PMID- 26625115
OWN - NLM
STAT- MEDLINE
DCOM- 20160623
LR  - 20220311
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 12
DP  - 2015
TI  - Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to 
      Identification of Susceptibility Loci?
PG  - e0142360
LID - 10.1371/journal.pone.0142360 [doi]
LID - e0142360
AB  - 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.
FAU - Barber, Robert C
AU  - Barber RC
AD  - Department of Molecular & Medical Genetics, University of North Texas Health 
      Science Center, Fort Worth, Texas, United States of America.
AD  - Institute for Aging and Alzheimer's Disease Research, University of North Texas 
      Health Science Center, Fort Worth, Texas, United States of America.
FAU - Phillips, Nicole R
AU  - Phillips NR
AD  - Department of Biology, University of Dallas, Dallas, Texas, United States of 
      America.
FAU - Tilson, Jeffrey L
AU  - Tilson JL
AD  - Renaissance Computing Institute, University of North Carolina, Chapel Hill, North 
      Carolina, United States of America.
FAU - Huebinger, Ryan M
AU  - Huebinger RM
AD  - Department of Surgery, University of Texas Southwestern Medical Center, Dallas, 
      Texas, United States of America.
FAU - Shewale, Shantanu J
AU  - Shewale SJ
AD  - Department of Molecular & Medical Genetics, University of North Texas Health 
      Science Center, Fort Worth, Texas, United States of America.
FAU - Koenig, Jessica L
AU  - Koenig JL
AD  - Department of Molecular & Medical Genetics, University of North Texas Health 
      Science Center, Fort Worth, Texas, United States of America.
FAU - Mitchel, Jeffrey S
AU  - Mitchel JS
AD  - Department of Molecular & Medical Genetics, University of North Texas Health 
      Science Center, Fort Worth, Texas, United States of America.
FAU - O'Bryant, Sid E
AU  - O'Bryant SE
AD  - Institute for Aging and Alzheimer's Disease Research, University of North Texas 
      Health Science Center, Fort Worth, Texas, United States of America.
AD  - Department of Internal Medicine, University of North Texas Health Science Center, 
      Fort Worth, Texas, United States of America.
FAU - Waring, Stephen C
AU  - Waring SC
AD  - Essentia Institute of Rural Health, Duluth, Minnesota, United States of America.
FAU - Diaz-Arrastia, Ramon
AU  - Diaz-Arrastia R
AD  - Center for Neuroscience and Regenerative Medicine, Uniformed Services University 
      of the Health Sciences, Rockville, Maryland, United States of America.
FAU - Chasse, Scott
AU  - Chasse S
AD  - Department of Genetics, University of North Carolina, Chapel Hill, North 
      Carolina, United States of America.
FAU - Wilhelmsen, Kirk C
AU  - Wilhelmsen KC
AD  - Renaissance Computing Institute, University of North Carolina, Chapel Hill, North 
      Carolina, United States of America.
AD  - Department of Genetic Medicine, University of North Carolina, Chapel Hill, North 
      Carolina, United States of America.
CN  - Alzheimer's Disease Neuroimaging Initiative
CN  - Texas Alzheimer's Research and Care Consortium
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
GR  - R01 DA030976/DA/NIDA NIH HHS/United States
GR  - U01 HG006487/HG/NHGRI NIH HHS/United States
GR  - P30AG12300-20/AG/NIA NIH HHS/United States
GR  - 1U01HG007437/HG/NHGRI NIH HHS/United States
GR  - U24 AA020024/AA/NIAAA NIH HHS/United States
GR  - 5U24 AA020024/AA/NIAAA NIH HHS/United States
GR  - 1U19HD077632/HD/NICHD NIH HHS/United States
GR  - 5R01DA030976/DA/NIDA NIH HHS/United States
GR  - RC2 AG036535/AG/NIA NIH HHS/United States
GR  - T32 AG020494/AG/NIA NIH HHS/United States
GR  - T32AG020494/AG/NIA NIH HHS/United States
GR  - 5P01DK058335/DK/NIDDK NIH HHS/United States
GR  - UL1 TR001111/TR/NCATS NIH HHS/United States
GR  - 1UL1TR001111/TR/NCATS NIH HHS/United States
GR  - U01 HG007437/HG/NHGRI NIH HHS/United States
GR  - U01 AG024904/AG/NIA NIH HHS/United States
GR  - P30 AG012300/AG/NIA NIH HHS/United States
GR  - 5U01HG006487/HG/NHGRI NIH HHS/United States
GR  - 5P01-DK058335/DK/NIDDK NIH HHS/United States
GR  - U19 HD077632/HD/NICHD NIH HHS/United States
GR  - 5U24AA020024/AA/NIAAA NIH HHS/United States
GR  - P01 DK058335/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20151201
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Biomarkers)
SB  - IM
MH  - Aged
MH  - Alzheimer Disease/*blood/diagnosis/*genetics
MH  - Biomarkers/blood
MH  - Endophenotypes
MH  - Female
MH  - Genetic Loci/*genetics
MH  - Genetic Predisposition to Disease/*genetics
MH  - Genomics
MH  - Humans
MH  - Male
MH  - Polymorphism, Single Nucleotide
MH  - Regression Analysis
PMC - PMC4666664
COIS- Competing Interests: The authors have declared that no competing interests exist.
