From genome to phenome-Simple inborn errors of metabolism as complex traits

Biochimica et Biophysica Acta - Molecular Basis of Disease

Volumn 1842, Issue 10, 2014, Pages 2021-2029

  Touw, C M L ^a,b   Derks, T G J ^a   Bakker, B M ^a,b   Groen, A K ^a,b   Smit, G P A ^a   Reijngoud, D J ^a,b  

^a UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^b UNIVERSITY OF GRONINGEN   (Netherlands)

Author keywords

Electron transport chain; FADH2; Mitochondrial fatty acid oxidation; NADH; Oxidative phosphorylation; Signaling pathway

Indexed keywords

COMPLEX I NADH DEHYDROGENASE DEFECT; COMPLEX II SUCCINATE DEHYDROGENASE DEFECT; COMPLEX III CYTOCHROME BC1 COMPLEX DEFECT; COMPLEX IV CYTOCHROME C OXIDASE DEFECT; DISEASE ASSOCIATION; FATTY ACID OXIDATION; GENOME; HUMAN; INBORN ERROR OF METABOLISM; LONG CHAIN MITOCHONDRIAL FATTY ACID OXIDATION DEFECT; MEDIUM CHAIN MITOCHONDRIAL FATTY ACID OXIDATION DEFECT; MITOCHONDRIAL FATTY ACID OXIDATION; MULTIPLE ACYL COA DEHYDROGENASE DEFICIENCY; NONHUMAN; OXIDATIVE PHOSPHORYLATION; OXIDATIVE PHOSPHORYLATION DEFECT; PHENOTYPE; REVIEW; SECONDARY FATTY ACID OXIDATION DEFECT; SECONDARY OXIDATIVE PHOSPHORYLATION DYSFUNCTION; SHORT CHAIN MITOCHONDRIAL FATTY ACID OXIDATION DEFECT; SIGNAL TRANSDUCTION;

EID: 84908325269     PISSN: 09254439     EISSN: 1879260X     Source Type: Journal    
DOI: 10.1016/j.bbadis.2014.05.032     Document Type: Review

References (84)

