Genes and Environment in Multiple Sclerosis project: A platform to investigate multiple sclerosis risk
Zongqi Xia MD, PhD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Search for more papers by this authorCharles C. White PhD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Search for more papers by this authorEmily K. Owen RN
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorAlina Von Korff BS
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorSarah R. Clarkson BS
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorCristin A. McCabe BS
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Search for more papers by this authorMaria Cimpean BA
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorPhoebe A. Winn BA
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorAshley Hoesing MS
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorSonya U. Steele MS
Division of Neuroimmunology and Neurovirology, National Institute for Neurologic Diseases and Stroke, Bethesda, MD
Search for more papers by this authorIrene C. M. Cortese MD
Division of Neuroimmunology and Neurovirology, National Institute for Neurologic Diseases and Stroke, Bethesda, MD
Search for more papers by this authorTanuja Chitnis MD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Search for more papers by this authorHoward L. Weiner MD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Search for more papers by this authorDaniel S. Reich MD, PhD
Division of Neuroimmunology and Neurovirology, National Institute for Neurologic Diseases and Stroke, Bethesda, MD
Search for more papers by this authorLori B. Chibnik PhD, MPH
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Search for more papers by this authorCorresponding Author
Philip L. De Jager MD, PhD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Address correspondence to Dr De Jager, Department of Neurology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB 168, Boston, MA 02115. E-mail: [email protected]Search for more papers by this authorZongqi Xia MD, PhD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Search for more papers by this authorCharles C. White PhD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Search for more papers by this authorEmily K. Owen RN
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorAlina Von Korff BS
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorSarah R. Clarkson BS
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorCristin A. McCabe BS
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Search for more papers by this authorMaria Cimpean BA
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorPhoebe A. Winn BA
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorAshley Hoesing MS
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Search for more papers by this authorSonya U. Steele MS
Division of Neuroimmunology and Neurovirology, National Institute for Neurologic Diseases and Stroke, Bethesda, MD
Search for more papers by this authorIrene C. M. Cortese MD
Division of Neuroimmunology and Neurovirology, National Institute for Neurologic Diseases and Stroke, Bethesda, MD
Search for more papers by this authorTanuja Chitnis MD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Search for more papers by this authorHoward L. Weiner MD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Search for more papers by this authorDaniel S. Reich MD, PhD
Division of Neuroimmunology and Neurovirology, National Institute for Neurologic Diseases and Stroke, Bethesda, MD
Search for more papers by this authorLori B. Chibnik PhD, MPH
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Search for more papers by this authorCorresponding Author
Philip L. De Jager MD, PhD
Program in Translational Neuropsychiatric Genomics and Partners Multiple Sclerosis Center, Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA
Address correspondence to Dr De Jager, Department of Neurology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB 168, Boston, MA 02115. E-mail: [email protected]Search for more papers by this authorAbstract
The Genes and Environment in Multiple Sclerosis project establishes a platform to investigate the events leading to multiple sclerosis (MS) in at-risk individuals. It has recruited 2,632 first-degree relatives from across the USA. Using an integrated genetic and environmental risk score, we identified subjects with twice the MS risk when compared to the average family member, and we report an initial incidence rate in these subjects that is 30 times greater than that of sporadic MS. We discuss the feasibility of large-scale studies of asymptomatic at-risk subjects that leverage modern tools of subject recruitment to execute collaborative projects. Ann Neurol 2016;79:178–189
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References
- 1 Compston A, Coles A. Multiple sclerosis. Lancet 2008; 372: 1502–1517.
- 2 Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 2009; 72: 800–805.
- 3 Engell T. A clinical patho-anatomical study of clinically silent multiple sclerosis. Acta Neurolo Scand 1989; 79: 428–430.
- 4 Dalton CM, Chard DT, Davies GR, et al. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain 2004; 127(pt 5): 1101–1107.
- 5 Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009; 374: 1503–1511.
- 6 Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol 2009; 8: 987–997.
- 7 Goodin DS, Reder AT, Ebers GC, et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012; 78: 1315–1322.
- 8 Lynch SG, Rose JW, Smoker W, Petajan JH. MRI in familial multiple sclerosis. Neurology 1990; 40: 900–903.
- 9 Fulton JC, Grossman RI, Mannon LJ, et al. Familial multiple sclerosis: volumetric assessment in clinically symptomatic and asymptomatic individuals. Mult Scler 1999; 5: 74–77.
- 10 De Stefano N, Cocco E, Lai M, et al. Imaging brain damage in first-degree relatives of sporadic and familial multiple sclerosis. Ann Neurol 2006; 59: 634–639.
- 11 Gabelic T, Ramasamy DP, Weinstock-Guttman B, et al. Prevalence of radiologically isolated syndrome and white matter signal abnormalities in healthy relatives of patients with multiple sclerosis. Am J Neuroradiol 2014; 35: 106–112.
