Genetic variants conferring susceptibility to Alzheimer’s disease in the general population; do they also predispose to dementia in Down’s syndrome

BMC Research Notes

Vee P Prasher⁴  Humaria Arshad²  Anisha Prasher⁷  Anthony H Barnett³  Stephen C Bain¹  M Ann Kelly⁵  Simon D Rees⁵  Ashok Patel⁶ 

[1] Institute of Life Science, Swansea University, Swansea, UK;South Birmingham Primary Care Trust, Birmingham, UK;Diabetes Centre, Heart of England NHS foundation Trust, Birmingham, UK;Liverpool John Moore University, Liverpool, UK;College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK;Department of Biomolecular and Sport Sciences, Faculty of Health and Life Sciences, Coventry University, Coventry, UK;Nottingham University, Nottingham, UK

关键词: SNPs;    Alzheimer’s disease;    Dementia;    Down syndrome;   

Others  :  1134777
DOI  :  10.1186/1756-0500-7-42

 received in 2013-07-08, accepted in 2013-12-04,  发布年份 2014

【 摘 要 】

Background

Down’s syndrome (DS) is caused by either complete or partial triplication of chromosome 21, affecting approximately 1/1000 live births, and it is widely accepted that individuals with DS are more likely to develop dementia of Alzheimer’s disease (DAD) compared with the general population. Recent collaborative genome-wide association studies of large case control data sets of individuals with and without Alzhemier’s disease (AD) have revealed new risk variants for dementia, as well as confirming previously identified risk variants. In this study, nine AD-derived SNPs, near or within the CR1 (rs3818361), BIN1 (rs744373), CD2AP (rs9349407), EPHA1 (rs11767557), CLU (rs1532278), MS4A6A/4A (rs610932), PICALM (rs561655), ABCA7 (rs3764650) and CD33 (rs3865444) genes were genotyped in 295 individuals with DS.

Results

There were no significant associations between these nine GWAS-derived SNPs and DAD in British Caucasian individuals with DS. Interestingly the CR1 rs3818361 variant appeared to be associated with mortality in our cohort, particularly in the subjects without dementia. To our knowledge, this is the first time that this variant has been implicated as a determinant of mortality and the finding warrants further investigation in other cohorts with DS.

Conclusions

This study shows negative associations of nine AD-derived SNPs with DAD in DS. This may be due to the modest size of our cohort, which may indicate that our study is insufficiently powered to pick up such associations. We cannot conclusively exclude a role for these SNPs in DAD in DS. Clearly, efforts to investigate genetic variants with small effects on disease risk require a much larger cohort of individuals with DS. In fact, we hypothesize that a sample size of 4465 individuals with DS would be needed to determine the role in DAD in DS of the nine AD-derived SNPs investigated in this study. We therefore recommend that all national and international clinics with access to individuals with DS should contribute DNA samples to form DS consortia.