1. Scriver C.R. After the genome-the phenome?. J. Inherit. Metab. Dis. 2004, 27:305-317.
2. Munnich A., Rotig A., Cormier-Daire V., Rustin P. Disorders of mitochondria function: clinical presentation of respiratory chain deficiency. The Online Metabolic and Molecular Basis of Inherited Disease 2005, McGraw-Hill. D. Valle (Ed.).
3. Roe C.R., Ding J. Disorders of mitochondrial function: mitochondrial fatty acid oxidation disorders. The Online Metabolic and Molecular Basis of Inherited Disease 2005, McGraw-Hill. D. Valle (Ed.).
4. Scaglia F., Towbin J.A., Craigen W.J., Belmont J.W., Smith E.O., Neish S.R., Ware S.M., Hunter J.V., Fernbach S.D., Vladutiu G.D., Wong L.J., Vogel H. Clinical spectrum, morbidity, and mortality in 113 pediatric patients with mitochondrial disease. Pediatrics 2004, 114:925-931.
5. Wilcken B. Fatty acid oxidation disorders: outcome and long-term prognosis. J. Inherit. Metab. Dis. 2010, 33:501-506.
6. van Maldegem B.T., Wanders R.J., Wijburg F.A. Clinical aspects of short-chain acyl-CoA dehydrogenase deficiency. J. Inherit. Metab. Dis. 2010, 33:507-511.
7. Horvath R. Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10). J. Inherit. Metab. Dis. 2012, 35:679-687.
8. Munnich A. Defects of the respiratory chain. Inborn Metabolic Diseases: Diagnosis and Treatment 2006, vol. 4th:197-210. J. Fernandes, J.M. Saudubray, G. Berghe, J.H. Walter (Eds.).
9. Parker A., Engel P.C. Preliminary evidence for the existence of specific functional assemblies between enzymes of the beta-oxidation pathway and the respiratory chain. Biochem. J. 2000, 345(Pt 3):429-435.
10. +]/[NADH] and [acetyl-CoA]/[CoA. Biochim. Biophys. Acta 1998, 1429:230-238.
11. Robinson B.H. Part 10: disorders of mitochondrial function, chapter 100: lactic acidaemia: disorders of pyruvate carboxylase and pyruvate dehydrogenase. The Online Metabolic and Molecular Basis of Inherited Disease 2005, McGraw-Hill. D. Valle (Ed.).
12. Pessayre D., Mansouri A., Haouzi D., Fromenty B. Hepatotoxicity due to mitochondrial dysfunction. Cell Biol. Toxicol. 1999, 15:367-373.
13. Kerstann K., Brown M.D., Vockley I., Wallace D.C. Chapter 105: mitochondria and neuro-ophthalmologic diseases. The Online Metabolic and Molecular Basis of Inherited Disease 2005, McGraw-Hill. D. Valle (Ed.).
14. Xu Q., Vu H., Liu L., Wang T.C., Schaefer W.H. Metabolic profiles show specific mitochondrial toxicities in vitro in myotube cells. J. Biomol. NMR 2011, 49:207-219.
15. Sue C.M., Hirano M., DiMauro S., De Vivo D.C. Neonatal presentations of mitochondrial metabolic disorders. Semin. Perinatol. 1999, 23:113-124.
16. Gargus J.J., Boyle K., Bocian M., Roe D.S., Vianey-Saban C., Roe C.R. Respiratory complex II defect in siblings associated with a symptomatic secondary block in fatty acid oxidation. J. Inherit. Metab. Dis. 2003, 26:659-670.
17. Goetzman E.S., Wang Y., He M., Mohsen A.W., Ninness B.K., Vockley J. Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. Mol. Genet. Metab. 2007, 91:138-147.
18. McAndrew R.P., Wang Y., Mohsen A.W., He M., Vockley J., Kim J.J. Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. J. Biol. Chem. 2008, 283:9435-9443.
19. Frerman F.E. Acyl-CoA dehydrogenases, electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase. Biochem. Soc. Trans. 1988, 16:416-418.
20. Sumegi B., Srere P.A. Complex I binds several mitochondrial NAD-coupled dehydrogenases. J. Biol. Chem. 1984, 259:15040-15045.
21. Kispal G., Sumegi B., Alkonyi I. Isolation and characterization of 3-hydroxyacyl coenzyme A dehydrogenase-binding protein from pig heart inner mitochondrial membrane. J. Biol. Chem. 1986, 261:14209-14213.
22. Wang Y., Mohsen A.W., Mihalik S.J., Goetzman E.S., Vockley J. Evidence for the Physical Association of Mitochondrial Fatty Acid Oxidation and Oxidative Phosphorylation Complexes. J. Biol. Chem. 2010, 285(39):29834-29841.
23. Schagger H. Respiratory chain supercomplexes. IUBMB Life 2001, 52:119-128.
