title: Complement receptor 1 coding variant p.Ser1610Thr in Alzheimer's disease and related endophenotypes.
abstract: We previously described an intragenic functional copy number variation (CNV) in complement receptor 1 (CR1) that is associated with Alzheimer disease (AD) risk. A recent study, however, reported a rare CR1 coding variant p.Ser1610Thr (rs4844609) associated with AD susceptibility, explaining the effect of genome wide association (GWA) top single nucleotide polymorphism rs6656401. We assessed the role of the Ser1610Thr variant in AD pathogenesis and the effect on AD-related endophenotypes in a Flanders-Belgian cohort. We evaluated whether this rare variant rather than the CR1 CNV could explain the association of CR1 in our population. The Ser1610Thr variant was not associated with AD, memory impairment, total tau, amyloid β(1-42) or tau phosphorylated at threonine 181 levels. It did not explain (part of) the association of genome wide association top single-nucleotide polymorphisms rs3818361/rs6656401, nor of the CR1 CNV, with AD in our cohort, whereas the CR1 CNV and rs3818361/rs6656401 represented the same association signal. These findings question a role for the Ser1610Thr variant in AD risk and related endophenotypes, and reaffirm our previous observation that the CR1 CNV could be the true functional risk factor explaining the association between CR1 and AD.
authors.affiliation: Department of Molecular Genetics, VIB, Antwerp, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Van Cauwenberghe
authors.forename: Karolien
authors.initials: K
authors.lastname: Bettens
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vandenbulcke
authors.forename: Jasper
authors.initials: J
authors.lastname: Van Dongen
authors.forename: Steven
authors.initials: S
authors.lastname: Vermeulen
authors.forename: Rik
authors.initials: R
authors.lastname: Vandenberghe
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics* / Q000502:physiology; D058068:Endophenotypes; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011951:Receptors, Complement / Q000235:genetics*; D012307:Risk Factors
chemical_list: D011951:Receptors, Complement