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Genetics and Epigenetics

Repeat length variations in polyglutamine disease-associated genes affect body mass index

International Journal of Obesity volume 43, pages 440–449 (2019)Cite this article

Subjects

Abstract

Background

The worldwide prevalence of obesity, a major risk factor for numerous debilitating chronic disorders, is increasing rapidly. Although a substantial amount of the variation in body mass index (BMI) is estimated to be heritable, the largest meta-analysis of genome-wide association studies (GWAS) to date explained only ~2.7% of the variation. To tackle this ‘missing heritability’ problem of obesity, here we focused on the contribution of DNA repeat length polymorphisms which are not detectable by GWAS.

Subjects and methods

We determined the cytosine–adenine–guanine (CAG) repeat length in the nine known polyglutamine disease-associated genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1 and AR) in two large cohorts consisting of 12,457 individuals and analyzed their association with BMI, using generalized linear mixed-effect models.

Results

We found a significant association between BMI and the length of CAG repeats in seven polyglutamine disease-associated genes (including ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP and AR). Importantly, these repeat variations could account for 0.75% of the total BMI variation.

Conclusions

Our findings incriminate repeat polymorphisms as an important novel class of genetic risk factors of obesity and highlight the role of the brain in its pathophysiology.

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References

  1. WHO. Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organization technical report series. 2000;894:i–xii, 1–253.

  2. Chagnon YC, Perusse L, Bouchard C. Familial aggregation of obesity, candidate genes and quantitative trait loci. Curr Opin Lipidol. 1997;8:205–11.

    Article  CAS  PubMed  Google Scholar 

  3. Chung WK. An overview of mongenic and syndromic obesities in humans. Pediatr Blood Cancer. 2012;58:122–8.

    Article  PubMed  Google Scholar 

  4. Goran MI. Genetic influences on human energy expenditure and substrate utilization. Behav Genet. 1997;27:389–99.

    Article  CAS  PubMed  Google Scholar 

  5. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hannan AJ. Tandem repeat polymorphisms: modulators of disease susceptibility and candidates for ‘missing heritability’. Trends Genet. 2010;26:59–65.

    Article  CAS  PubMed  Google Scholar 

  7. Hannan AJ. TRPing up the genome: tandem repeat polymorphisms as dynamic sources of genetic variability in health and disease. Discov Med. 2010;10:314–21.

    PubMed  Google Scholar 

  8. Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010;363:166–76.

    Article  CAS  PubMed  Google Scholar 

  9. Duitama J, Zablotskaya A, Gemayel R, Jansen A, Belet S, Vermeesch JR, et al. Large-scale analysis of tandem repeat variability in the human genome. Nucleic Acids Res. 2014;42:5728–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bettencourt C, Hensman-Moss D, Flower M, Wiethoff S, Brice A, Goizet C, et al. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases. Ann Neurol. 2016;79:983–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fan HC, Ho LI, Chi CS, Chen SJ, Peng GS, Chan TM, et al. Polyglutamine (PolyQ) diseases: genetics to treatments. Cell Transplant. 2014;23:441–58.

    Article  PubMed  Google Scholar 

  12. Gardiner SL, van Belzen MJ, Boogaard MW, van Roon-Mom WMC, Rozing MP, van Hemert AM, et al. Large normal-range TBP and ATXN7 CAG repeat lengths are associated with increased lifetime risk of depression. Transl Psychiatry. 2017;7:e1143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gardiner SL, van Belzen MJ, Boogaard MW, van Roon-Mom WMC, Rozing MP, van Hemert AM, et al. Huntington gene repeat size variations affect risk of lifetime depression. Transl Psychiatry. 2017;7:1277–84

  14. Killoran A, Biglan KM, Jankovic J, Eberly S, Kayson E, Oakes D, et al. Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS. Neurology. 2013;80:2022–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. de Mutsert R, den Heijer M, Rabelink TJ, Smit JW, Romijn JA, Jukema JW, et al. The Netherlands Epidemiology of Obesity (NEO) study: study design and data collection. Eur J Epidemiol. 2013;28:513–23.

    Article  PubMed  Google Scholar 

  16. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30.

    Article  CAS  PubMed  Google Scholar 

  17. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–91.

    Article  PubMed  Google Scholar 

  18. Tezenas du MS, Durr A, Bauer P, Figueroa KP, Ichikawa Y, Brussino A, et al. Modulation of the age at onset in spinocerebellar ataxia by CAG tracts in various genes. Brain. 2014;137:2444–55.