24. Lapuente-Brun E., Moreno-Loshuertos H., Acin-Perez R., Latorre-Pellicer A., Colas C., Balsa E., Perales-Clemente E., Quiros P.M., Calvo E., Rodriguez-Hernandez M.A., Navas P., Cruz R., Carracedo A., Lopez-Otin C., Perez-Martos A., Fernandez-Silva P., Fernandez-Vizarra E., Enriquez J.A. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain 2013, 340:1567-1570.
25. Maranzana E., Barbero G., Falasca A.I., Lenaz G., Genova M.L. Mitochondrial respiratory supercomplex association limits production of reactive oxygen species from complex I. Antioxid. Redox Signal. 2013, 19(13):1469-1480.
26. Eaton S., Pourfarzam M., Bartlett K. The effect of respiratory chain impairment of beta-oxidation in rat heart mitochondria. Biochem. J. 1996, 319(Pt 2):633-640.
27. Bremer J. Pyruvate dehydrogenase, substrate specificity and product inhibition. Eur. J. Biochem. 1969, 8:535-540.
28. Infante J.P., Huszagh V.A. Secondary carnitine deficiency and impaired docosahexaenoic (22:6n-3) acid synthesis: a common denominator in the pathophysiology of diseases of oxidative phosphorylation and beta-oxidation. FEBS Lett. 2000, 468:1-5.
29. Mayatepek E., Wanders R.J., Becker M., Bremer H.J., Hoffmann G.F. Mitochondropathy presenting with non-ketotic hypoglycaemia as 3-hydroxydicarboxylic aciduria. J. Inherit. Metab. Dis. 1995, 18:249-252.
30. Koene S., Rodenburg R.J., van der Knaap M.S., Willemsen M.A., Sperl W., Laugel V., Ostergaard E., Tarnopolsky M., Martin M.A., Nesbitt V., Fletcher J., Edvardson S., Procaccio V., Slama A., van den Heuvel L.P., Smeitink J.A. Natural disease course and genotype-phenotype correlations in complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. J. Inherit. Metab. Dis. 2012, 35:737-747.
31. Bonnefont J.P., Specola N.B., Vassault A., Lombes A., Ogier H., de Klerk J.B., Munnich A., Coude M., Paturneau-Jouas M., Saudubray J.M. The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur. J. Pediatr. 1990, 150:80-85.
32. Watmough N.J., Bindoff L.A., Birch-Machin M.A., Jackson S., Bartlett K., Ragan C.I., Poulton J., Gardiner R.M., Sherratt H.S., Turnbull D.M. Impaired mitochondrial beta-oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria. J. Clin. Invest. 1990, 85:177-184.
33. Beckmann J.D., Frerman F.E., McKean M.C. Inhibition of general acyl CoA dehydrogenase by electron transfer flavoprotein semiquinone. Biochem. Biophys. Res. Commun. 1981, 102:1290-1294.
34. Enns G.M., Bennett M.J., Hoppel C.L., Goodman S.I., Weisiger K., Ohnstad C., Golabi M., Packman S. Mitochondrial respiratory chain complex I deficiency with clinical and biochemical features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. J. Pediatr. 2000, 136:251-254.
35. 3H] palmitate by human leukocytes: a simple in situ assay to assess mitochondrial toxicity in the presence of toxins. Toxicol. Mech. Methods 2000, 10:99-109.
36. Venizelos N., von Dobeln U., Hagenfeldt L. Fatty acid oxidation in fibroblasts from patients with defects in beta-oxidation and in the respiratory chain. J. Inherit. Metab. Dis. 1998, 21:409-415.
37. Sim K.G., Carpenter K., Hammond J., Christodoulou J., Wilcken B. Acylcarnitine profiles in fibroblasts from patients with respiratory chain defects can resemble those from patients with mitochondrial fatty acid beta-oxidation disorders. Metabolism 2002, 51:366-371.
38. Mochel F., Slama A., Touati G., Desguerre I., Giurgea I., Rabier D., Brivet M., Rustin P., Saudubray J.M., DeLonlay P. Respiratory chain defects may present only with hypoglycemia. J. Clin. Endocrinol. Metab. 2005, 90:3780-3785.
39. van Eunen K., Simons S.M.J., Gerding A., Bleeker A., den Besten G., Touw C.M.L., Houten S.M., Groen A.K., Krab K., Reijngoud D.J., Bakker B.M. Biochemical competition makes fatty-acid beta-oxidation vulnerable to substrate overload. PLoS Comput. Biol. 2013, 9(8):e1003186.
