title: Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?
abstract: Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated.
authors.affiliation: Department of Molecular & Medical Genetics, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.|Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Barber
authors.affiliation: Department of Biology, University of Dallas, Dallas, Texas, United States of America.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Phillips
authors.affiliation: Renaissance Computing Institute, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Tilson
authors.affiliation: Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Huebinger
authors.affiliation: Department of Molecular & Medical Genetics, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.
authors.forename: Shantanu J
authors.initials: SJ
authors.lastname: Shewale
authors.affiliation: Department of Molecular & Medical Genetics, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Koenig
authors.affiliation: Department of Molecular & Medical Genetics, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Mitchel
authors.affiliation: Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.|Department of Internal Medicine, University of North Texas Health Science Center, Fort Worth, Texas, United States of America.
authors.forename: Sid E
authors.initials: SE
authors.lastname: O'Bryant
authors.affiliation: Essentia Institute of Rural Health, Duluth, Minnesota, United States of America.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Waring
authors.affiliation: Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Rockville, Maryland, United States of America.
authors.forename: Ramon
authors.initials: R
authors.lastname: Diaz-Arrastia
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Chasse
authors.affiliation: Renaissance Computing Institute, University of North Carolina, Chapel Hill, North Carolina, United States of America.|Department of Genetic Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Wilhelmsen
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D058068:Endophenotypes; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis
chemical_list: D015415:Biomarkers