    Article  Google Scholar 

  19. Shiffman D, Trompet S, Louie JZ, Rowland CM, Catanese JJ, Iakoubova OA, et al. Genome-wide study of gene variants associated with differential cardiovascular event reduction by pravastatin therapy. PLoS ONE. 2012;7:e38240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Blauw LL, Noordam R, Trompet S, Berbee JFP, Rosendaal FR, van Heemst D, et al. Genetic variation in the obesity gene FTO is not associated with decreased fat oxidation: the NEO study. Int J Obes (Lond). 2017;41:1594–600.

    Article  CAS  Google Scholar 

  21. Nakagawa S, Schielzeth H. A general and simple method for obtaining R2 from generalized linear mixed-effects models. Methods Ecol Evol. 2013;4:9.

    Article  Google Scholar 

  22. Benjamini Y, Hochberg Y. Controling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B (Methodol). 1995;57:289–300.

    Google Scholar 

  23. Aziz NA, van der Marck MA, Pijl H, Olde Rikkert MG, Bloem BR, Roos RA. Weight loss in neurodegenerative disorders. J Neurol. 2008;255:1872–80.

    Article  CAS  PubMed  Google Scholar 

  24. Saute JA, da Silva AC, Muller AP, Hansel G, de Mello AS, Maeda F, et al. Serum insulin-like system alterations in patients with spinocerebellar ataxia type 3. Mov Disord. 2011;26:731–5.

    Article  PubMed  Google Scholar 

  25. Saute JA, Silva AC, Souza GN, Russo AD, Donis KC, Vedolin L, et al. Body mass index is inversely correlated with the expanded CAG repeat length in SCA3/MJD patients. Cerebellum. 2012;11:771–4.

    Article  CAS  PubMed  Google Scholar 

  26. Schmitz-Hubsch T, Coudert M, Bauer P, Giunti P, Globas C, Baliko L, et al. Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms. Neurology. 2008;71:982–9.

    Article  CAS  PubMed  Google Scholar 

  27. Mahler A, Steiniger J, Endres M, Paul F, Boschmann M, Doss S. Increased catabolic state in spinocerebellar ataxia type 1 patients. Cerebellum. 2014;13:440–6.

    Article  PubMed  Google Scholar 

  28. Ashkenazi A, Bento CF, Ricketts T, Vicinanza M, Siddiqi F, Pavel M, et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature. 2017;545:108–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gustafson DR, Wen MJ, Koppanati BM. Androgen receptor gene repeats and indices of obesity in older adults. Int J Obes Relat Metab Disord. 2003;27:75–81.

    Article  CAS  PubMed  Google Scholar 

  30. Zitzmann M, Gromoll J, von Eckardstein A, Nieschlag E. The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men. Diabetologia. 2003;46:31–9.

    Article  CAS  PubMed  Google Scholar 

  31. Kiehl TR, Nechiporuk A, Figueroa KP, Keating MT, Huynh DP, Pulst SM. Generation and characterization of Sca2 (ataxin-2) knockout mice. Biochem Biophys Res Commun. 2006;339:17–24.

    Article  CAS  PubMed  Google Scholar 

  32. Lastres-Becker I, Brodesser S, Lutjohann D, Azizov M, Buchmann J, Hintermann E, et al. Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice. Hum Mol Genet. 2008;17:1465–81.

    Article  CAS  PubMed  Google Scholar 

  33. Shibata H, Huynh DP, Pulst SM. A novel protein with RNA-binding motifs interacts with ataxin-2. Hum Mol Genet. 2000;9:1303–13.

    Article  CAS  PubMed  Google Scholar 

  34. Carmo-Silva S, Nobrega C, Pereira de Almeida L, Cavadas C. Unraveling the role of ataxin-2 in metabolism. Trends Endocrinol Metab. 2017;28:309–18.

    Article  CAS  PubMed  Google Scholar 

  35. Arkova OV, Ponomarenko MP, Rasskazov DA, Drachkova IA, Arshinova TV, Ponomarenko PM, et al. Obesity-related known and candidate SNP markers can significantly change affinity of TATA-binding protein for human gene promoters. BMC Genomics. 2015;16:S5. Suppl 13

    Article  PubMed  PubMed Central  Google Scholar 

  36. Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BW, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry. 2010;67:220–9.

    Article  PubMed  Google Scholar 

  37. Helmlinger D, Hardy S, Eberlin A, Devys D, Tora L. Both normal and polyglutamine- expanded ataxin-7 are components of TFTC-type GCN5 histone acetyltransferase-containing complexes. Biochem Soc Symp. 2006;73:155–63.