40. Lehnert W., Ruitenbeek W. Ethylmalonic aciduria associated with progressive neurological disease and partial cytochrome c oxidase deficiency. J. Inherit. Metab. Dis. 1993, 16:557-559.
41. Christensen E., Brandt N.J., Schmalbruch H., Kamieniecka Z., Hertz B., Ruitenbeek W. Muscle cytochrome c oxidase deficiency accompanied by a urinary organic acid pattern mimicking multiple acyl-CoA dehydrogenase deficiency. J. Inherit. Metab. Dis. 1993, 16:553-556.
42. Amendt B.A., Freneaux E., Reece C., Wood P.A., Rhead W.J. Short-chain acyl-coenzyme A dehydrogenase activity, antigen, and biosynthesis are absent in the BALB/cByJ mouse. Pediatr. Res. 1992, 31:552-556.
43. Das A.M., Fingerhut R., Wanders R.J., Ullrich K. Secondary respiratory chain defect in a boy with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: possible diagnostic pitfalls. Eur. J. Pediatr. 2000, 159:243-246.
44. Grunewald S., Bakkeren J., Wanders R.A., Wendel U. Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect. J. Inherit. Metab. Dis. 1997, 20:835-836.
45. Hui J., Kirby D.M., Thorburn D.R., Boneh A. Decreased activities of mitochondrial respiratory chain complexes in non-mitochondrial respiratory chain diseases. Dev. Med. Child Neurol. 2006, 48:132-136.
46. Tyni T., Majander A., Kalimo H., Rapola J., Pihko H. Pathology of skeletal muscle and impaired respiratory chain function in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528C mutation. Neuromuscul. Disord. 1996, 6:327-337.
47. Ventura F.V., Ruiter J.P., Ijlst L., Almeida I.T., Wanders R.J. Inhibition of oxidative phosphorylation by palmitoyl-CoA in digitonin permeabilized fibroblasts: implications for long-chain fatty acid beta-oxidation disorders. Biochim. Biophys. Acta 1995, 1272:14-20.
48. Ventura F.V., Ruiter J.P., Ijlst L., de Almeida I.T., Wanders R.J. Inhibitory effect of 3-hydroxyacyl-CoAs and other long-chain fatty acid beta-oxidation intermediates on mitochondrial oxidative phosphorylation. J. Inherit. Metab. Dis. 1996, 19:161-164.
49. Ventura F.V., Ruiter J., Ijlst L., de Almeida I.T., Wanders R.J. Differential inhibitory effect of long-chain acyl-CoA esters on succinate and glutamate transport into rat liver mitochondria and its possible implications for long-chain fatty acid oxidation defects. Mol. Genet. Metab. 2005, 86:344-352.
50. Ventura F.V., Tavares de Almeida I., Wanders R.J. Inhibition of adenine nucleotide transport in rat liver mitochondria by long-chain acyl-coenzyme A beta-oxidation intermediates. Biochem. Biophys. Res. Commun. 2007, 352:873-878.
51. Tonin A.M., Ferreira G.C., Grings M., Viegas C.M., Busanello E.N., Amaral A.U., Zanatta A., Schuck P.F., Wajner M. Disturbance of mitochondrial energy homeostasis caused by the metabolites accumulating in LCHAD and MTP deficiencies in rat brain. Life Sci. 2010, 86:825-831.
52. Ciapaite J., van Eikenhorst G., Bakker S.J., Diamant M., Heine R.J., Wagner M.J., Westerhoff H.V., Krab K. Modular kinetic analysis of the adenine nucleotide translocator-mediated effects of palmitoyl-CoA on the oxidative phosphorylation in isolated rat liver mitochondria. Diabetes 2005, 54:944-951.
53. Tonin A.M., Amaral A.U., Busanello E.N., Grings M., Castilho R.F., Wajner M. Long-chain 3-hydroxy fatty acids accumulating in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial trifunctional protein deficiencies uncouple oxidative phosphorylation in heart mitochondria. J. Bioenerg. Biomembr. 2013, 45:47-57.
54. Borst P., Loos J.A., Christ E.J., Slater E.C. Uncoupling activity of long-chain fatty acids. Biochim. Biophys. Acta 1962, 62:509-518.
55. Nedergaard J., Ricquier D., Kozak L.P. Uncoupling proteins: current status and therapeutic prospects. EMBO Rep. 2005, 6:917-921.
56. Schuck P.F., Ferreira Gda C., Tonin A.M., Viegas C.M., Busanello E.N., Moura A.P., Zanatta A., Klamt F., Wajner M. Evidence that the major metabolites accumulating in medium-chain acyl-CoA dehydrogenase deficiency disturb mitochondrial energy homeostasis in rat brain. Brain Res. 2009, 1296:117-126.
