title: Genetic association of sequence variants near AGER/NOTCH4 and dementia.
abstract: We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia casesand 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19–1.56, p = 1.36×10(–6)). Imputation of the associated genomic interval provided an improved signal atrs8365, near the 3UTR of AGER (p = 7.34×10(–7)). The associated region extends 120 kb encompassing 11 candidate genes.While AGER encodes a key receptor for amyloid-β protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (AβPP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Bennet
authors.forename: Chandra A
authors.initials: CA
authors.lastname: Reynolds
authors.forename: Ulrika K
authors.initials: UK
authors.lastname: Eriksson
authors.forename: Mun-Gwan
authors.initials: MG
authors.lastname: Hong
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Margaret
authors.initials: M
authors.lastname: Gatz
authors.forename: Andrey
authors.initials: A
authors.lastname: Alexeyenko
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Prince
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003704:Dementia / Q000134:cerebrospinal fluid / Q000150:complications / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000235:genetics; D008297:Male; D011518:Proto-Oncogene Proteins / Q000134:cerebrospinal fluid / Q000235:genetics*; D000067759:Receptor for Advanced Glycation End Products; D000074562:Receptor, Notch4; D011971:Receptors, Immunologic / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics*; D012307:Risk Factors; D018709:Statistics, Nonparametric
chemical_list: C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000067759:Receptor for Advanced Glycation End Products; D000074562:Receptor, Notch4; D011971:Receptors, Immunologic; D051880:Receptors, Notch