FIR - Doody, Rachelle
IR  - Doody R
FIR - Dang, Mimi M
IR  - Dang MM
FIR - Pavlik, Valory
IR  - Pavlik V
FIR - Chan, Wen
IR  - Chan W
FIR - Massman, Paul
IR  - Massman P
FIR - Darby, Eveleen
IR  - Darby E
FIR - Evans, Tracy
IR  - Evans T
FIR - Khaleeq, Aisha
IR  - Khaleeq A
FIR - Wu, Chuang-Kuo
IR  - Wu CK
FIR - Lambert, Matthew
IR  - Lambert M
FIR - Perez, Victoria
IR  - Perez V
FIR - Hernandez, Michelle
IR  - Hernandez M
FIR - Fairchild, Thomas
IR  - Fairchild T
FIR - Knebl, Janice
IR  - Knebl J
FIR - Hall, James R
IR  - Hall JR
FIR - Johnson, Leigh
IR  - Johnson L
FIR - Mains, Douglas
IR  - Mains D
FIR - Alvarez, Lisa
IR  - Alvarez L
FIR - McCallum, Rosemary
IR  - McCallum R
FIR - Adams, Perrie
IR  - Adams P
FIR - Cullum, Munro
IR  - Cullum M
FIR - Rosenberg, Roger
IR  - Rosenberg R
FIR - Williams, Benjamin
IR  - Williams B
FIR - Quiceno, Mary
IR  - Quiceno M
FIR - Reisch, Joan
IR  - Reisch J
FIR - Martinez, Natalie
IR  - Martinez N
FIR - Smith, Janet
IR  - Smith J
FIR - Royall, Donald
IR  - Royall D
FIR - Palmer, Raymond
IR  - Palmer R
FIR - Polk, Marsha
IR  - Polk M
FIR - Sohrabji, Farida
IR  - Sohrabji F
FIR - Balsis, Steve
IR  - Balsis S
FIR - Miranda, Rajesh
IR  - Miranda R
FIR - Weiner, Michael W
IR  - Weiner MW
FIR - Aisen, Paul
IR  - Aisen P
FIR - Petersen, Ronald
IR  - Petersen R
FIR - Jack, Clifford R Jr
IR  - Jack CR Jr
FIR - Jagust, William
IR  - Jagust W
FIR - Trojanowski, John Q
IR  - Trojanowski JQ
FIR - Toga, Arthur W
IR  - Toga AW
FIR - Beckett, Laurel
IR  - Beckett L
FIR - Green, Robert C
IR  - Green RC
FIR - Saykin, Andrew J
IR  - Saykin AJ
FIR - Morris, John
IR  - Morris J
FIR - Shaw, Leslie M
IR  - Shaw LM
EDAT- 2015/12/02 06:00
MHDA- 2016/06/24 06:00
PMCR- 2015/12/01
CRDT- 2015/12/02 06:00
PHST- 2015/06/02 00:00 [received]
PHST- 2015/10/21 00:00 [accepted]
PHST- 2015/12/02 06:00 [entrez]
PHST- 2015/12/02 06:00 [pubmed]
PHST- 2016/06/24 06:00 [medline]
PHST- 2015/12/01 00:00 [pmc-release]
AID - PONE-D-15-23462 [pii]
AID - 10.1371/journal.pone.0142360 [doi]
PST - epublish
SO  - PLoS One. 2015 Dec 1;10(12):e0142360. doi: 10.1371/journal.pone.0142360. 
      eCollection 2015.