57. Schuck P.F., Ferreira Gda C., Tahara E.B., Klamt F., Kowaltowski A.J., Wajner M. cis-4-decenoic acid provokes mitochondrial bioenergetic dysfunction in rat brain. Life Sci. 2010, 87:139-146.
58. Reis de Assis D., Maria Rde C., Borba Rosa R., Schuck P.F., Ribeiro C.A., Costa Ferreira G., Dutra-Filho C.S., Terezinha de Souza Wyse A., Duval Wannmacher C.M., Santos Perry M.L., Wajner M. Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency. Brain Res. 2004, 1030:141-151.
59. Wojtczak A.B., Lenartowicz E., Rodionova M.A., Duszynski J. Effect of fatty acids on pyruvate carboxylation in rat liver mitochondria. FEBS Lett. 1972, 28:253-258.
60. Hird F.J., Weidemann M.J. Oxidative phosphorylation accompanying oxidation of short-chain fatty acids by rat-liver mitochondria. Biochem. J. 1966, 98:378-388.
61. Sauer S.W., Okun J.G., Hoffmann G.F., Koelker S., Morath M.A. Impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on mitochondrial energy metabolism. Biochim. Biophys. Acta 2008, 1777:1276-1282.
62. Ferreira Gda C., Andre K.R., Schuck P.F., Viegas C.M., Tonin A., Coelho Dde M., Wyse A.T., Wannmacher C.M., Vargas C.R., Wajner M. Effect of in vivo administration of ethylmalonic acid on energy metabolism in rat tissues. Metab. Brain Dis. 2006, 21:29-39.
63. Hatefi Y., Stempel K.E. Resolution of complex I (DPNH-coenzyme Q reductase) of the mitochondrial electron transfer system. Biochem. Biophys. Res. Commun. 1967, 26:301-308.
64. Barschak A.G., Ferreira Gda C., Andre K.R., Schuck P.F., Viegas C.M., Tonin A., Dutra Filho C.S., Wyse A.T.S., Wannmacher C.M.D., Vargas C.R., Wajner M. Inhibition of the electron transport chain and creatine kinase activity by ethylmalonic acid in human skeletal muscle. Metab. Brain Dis. 2006, 21:11-19.
65. Antozzi C., Garavaglia B., Mora M., Rimoldi M., Morandi L., Ursino E., DiDonato S. Late-onset riboflavin-responsive myopathy with combined multiple acyl coenzyme A dehydrogenase and respiratory chain deficiency. Neurology 1994, 44:2153-2158.
66. Gianazza E., Vergani L., Wait R., Brizio C., Brambilla D., Begum S., Giancaspero T.A., Conserva F., Eberini I., Bufano D., Angelini C., Pegoraro E., Tramontano A., Barile M. Coordinated and reversible reduction of enzymes involved in terminal oxidative metabolism in skeletal muscle mitochondria from a riboflavin-responsive, multiple acyl-CoA dehydrogenase deficiency patient. Electrophoresis 2006, 27:1182-1198.
67. Liang W.C., Ohkuma A., Hayashi Y.K., Lopez L.C., Hirano M., Nonaka I., Noguchi S., Chen L.H., Jong Y.J., Nishino I. ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. Neuromuscul. Disord. 2009, 19:212-216.
68. Cornelius N., Byron C., Hargreaves I., Guerra P.F., Furdek A.K., Land J., Radford W.W., Frerman F., Corydon T.J., Gregersen N., Olsen R.K. Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency. Hum. Mol. Genet. 2013, 22:3819-3827.
69. Zhang Z., Tsukikawa M., Peng M., Polyak E., Nakamaru-Ogiso E., Ostrovsky J., McCormack S., Place E., Clarke C., Reiner G., McCormick E., Rappaport E., Haas R., Baur J.A., Falk M.J. Primary respiratory chain disease causes tissue-specific dysregulation of the global transcriptome and nutrient-sensing signaling network. PLoS One 2013, 8:e69282.
70. Karamanlidis G., Lee C.F., Garcia-Menendez L., Kolwicz S.C., Suthammarak W., Gong G., Sedensky M.M., Morgan P.G., Wang W., Tian R. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 2013, 18:239-250.
71. Johnson S.C., Yanos M.E., Kayser E.B., Quintana A., Sangesland M., Castanza A., Uhde L., Hui J., Wall V.Z., Gagnidze A., Oh K., Wasko B.M., Ramos F.J., Palmiter R.D., Rabinovitch P.S., Morgan P.G., Sedensky M.M., Kaeberlein M. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 2013, 342:1524-1528.