    Article  CAS  Google Scholar 

  38. Emery CF, Fondow MD, Schneider CM, Christofi FL, Hunt C, Busby AK, et al. Gastric bypass surgery is associated with reduced inflammation and less depression: a preliminary investigation. Obes Surg. 2007;17:759–63.

    Article  PubMed  Google Scholar 

  39. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132:2169–80.

    Article  CAS  PubMed  Google Scholar 

  40. Vaccarino V, Johnson BD, Sheps DS, Reis SE, Kelsey SF, Bittner V, et al. Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study. J Am Coll Cardiol. 2007;50:2044–50.

    Article  PubMed  Google Scholar 

  41. Bremmer MA, Beekman AT, Deeg DJ, Penninx BW, Dik MG, Hack CE, et al. Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord. 2008;106:249–55.

    Article  CAS  PubMed  Google Scholar 

  42. Milaneschi Y, Corsi AM, Penninx BW, Bandinelli S, Guralnik JM, Ferrucci L. Interleukin-1 receptor antagonist and incident depressive symptoms over 6 years in older persons: the InCHIANTI study. Biol Psychiatry. 2009;65:973–8.

    Article  CAS  PubMed  Google Scholar 

  43. Pasquali R, Vicennati V. Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Int J Obes Relat Metab Disord. 2000;24 Suppl 2:S47–9.

    Article  CAS  PubMed  Google Scholar 

  44. Walker BR. Activation of the hypothalamic-pituit ary-adrenal axis in obesity: cause or consequence?. Growth Horm IGF Res. 2001;11 Suppl A:S91–5.

    Article  Google Scholar 

  45. Belanoff JK, Kalehzan M, Sund B, Fleming Ficek SK, Schatzberg AF. Cortisol activity and cognitive changes in psychotic major depression. Am J Psychiatry. 2001;158:1612–6.

    Article  CAS  PubMed  Google Scholar 

  46. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23:477–501.

    Article  CAS  PubMed  Google Scholar 

  47. Lee WJ, Lee YC, Ser KH, Chen JC, Chen SC. Improvement of insulin resistance after obesity surgery: a comparison of gastric banding and bypass procedures. Obes Surg. 2008;18:1119–25.

    Article  PubMed  Google Scholar 

  48. Huber JD. Diabetes, cognitive function, and the blood-brain barrier. Curr Pharm Des. 2008;14:1594–600.

    Article  CAS  PubMed  Google Scholar 

  49. Ajilore O, Haroon E, Kumaran S, Darwin C, Binesh N, Mintz J, et al. Measurement of brain metabolites in patients with type 2 diabetes and major depression using proton magnetic resonance spectroscopy. Neuropsychopharmacology. 2007;32:1224–31.

    Article  CAS  PubMed  Google Scholar 

  50. Atlantis E, Ball K. Association between weight perception and psychological distress. Int J Obes (Lond). 2008;32:715–21.

    Article  CAS  Google Scholar 

  51. Derenne J, Beresin E. Body image, media, and eating disorders-a 10-year update. Acad Psychiatry. 2018;42:129–34.

    Article  PubMed  Google Scholar 

  52. Beesdo K, Jacobi F, Hoyer J, Low NC, Hofler M, Wittchen HU. Pain associated with specific anxiety and depressive disorders in a nationally representative population sample. Soc Psychiatry Psychiatr Epidemiol. 2010;45:89–104.

    Article  PubMed  Google Scholar 

  53. Paans NPG, Bot M, van Strien T, Brouwer IA, Visser M, Penninx B. Eating styles in major depressive disorder: results from a large-scale study. J Psychiatr Res. 2018;97:38–46.

    Article  PubMed  Google Scholar 

  54. Zitzmann M. Mechanisms of disease: pharmacogenetics of testosterone therapy in hypogonadal men. Nat Clin Pract Urol. 2007;4:161–6.

    Article  CAS  PubMed  Google Scholar 

  55. Colangelo LA, Sharp L, Kopp P, Scholtens D, Chiu BC, Liu K, et al. Total testosterone, androgen receptor polymorphism, and depressive symptoms in young black and white men: the CARDIA Male Hormone Study. Psychoneuroendocrinology. 2007;32:951–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vermeersch H, T’Sjoen G, Kaufman JM, Vincke J, Van Houtte M. Testosterone, androgen receptor gene CAG repeat length, mood and behaviour in adolescent males. Eur J Endocrinol. 2010;163:319–28.

