Meta-analysis of the association between variants in SORL1 and Alzheimer disease

Christiane Reitz, Rong Cheng, Ekaterina Rogaeva, Joseph H. Lee, Shinya Tokuhiro, Fanggeng Zou, Karolien Bettens, Kristel Sleegers, Eng King Tan, Ryo Kimura, Nobuto Shibata, Heii Arai, M. Ilyas Kamboh, Jonathan A. Prince, Wolfgang Maier, Matthias Riemenschneider, Michael Owen, Denise Harold, Paul Hollingworth, Elena CelliniSandro Sorbi, Benedetta Nacmias, Masatoshi Takeda, Margaret A. Pericak-Vance, Jonathan L. Haines, Steven Younkin, Julie Williams, Christine Van Broeckhoven, Lindsay A. Farrer, Peter H. St George-Hyslop, Richard Mayeux

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

Objective: To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD). Design: Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies. Setting: Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy. Participants: All published white and Asian case-control data sets, which included a total of 12 464 cases and 17 929 controls. Main Outcome Measures: Alzheimer disease according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and theNational Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association). Results: In the white data sets, several markers were associated with AD after correction for multiple testing, including previously reported SNPs 8, 9, and 10 (P < .001). In addition, the C-G-C haplotype at SNPs 8 through 10 was associated with AD risk (P < .001). In the combined Asian data sets, SNPs 19 and 23 through 25 were associated withADrisk (P < .001). The disease-associated alleles at SNPs 8, 9, and 10 (120 873 131-120 886 175 base pairs [bp]; C-G-C alleles), at SNP 19 (120 953 300 bp; G allele), and at SNPs 24 through 25 (120 988 611 bp; T and C alleles) were the same previously reported alleles. The SNPs 4 through 5, 8 through 10, 12, and 19 through 25 belong to distinct linkage disequilibrium blocks. The same alleles at SNPs 8 through 10 (C-G-C), 19 (G), and 24 and 25 (T and C) have also been associated with AD endophenotypes, including white matter hyperintensities and hippocampal atrophy on magnetic resonance imaging, cerebrospinal fluid measures of amyloid β-peptide 42, and full-length SORL1 expression in the human brain. Conclusion: This comprehensive meta-analysis provides confirmatory evidence that multiple SORL1 variants in distinct linkage disequilibrium blocks are associated with AD.

Original languageEnglish (US)
Pages (from-to)99-106
Number of pages8
JournalArchives of neurology
Volume68
Issue number1
DOIs
StatePublished - Jan 1 2011

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

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    Reitz, C., Cheng, R., Rogaeva, E., Lee, J. H., Tokuhiro, S., Zou, F., Bettens, K., Sleegers, K., Tan, E. K., Kimura, R., Shibata, N., Arai, H., Kamboh, M. I., Prince, J. A., Maier, W., Riemenschneider, M., Owen, M., Harold, D., Hollingworth, P., ... Mayeux, R. (2011). Meta-analysis of the association between variants in SORL1 and Alzheimer disease. Archives of neurology, 68(1), 99-106. https://doi.org/10.1001/archneurol.2010.346