72. Tyynismaa H., Carroll C.J., Raimundo N., Ahola-Erkkila S., Wenz T., Ruhanen H., Guse K., Hemminki A., Peltola-Mjosund K.E., Tulkki V., Oresic M., Moraes C.T., Pietilainen K., Hovatta I., Suomalainen A. Mitochondrial myopathy induces a starvation-like response. Hum. Mol. Genet. 2010, 19:3948-3958.
73. Kim S.H., Scott S.A., Bennett M.J., Carson R.P., Fessel J., Brown H.A., Ess K.C. Multi-organ abnormalities and mTORC1 activation in zebrafish model of multiple acyl-CoA dehydrogenase deficiency. PLoS Genet. 2013, 9:e1003563.
74. Houten S.M., Herrema H., Te Brinke H., Denis S., Ruiter J.P., van Dijk T.H., Argmann C.A., Ottenhoff R., Muller M., Groen A.K., Kuipers F., Reijngoud D.J., Wanders R.J. Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects. Hum. Mol. Genet. 2013.
75. Munnich A., Rotig A., Chretien D., Saudubray J.M., Cormier V., Rustin P. Clinical presentations and laboratory investigations in respiratory chain deficiency. Eur. J. Pediatr. 1996, 155:262-274.
76. Vafai S.B., Mootha V.K. Medicine. A common pathway for a rare disease?. Science 2013, 342:1453-1454.
77. Westermann B., Neupert W. 'Omics' of the mitochondrion. Nat. Biotechnol. 2003, 21:239-240.
78. Lamari F., Mochel F., Sedel F., Saudubray J.M. Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases. J. Inherit. Metab. Dis. 2013, 36:411-425.
79. Wortmann S.B., Vaz F.M., Gardeitchik T., Vissers L.E., Renkema G.H., Schuurs-Hoeijmakers J.H., Kulik W., Lammens M., Christin C., Kluijtmans L.A., Rodenburg R.J., Nijtmans L.G., Grunewald A., Klein C., Gerhold J.M., Kozicz T., van Hasselt P.M., Harakalova M., Kloosterman W., Baric I., Pronicka E., Ucar S.K., Naess K., Singhal K.K., Krumina Z., Gilissen C., van Bokhoven H., Veltman J.A., Smeitink J.A., Lefeber D.J., Spelbrink J.N., Wevers R.A., Morava E., de Brouwer A.P. Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat. Genet. 2012, 44:797-802.
80. Illig T., Gieger C., Zhai G., Romisch-Margl W., Wang-Sattler R., Prehn C., Altmaier E., Kastenmuller G., Kato B.S., Mewes H.W., Meitinger T., de Angelis M.H., Kronenberg F., Soranzo N., Wichmann H.E., Spector T.D., Adamski J., Suhre K. A genome-wide perspective of genetic variation in human metabolism. Nat. Genet. 2010, 42:137-141.
81. Petersen A.K., Zeilinger S., Kastenmuller G., Romisch-Margl W., Brugger M., Peters A., Meisinger C., Strauch K., Hengstenberg C., Pagel P., Huber F., Mohney R.P., Grallert H., Illig T., Adamski J., Waldenberger M., Gieger C., Suhre K. Epigenetics meets metabolomics: an epigenome-wide association study with blood serum metabolic traits. Hum. Mol. Genet. 2014, 23:534-545.
82. Kohler S., Doelken S.C., Mungall C.J., Bauer S., Firth H.V., Bailleul-Forestier I., Black G.C., Brown D.L., Brudno M., Campbell J., FitzPatrick D.R., Eppig J.T., Jackson A.P., Freson K., Girdea M., Helbig I., Hurst J.A., Jahn J., Jackson L.G., Kelly A.M., Ledbetter D.H., Mansour S., Martin C.L., Moss C., Mumford A., Ouwehand W.H., Park S.M., Riggs E.R., Scott R.H., Sisodiya S., Van Vooren S., Wapner R.J., Wilkie A.O., Wright C.F., Vulto-van Silfhout A.T., de Leeuw N., de Vries B.B., Washingthon N.L., Smith C.L., Westerfield M., Schofield P., Ruef B.J., Gkoutos G.V., Haendel M., Smedley D., Lewis S.E., Robinson P.N. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data. Nucleic Acids Res. 2014, 42:D966-D974.
83. Oetting W.S., Robinson P.N., Greenblatt M.S., Cotton R.G., Beck T., Carey J.C., Doelken S.C., Girdea M., Groza T., Hamilton C.M., Hamosh A., Kerner B., MacArthur J.A., Maglott D.R., Mons B., Rehm H.L., Schofield P.N., Searle B.A., Smedley D., Smith C.L., Bernstein I.T., Zankl A., Zhao E.Y. Getting ready for the Human Phenome Project: the 2012 forum of the Human Variome Project. Hum. Mutat. 2013, 34:661-666.
84. Riggs E.R., Jackson L., Miller D.T., Van Vooren S. Phenotypic information in genomic variant databases enhances clinical care and research: the International Standards for Cytogenomic Arrays Consortium experience. Hum. Mutat. 2012, 33:787-796.