title: A putative Alzheimer's disease risk allele in PCK1 influences brain atrophy in multiple sclerosis.
abstract: BACKGROUND
  Brain atrophy and cognitive dysfunction are neurodegenerative features of Multiple Sclerosis (MS). We used a candidate gene approach to address whether genetic variants implicated in susceptibility to late onset Alzheimer's Disease (AD) influence brain volume and cognition in MS patients.
  
  
  RESULTS
  MS subjects were genotyped for five single nucleotide polymorphisms (snps) associated with susceptibility to AD: PICALM, CR1, CLU, PCK1, and ZNF224. We assessed brain volume using Brain Parenchymal Fraction (BPF) measurements obtained from Magnetic Resonance Imaging (MRI) data and cognitive function using the Symbol Digit Modalities Test (SDMT). Genotypes were correlated with cross-sectional BPF and SDMT scores using linear regression after adjusting for sex, age at symptom onset, and disease duration. 722 MS patients with a mean (±SD) age at enrollment of 41 (±10) years were followed for 44 (±28) months. The AD risk-associated allele of a non-synonymous SNP in the PCK1 locus (rs8192708G) is associated with a smaller average brain volume (P=0.0047) at the baseline MRI, but it does not impact our baseline estimate of cognition. PCK1 is additionally associated with higher baseline T2-hyperintense lesion volume (P=0.0088). Finally, we provide technical validation of our observation in a subset of 641 subjects that have more than one MRI study, demonstrating the same association between PCK1 and smaller average brain volume (P=0.0089) at the last MRI visit.
  
  
  CONCLUSIONS
  Our study provides suggestive evidence for greater brain atrophy in MS patients bearing the PCK1 allele associated with AD-susceptibility, yielding new insights into potentially shared neurodegenerative process between MS and late onset AD.
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Zongqi
authors.initials: Z
authors.lastname: Xia
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.forename: Bonnie I
authors.initials: BI
authors.lastname: Glanz
authors.forename: Maria
authors.initials: M
authors.lastname: Liguori
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.forename: Dong
authors.initials: D
authors.lastname: Tran
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.forename: Tanuja
authors.initials: T
authors.lastname: Chitnis
authors.forename: Todd
authors.initials: T
authors.lastname: Holyoak
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.forename: Charles R G
authors.initials: CR
authors.lastname: Guttmann
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
mesh_terms: D000328:Adult; D000483:Alleles; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D001284:Atrophy; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D003071:Cognition / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics; D059948:HLA-B44 Antigen; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D008959:Models, Neurological; D009103:Multiple Sclerosis / Q000150:complications*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D015235:HLA-B Antigens; C495439:HLA-B*44:03 antigen; D059948:HLA-B44 Antigen; D047908:Intracellular Signaling Peptides and Proteins; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP)