Christian), Järvelin, M.-R. (Marjo-Riitta), Levy, D. (Daniel), Arnett, D. K. (Donna K.), Aslibekyan, S. (Stella), Agha, G. (Golareh), Colicino, E. (Elena), Do, A. N. (Anh N.), Lahti, J. (Jari), Ligthart, S. (Symen), Marioni, R. E. (Riccardo E.), Marzi, C. (Carola), Mendelson, M. M. (Michael M.), Tanaka, T. (Toshiko), Wielscher, M. (Matthias), Absher, D. M. (Devin M.), Ferrucci, L. (Luigi), Franco, O. H. (Oscar H.), Gieger, C. (Christian), Grallert, H. (Harald), Hernandez, D. (Dena), Huan, T. (Tianxiao), Iurato, S. (Stella), Joehanes, R. (Roby), Just, A. C. (Allan C.), Kunze, S. (Sonja), Lin, H. (Honghuang), Liu, C. (Chunyu), Meigs, J. B. (James B.), van Meurs, J. B. (Joyce B.J.), Moore, A. Z. (Ann Zenobia), Peters, A. (Annette), Prokisch, H. (Holger), Räikkönen, K. (Katri), Rathmann, W. (Wolfgang), Roden, M. (Michael), Schramm, K. (Katharina), Schwartz, J. D. (Joel D.), Starr, J. M. (John M.), Uitterlinden, A. G. (André G.), Vokonas, P. (Pantel), Waldenberger, M. (Melanie), Yao, C. (Chen), Zhi, D. (Degui), Baccarelli, A. A. (Andrea A.), Bandinelli, S. (Stefania), Deary, I. J. (Ian J.), Dehghan, A. (Abbas), Eriksson, J. (Johan), Herder, C. (Christian), Järvelin, M.-R. (Marjo-Riitta), Levy, D. (Daniel), and Arnett, D. K. (Donna K.)

Abstract

Importance: Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision. Objective: To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings. Design, Setting, and Participants: This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events. Exposures: Circulating TNF-α concentration. Main Outcomes and Measures: DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease. Results: The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (β [SE] = −0.01 [0.003]; P = 7.36×10⁻⁸), cg08122652 (β [SE] = −0.008 [0.002]; P = 2.24×10⁻⁷), and cg22930808(β [SE] = −0.01 [0.002]; P = 6.92×10⁻⁸); NLRC5 at cg16411857 (β [SE] = −0.01 [0.002]; P = 2.14×10⁻¹³) and cg07839457 (β [SE] = −0.02 [0.003]; P = 6.31×10⁻¹⁰); or ABO, at cg13683939 (β [SE] = 0.04 [0.008]; P = 1.42×10⁻⁷) and cg24267699 (β [SE] = −0.009 [0.002]; P = 1.67 × 10⁻⁷), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-α–linked CpG sites were associ

Published
2018

50. A DNA methylation biomarker of alcohol consumption

Author

Liu, C. (C.), Marioni, R.E. (Riccardo), Hedman, A.K. (Asa), Pfeiffer, L. (L.), Tsai, P.-C. (P. C.), Reynolds, L.M. (Lindsay), Just, A.C. (A. C.), Duan, Q. (Qing), Boer, C.G. (Cindy), Tanaka, T. (T.), Elks, C.E. (Cathy), Aslibekyan, S. (S.), Brody, J.A. (Jennifer A.), Kuhnel, B. (Brigitte), Herder, C. (Christian), Almli, L.M. (L. M.), Zhi, D. (D.), Wang, Y. (Y.), Huan, T. (T.), Yao, C. (C.), Mendelson, M.M. (M. M.), Joehanes, R. (Roby), Liang, L. (Liming), Love, S.-A. (S. A.), Guan, W. (Weihua), Shah, S. (S.), McRae, A.F. (A. F.), Kretschmer, A. (A.), Prokisch, H. (Holger), Strauch, K. (K.), Peters, A. (Annette), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Guo, X. (Xiuqing), Wiggins, K.L. (Kerri), Smith, A.K. (A. K.), Binder, E.B. (Elisabeth), Ressler, K.J. (Kerry), Irvin, M.R. (M. R.), Absher, D.M. (D. M.), Hernandez, D.G. (Dena), Ferrucci, L. (Luigi), Bandinelli, S. (Stefania), Lohman, K. (K.), Ding, J. (J.), Trevisi, L. (L.), Gustafsson, S. (Stefan), Sandling, J.K. (Johanna), Stolk, L. (Lisette), Uitterlinden, A.G. (André), Yet, I. (Idil), Castillo-Fernandez, J.E. (J. E.), Spector, T.D. (Timothy), Schwartz, J.D. (J. D.), Vokonas, P. (P.), Kao, W.H.L. (Wen), Li, Y. (Y.), Fornage, M. (Myriam), Arnett, D.K. (Donna), Wareham, N.J. (Nick), Sotoodehnia, N. (Nona), Ong, K.K. (Ken), Meurs, J.B.J. (Joyce) van, Conneely, K.N. (Karen N.), Baccarelli, A.A. (A. A.), Deary, I.J. (Ian), Bell, J.T. (J. T.), North, K.E. (Kari), Liu, Y. (YongMei), Waldenberger, M. (M.), London, S.J. (S. J.), Ingelsson, E. (Erik), Levy, D. (D.), Liu, C. (C.), Marioni, R.E. (Riccardo), Hedman, A.K. (Asa), Pfeiffer, L. (L.), Tsai, P.-C. (P. C.), Reynolds, L.M. (Lindsay), Just, A.C. (A. C.), Duan, Q. (Qing), Boer, C.G. (Cindy), Tanaka, T. (T.), Elks, C.E. (Cathy), Aslibekyan, S. (S.), Brody, J.A. (Jennifer A.), Kuhnel, B. (Brigitte), Herder, C. (Christian), Almli, L.M. (L. M.), Zhi, D. (D.), Wang, Y. (Y.), Huan, T. (T.), Yao, C. (C.), Mendelson, M.M. (M. M.), Joehanes, R. (Roby), Liang, L. (Liming), Love, S.-A. (S. A.), Guan, W. (Weihua), Shah, S. (S.), McRae, A.F. (A. F.), Kretschmer, A. (A.), Prokisch, H. (Holger), Strauch, K. (K.), Peters, A. (Annette), Visscher, P.M. (Peter), Wray, N.R. (Naomi), Guo, X. (Xiuqing), Wiggins, K.L. (Kerri), Smith, A.K. (A. K.), Binder, E.B. (Elisabeth), Ressler, K.J. (Kerry), Irvin, M.R. (M. R.), Absher, D.M. (D. M.), Hernandez, D.G. (Dena), Ferrucci, L. (Luigi), Bandinelli, S. (Stefania), Lohman, K. (K.), Ding, J. (J.), Trevisi, L. (L.), Gustafsson, S. (Stefan), Sandling, J.K. (Johanna), Stolk, L. (Lisette), Uitterlinden, A.G. (André), Yet, I. (Idil), Castillo-Fernandez, J.E. (J. E.), Spector, T.D. (Timothy), Schwartz, J.D. (J. D.), Vokonas, P. (P.), Kao, W.H.L. (Wen), Li, Y. (Y.), Fornage, M. (Myriam), Arnett, D.K. (Donna), Wareham, N.J. (Nick), Sotoodehnia, N. (Nona), Ong, K.K. (Ken), Meurs, J.B.J. (Joyce) van, Conneely, K.N. (Karen N.), Baccarelli, A.A. (A. A.), Deary, I.J. (Ian), Bell, J.T. (J. T.), North, K.E. (Kari), Liu, Y. (YongMei), Waldenberger, M. (M.), London, S.J. (S. J.), Ingelsson, E. (Erik), and Levy, D. (D.)

Abstract

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal = 13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n = 6926) and identified 144 CpGs that provided substantial discrimination (area under the curve = 0.90-0.99) for current heavy alcohol intake (≥42 g per day in men and ≥28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1×10-7. Analysis of the monocyte-derived DNA (n = 1251) identified 62 alcohol-related CpGs at P<1×10-7. In whole-blood samples of people of European ancestry, we detected differen

Published
2018
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