title: Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy.
abstract: The precise physiologic function of many of the recently discovered Alzheimer's disease risk variants remains unknown. The downstream effects of genetic variants remain largely unexplored. We studied the relationship between the top 10 non-APOE genes with cortical and hippocampal atrophy as markers of neurodegeneration using 1.5T magnetic resonance imaging, 1-million single nucleotide polymorphism Illumina Human Omni-Quad array and Illumina Human BeadChip peripheral blood expression array data on 50 cognitively normal and 98 mild cognitive impairment subjects. After explicit matching of cortical and hippocampal morphology, we computed in 3D, the cortical thickness and hippocampal radial distance measures for each participant. Associations between the top 10 non-APOE genome-wide hits and neurodegeneration were explored using linear regression. Map-wise statistical significance was determined with permutations using threshold of p < 0.01. MS4A6A rs610932 and ABCA7 rs3764650 demonstrated significant associations with cortical and hippocampal atrophy. Exploratory MS4A6A and ABCA7 peripheral blood expression analyses revealed a similar pattern of associations with cortical neurodegeneration. To our knowledge, this is the first report of the effect of ABCA7 and MS4A6A on neurodegeneration.
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Ramirez
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Naira
authors.initials: N
authors.lastname: Goukasian
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Shai
authors.initials: S
authors.lastname: Porat
authors.affiliation: Oakland University William Beaumont School of Medicine, Rochester, MI, USA.
authors.forename: Kristy S
authors.initials: KS
authors.lastname: Hwang
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Eastman
authors.affiliation: Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Sona
authors.initials: S
authors.lastname: Hurtz
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Family Medicine, University of Minnesota, Twin Cities, MN, USA.
authors.forename: Nouchee
authors.initials: N
authors.lastname: Vang
authors.affiliation: Department of Psychiatry, UCLA, Los Angeles, CA, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Sears
authors.affiliation: Department of Psychiatry, UCLA, Los Angeles, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Klein
authors.affiliation: Department of Psychiatry, UCLA, Los Angeles, CA, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Neurology, UCLA, Los Angeles, CA, USA; Department of Neurology, Indiana University, Indianapolis, IN, USA; Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA. Electronic address: lapostol@iu.edu.
authors.forename: Liana G
authors.initials: LG
authors.lastname: Apostolova
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000097:blood / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D001284:Atrophy / Q000235:genetics; D002540:Cerebral Cortex / Q000473:pathology*; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics*; D008875:Middle Aged
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; C574492:MS4A6A protein, human; D008565:Membrane Proteins
keywords: AD risk genes; Alzheimer's disease; Cortical atrophy; Cortical thickness; Hippocampal atrophy; Neurodegeneration