Meta-analysis of the Association Between Variants in SORL1 and Alzheimer Disease

• Published in: Archives of neurology (Chicago) Vol. 68; no. 1; pp. 99 - 106
• Main Authors: Reitz, Christiane, Cheng, Rong, Rogaeva, Ekaterina, Lee, Joseph H, Tokuhiro, Shinya, Zou, Fanggeng, Bettens, Karolien, Sleegers, Kristel, Tan, Eng King, Kimura, Ryo, Shibata, Nobuto, Arai, Heii, Kamboh, M. Ilyas, Prince, Jonathan A, Maier, Wolfgang, Riemenschneider, Matthias, Owen, Michael, Harold, Denise, Hollingworth, Paul, Cellini, Elena, Sorbi, Sandro, Nacmias, Benedetta, Takeda, Masatoshi, Pericak-Vance, Margaret A, Haines, Jonathan L, Younkin, Steven, Williams, Julie, van Broeckhoven, Christine, Farrer, Lindsay A, St George–Hyslop, Peter H, Mayeux, Richard
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 01.01.2011
• Subjects: Alleles; Alzheimer Disease - epidemiology; Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer's disease; Biological and medical sciences; Brain; Case-Control Studies; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Genes; Genetic Variation - genetics; Humans; LDL-Receptor Related Proteins - genetics; Medical research; Medical sciences; Medicin och hälsovetenskap; Membrane Transport Proteins - genetics; Meta-analysis; Nerve Tissue Proteins - genetics; Neurology; Polymorphism; Polymorphism, Single Nucleotide - genetics; Systematic review; Canada; Netherlands; Singapore; Belgium; United Kingdom > UK; United States > US; Nervous system diseases; Degenerative disease; Alzheimer disease; Central nervous system disease; Cerebral disorder
• ISSN: 0003-9942; 2168-6149; 1538-3687; 1538-3687; 2168-6157
• DOI: 10.1001/archneurol.2010.346

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 DESIGN Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies.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 the National 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 with AD risk (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.Arch Neurol. 2011;68(1):99-106-->