【 授权许可】

   
2014 Patel et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Mrak RE, Griffin WS: Trisomy 21 and the brain. J Neuropathol Exp Neurol 2004, 63(7):679-685.
• [2]Vis JC, Duffels MG, Winter MM, Weijerman ME, Cobben JM, Huisman SA, Mulder BJ: Down syndrome: a cardiovascular perspective. J Intellect Disabil Res 2009, 53(5):419-425.
• [3]Yang Q, Rasmussen SA, Friedman JM: Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study. Lancet 2002, 359(9311):1019.
• [4]Mann DM: The pathological association between Down syndrome and Alzheimer disease. Mech Ageing Dev 1988, 43(2):99-136.
• [5]Ness S, Rafii M, Aisen P, Krams M, Silverman W, Manji H: Down’s syndrome and Alzheimer’s disease: towards secondary prevention. Nat Rev Drug Discov 2012, 11(9):655-656.
• [6]Schupf N, Sergievsky GH: Genetic and host factors for dementia in Down’s syndrome. Br J Psychiatry 2002, 180:405-410.
• [7]Oliver C, Holland AJ: Down’s syndrome and Alzheimer’s disease: a review. Psychol Med 1986, 16(2):307-322.
• [8]Wisniewski KE, Dalton AJ, McLachlan C, Wen GY, Wisniewski HM: Alzheimer’s disease in Down’s syndrome: clinicopathologic studies. Neurology 1985, 35(7):957-961.
• [9]Lai F, Williams RS: A prospective study of Alzheimer disease in Down syndrome. Arch Neurol 1989, 46(8):849-853.
• [10]Prasher VP, Krishnan VH: Mental disorders and adaptive behaviour in people with Down’s syndrome. Br J Psychiatry 1993, 162:848-850.
• [11]Nieuwenhuis-Mark RE: Diagnosing Alzheimer’s dementia in Down syndrome: problems and possible solutions. Res Dev Disabil 2009, 30(5):827-838.
• [12]Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G, Martins R, Hockey A, Montgomery P, Beyreuther K, Masters CL: Amyloid A4 protein and its precursor in Down’s syndrome and Alzheimer’s disease. N Engl J Med 1989, 320(22):1446-1452.
• [13]Prasher VP, Sajith SG, Rees SD, Patel A, Tewari S, Schupf N, Zigman WB: Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer’s disease and mortality in persons with Down syndrome. Int J Geriatr Psychiatry 2008, 23(11):1134-1140.
• [14]Coppus AM, Evenhuis HM, Verberne GJ, Visser FE, Eikelenboom P, Van Gool WA, Janssens AC, Van Duijn CM: Early age at menopause is associated with increased risk of dementia and mortality in women with Down syndrome. J Alzheimers Dis 2010, 19(2):545-550.
• [15]Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993, 261(5123):921-923.
• [16]Mayeux R, Stern Y, Ottman R, Tatemichi TK, Tang MX, Maestre G, Ngai C, Tycko B, Ginsberg H: The apolipoprotein epsilon 4 allele in patients with Alzheimer’s disease. Ann Neurol 1993, 34(5):752-754.
• [17]Saunders AM, Schmader K, Breitner JC, Benson MD, Brown WT, Goldfarb L, Goldgaber D, Manwaring MG, Szymanski MH, McCown N: Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer’s disease and in other amyloid-forming diseases. Lancet 1993, 342(8873):710-711.
• [18]Meyer MR, Tschanz JT, Norton MC, Welsh-Bohmer KA, Steffens DC, Wyse BW, Breitner JC: APOE genotype predicts when–not whether–one is predisposed to develop Alzheimer disease. Nat Genet 1998, 19(4):321-322.
• [19]Khachaturian AS, Corcoran CD, Mayer LS, Zandi PP, Breitner JC, Cache County Study Investigators: Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study. Arch Gen Psychiatry 2004, 61(5):518-524.
• [20]Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE: Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994, 7(2):180-184.
• [21]Roses AD, Saunders AM: APOE is a major susceptibility gene for Alzheimer’s disease. Curr Opin Biotechnol 1994, 5(6):663-667.
• [22]Coppus AMW, Evenhuis HM, Verberne G, Visser FE, Arias-Vasquez A, Sayed-Tabatabaei F, Vergeer-Drop J, Eikelenboom P, Van Gool WA, Van Duijn CM: The impact of apolipoprotein E on dementia in persons with Down’s syndrome. Neurobiol Aging 2008, 29(6):828-835.
• [23]Deb S, Braganza J, Norton N, Williams H, Kehoe PG, Williams J, Owen MJ: APOE epsilon 4 influences the manifestation of Alzheimer’s disease in adults with Down’s syndrome. Br J Psychiatry 2000, 176:468-472.
• [24]Lucarelli P, Piciullo A, Verdecchia M, Palmarino M, Arpino C, Curatolo P: The role of −850 tumor necrosis factor-α and apolipoprotein E genetic polymorphism in patients with Down’s syndrome-related dementia. Neurosci Lett 2003, 352(1):29.
• [25]Anello G, Gueant J, Romano C, Barone C, Pettinato R, Pillot T, Rodriguez R, Romano A, Bosco P: Allele varepsilon4 of apolipoprotein E gene is less frequent in Down syndrome patient of the Sicilian population and has no influence on the grade of mental retardation. Neurosci Lett 2001, 306(1–2):129-131.