- 12 International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851–862.
- 13 Bahlo M, Booth DR, Broadley SA, et al. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet 2009; 41: 824–828.
- 14 De Jager PL, Jia X, Wang J, et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 2009; 41: 776–782.
- 15 Baranzini SE, Wang J, Gibson RA, et al. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 2009; 18: 767–778.
- 16 Patsopoulos NA, Bayer Pharma MS Genetics Working Group, Steering Committees of Studies Evaluating IFNβ-1b and a CCR1-Antagonist, et al. Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol 2011; 70: 897–912.
- 17 International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer S, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011; 476: 214–219.
- 18 Beecham AH, Patsopoulos NA, Xifara DK, et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013; 45: 1353–1360.
- 19 Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 2007; 61: 504–513.
- 20 Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 2007; 61: 288–299.
- 21 Ascherio A, Munger KL, Lünemann JD. The initiation and prevention of multiple sclerosis. Nat Rev Neurol 2012; 8: 602–612.
- 22 Ebers GC. Environmental factors and multiple sclerosis. Lancet Neurol 2008; 7: 268–277.
- 23 Hedström AK, Lima Bomfim I, Hillert J, et al. Obesity interacts with infectious mononucleosis in risk of multiple sclerosis. Eur J Neurol 2015; 22: 578–e38.
- 24 Hedström AK, Olsson T, Alfredsson L. High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women. Mult Scler 2012; 18: 1334–1336.
- 25 Hedström AK, Lima Bomfim I, Barcellos L, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology 2014; 82: 865–872.
- 26 Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013; 80: 548–552.
- 27 Munger KL, Bentzen J, Laursen B, et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. Mult Scler 2013; 19: 1323–1329.
- 28 De Jager PL, Simon KC, Munger KL, et al. Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis. Neurology 2008; 70(13 pt 2): 1113–1118.
- 29 De Jager PL, Chibnik LB, Cui J, et al. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score. Lancet Neurol 2009; 8: 1111–1119.
- 30 Gourraud P-A, McElroy JP, Caillier SJ, et al. Aggregation of multiple sclerosis genetic risk variants in multiple and single case families. Ann Neurol 2011; 69: 65–74.
- 31 Rewers M, Bugawan TL, Norris JM, et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetologia 1996; 39: 807–812.
- 32 Hernan MA, Zhang SM, Lipworth L, et al. Multiple sclerosis and age at infection with common viruses. Epidemiology 2001; 12: 301–306.
- 33 Simon K, Schmidt H, Loud S, Ascherio A. Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis. Mult Scler 2015; 21: 703–709.
- 34 Wallin MT, Culpepper WJ, Coffman P, et al. The Gulf War era multiple sclerosis cohort: age and incidence rates by race, sex and service. Brain 2012; 135: 1778–1785.
- 35 Thacker EL, Mirzaei F, Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 2006; 59: 499–503.
- 36 Hernán MA, Jick SS, Logroscino G, et al. Cigarette smoking and the progression of multiple sclerosis. Brain 2005; 128(pt 6): 1461–1465.
- 37 Hedström AK, Bäärnhielm M, Olsson T, Alfredsson L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 2009; 73: 696–701.
- 38 Hedström AK, Sundqvist E, Bäärnhielm M, et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain 2011; 134(pt 3): 653–664.
- 39 Raj T, Rothamel K, Mostafavi S, et al. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 2014; 344: 519–523.
- 40 Xia Z, Secor E, Chibnik LB, et al. Modeling disease severity in multiple sclerosis using electronic health records. PLoS One 2013; 8: e78927.
- 41 Xia Z, Chibnik LB, Glanz BI, et al. A putative Alzheimer's disease risk allele in PCK1 influences brain atrophy in multiple sclerosis. PLoS One 2010; 5: e14169.
- 42 Karlson EW, Chibnik LB, Kraft P, et al. Cumulative association of 22 genetic variants with seropositive rheumatoid arthritis risk. Ann Rheum Dis 2010; 69: 1077–1085.
- 43 Wilson PW, D'Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837–1847.
- 44 Ebers GC, Sadovnick AD, Risch NJ. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 1995; 377: 150–151.
- 45 Fricska-Nagy Z, Bencsik K, Rajda C, et al. Epidemiology of familial multiple sclerosis in Hungary. Mult Scler 2007; 13: 260–261.
- 46 Hader WJ, Yee IM. The prevalence of familial multiple sclerosis in Saskatoon, Saskatchewan. Mult Scler Int 2014; 2014: 545080.
- 47 Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292–302.
- 48 Baum HM, Rothschild BB. The incidence and prevalence of reported multiple sclerosis. Ann Neurol 1981; 10: 420–428.
- 49 Alonso A, Hernán MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. Neurology 2008; 71: 129–135.
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