    Article  CAS  PubMed  Google Scholar 

  57. Higgs S, Spetter MS. Cognitive control of eating: the role of memory in appetite and weight gain. Curr Obes Rep. 2018;7:50–9.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008;40:768–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hannan AJ. Tandem repeats mediating genetic plasticity in health and disease. Nat Rev Genet. 2018;19:286–98.

    Article  CAS  PubMed  Google Scholar 

  61. Saini S, Mitra I, Gymrek M. A reference haplotype panel for genome-wide imputation of short tandem repeats. bioRxiv. 2018 1–23.

  62. Mittal U, Sharma S, Chopra R, Dheeraj K, Pal PK, Srivastava AK, et al. Insights into the mutational history and prevalence of SCA1 in the Indian population through anchored polymorphisms. Hum Genet. 2005;118:107–14.

    Article  CAS  PubMed  Google Scholar 

  63. Krysa W, Sulek A, Rakowicz M, Szirkowiec W, Zaremba J. High relative frequency of SCA1 in Poland reflecting a potential founder effect. Neurol Sci. 2016;37:1319–25.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Craig K, Takiyama Y, Soong BW, Jardim LB, Saraiva-Pereira ML, Lythgow K, et al. Pathogenic expansions of the SCA6 locus are associated with a common CACNA1A haplotype across the globe: founder effect or predisposing chromosome? Eur J Human Genet. 2008;16:841–7.

    Article  CAS  Google Scholar 

  65. Faruq M, Magana JJ, Suroliya V, Narang A, Murillo-Melo NM, Hernandez-Hernandez O, et al. A complete association of an intronic SNP rs6798742 with origin of spinocerebellar ataxia type 7-CAG expansion loci in the Indian and Mexican population. Ann Hum Genet. 2017;81:197–204.

    Article  CAS  PubMed  Google Scholar 

  66. Magana JJ, Gomez R, Maldonado-Rodriguez M, Velazquez-Perez L, Tapia-Guerrero YS, Cortes H, et al. Origin of the spinocerebellar ataxia type 7 gene mutation in Mexican population. Cerebellum. 2013;12:902–5.

    Article  CAS  PubMed  Google Scholar 

  67. Terry KL, De Vivo I, Titus-Ernstoff L, Shih MC, Cramer DW. Androgen receptor cytosine, adenine, guanine repeats, and haplotypes in relation to ovarian cancer risk. Cancer Res. 2005;65:5974–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kashi Y, King DG. Simple sequence repeats as advantageous mutators in evolution. Trends Genet. 2006;22:253–9.

    Article  CAS  PubMed  Google Scholar 

  69. Keiser MS, Kordasiewicz HB, McBride JL. Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington’s disease and spinocerebellar ataxia. Hum Mol Genet. 2016;25:R53–64.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to express our gratitude to all individuals who participated in the NEO and PROSPER study as well as all research staff for collecting the data and I. de Jonge for data management. Dr. Anton de Craen’s guidance was crucial for the design of this study for which we posthumously wish to express our utmost appreciation. This study was supported by a VENI-grant (#91615080) from the Netherlands Organization of Scientific Research and a Marie Sklodowska-Curie Individual Fellowship grant from the European Union (Horizon 2020, #701130; NAA). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Centre, and by the Leiden University, Research Profile Area ‘Vascular and Regenerative Medicine’.

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Authors and Affiliations

  1. Department of Neurology, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands

    Sarah L. Gardiner, Merel W. Boogaard, Raymund A. C. Roos & N. Ahmad Aziz

  2. Department of Human Genetics, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands

    Sarah L. Gardiner & Ko Willems van Dijk

  3. Department of Epidemiology, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands

    Renée de Mutsert & Frits R. Rosendaal

  4. Department of Internal Medicine, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands

    Stella Trompet, Ko Willems van Dijk & Hanno Pijl

  5. Department of Clinical Genetics, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands

    Merel W. Boogaard

  6. Department of Cardiology, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands

    P. J. Wouter Jukema

  7. Department of Molecular Epidemiology, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands

    P. Eline Slagboom

  8. German Center for Neurodegenerative Diseases (DZNE), Bonn, 53127, Germany

    N. Ahmad Aziz

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  1. Sarah L. Gardiner
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Correspondence to Sarah L. Gardiner.

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Gardiner, S.L., de Mutsert, R., Trompet, S. et al. Repeat length variations in polyglutamine disease-associated genes affect body mass index. Int J Obes 43, 440–449 (2019). https://doi.org/10.1038/s41366-018-0161-7

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