• [26]Van Gool WA, Evenhuis HM, Van Duijn CM: A case–control study of apolipoprotein E genotypes in Alzheimer’s disease associated with Down’s syndrome. Dutch Study Group on Down’s Syndrome and Ageing. Ann Neurol 1995, 38(2):225-230.
• [27]Prasher VP, Chowdhury TA, Rowe BR, Bain SC: ApoE genotype and Alzheimer’s disease in adults with Down syndrome: meta-analysis. Am J Ment Retard 1997, 102(2):103-110.
• [28]Tyrrell J, Cosgrave M, Hawi Z, McPherson J, O’Brien C, McCalvert J, McLaughlin M, Lawlor B, Gill M: A protective effect of apolipoprotein E e2 allele on dementia in Down’s syndrome. Biol Psychiatry 1998, 43(6):397-400.
• [29]Lai F, Kammann E, Rebeck GW, Anderson A, Chen Y, Nixon RA: APOE genotype and gender effects on Alzheimer disease in 100 adults with Down syndrome. Neurology 1999, 53(2):331-336.
• [30]Rubinsztein DC, Hon J, Stevens F, Pyrah I, Tysoe C, Huppert FA, Easton DF, Holland AJ: Apo E genotypes and risk of dementia in Down syndrome. Am J Med Genet 1999, 88(4):344-347.
• [31]Folin M, Baiguera S, Conconi MT, Pati T, Grandi C, Parnigotto PP, Nussdorfer GG: The impact of risk factors of Alzheimer’s disease in the Down syndrome. Int J Mol Med 2003, 11(2):267-270.
• [32]Edland SD, Wijsman EM, Schoder-Ehri GL, Leverenz JB: Little evidence of reduced survival to adulthood of apoE epsilon4 homozygotes in Down’s syndrome. Neuroreport 1997, 8(16):3463-3465.
• [33]Gold G, Blouin JL, Herrmann FR, Michon A, Mulligan R, Duriaux Sail G, Bouras C, Giannakopoulos P, Antonarakis SE: Specific BACE1 genotypes provide additional risk for late-onset Alzheimer disease in APOE epsilon 4 carriers. Am J Med Genet B Neuropsychiatr Genet 2003, 119B(1):44-47.
• [34]Lucarelli P, Piciullo A, Palmarino M, Verdecchia M, Saccucci P, Arpino C, Curatolo P: Association between presenilin-1–48C/T polymorphism and Down’s syndrome. Neurosci Lett 2004, 367(1):88-91.
• [35]Lee JH, Chulikavit M, Pang D, Zigman WB, Silverman W, Schupf N: Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer’s disease in adults with Down syndrome. Neurosci Lett 2007, 425(2):105-109.
• [36]Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK, Larson EB, Bird TD, Boeve BF, Graff-Radford NR, De Jager PL, Evans D, Schneider JA, Carrasquillo MM, Ertekin-Taner N, Younkin SG, Cruchaga C, Kauwe JS, Nowotny P, Kramer P, Hardy J, Huentelman MJ, Myers AJ, Barmada MM, Demirci FY, Baldwin CT, et al.: Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 2011, 43(5):436-441.
• [37]Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, et al.: Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 2011, 43(5):429-435.
• [38]Patel A, Rees SD, Kelly MA, Bain SC, Barnett AH, Thalitaya D, Prasher VP: Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1 with dementia in Alzheimer’s disease in subjects with Down syndrome. Neurosci Lett 2011, 487(2):144-148.
• [39]Janca A, Ustun TB, Van Drimmelen J, Dittmann V, Isaac M: ICD-10 Symptom Checklist for Mental Disorders, Version 1.1. Geneva: Division of Mental Health, World Health Organization; 1994.
• [40]The ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic Criteria for Research. Geneva: World Health Organisation; 1993a.
• [41]The ICD-10 Classification of Mental and Behavioural Disorders. Clinical Descriptions and Diagnostic Guidelines. Geneva: World health Organization; 1992b.
• [42]Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS, Valladares O, Lin CF, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue M, Baldwin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RC, Griffith P, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, et al.: Alzheimer Disease Genetics Consortium: Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4, and the risk of late-onset Alzheimer disease in African Americans. JAMA 2013, 309(14):1483-1492.
• [43]Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, Crook JE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, Morgan K, Younkin SG: Replication of BIN1 association with Alzheimer’s disease and evaluation of genetic interactions. J Alzheimers Dis 2011, 24(4):751-758.
• [44]Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, Crook JE, Pankratz VS, Dickson DW, Graff-Radford NR, Petersen RC, Morgan K, Younkin SG: Replication of CLU, CR1, and PICALM associations with alzheimer disease. Arch Neurol 2010, 67(8):961-964.