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Plasma AB as a Surrogate Genetic Marker for LOAD
1 April 2000 - 31 May 2013
NATIONAL INSTITUTE ON AGING
Total Funding: $ 2,985,762
DESCRIPTION (provided by applicant): In an effort to understand and to overcome the factors that thwart replication of genetic association studies, we recently studied variants in the conserved regions of the gene (IDE) that encodes the insulin/AB degrading enzyme gene in considerable detail. A remarkably high percentage of these variants had modest effects that showed replicable association when analyzed in our large case/control series. Based on these results, our current working hypothesis is that progress in identifying novel LOAD genes has been slow because most LOAD genes are like IDE;they have multiple susceptibility alleles with modest effect size. The effect of genes with powerful variants like the ApoE 4 allele is easily detected and replicated in small case/control series. But the net effect of genes with multiple susceptibility alleles that have modest effects, though substantial, cannot be detected and replicated well unless large case/control series are employed to evaluate a set of variants selected for their likely functional effect. Using the scientific infrastructure developed in the last cycle we propose to pursue this hypothesis by targeting genes in the AB processing pathway. We will perform an unbiased, genome-wide search for AB QTLs likely to harbor novel LOAD genes in the AB processing pathway. In addition, we will search thoroughly for and examine the function of additional susceptibility alleles in the known, major genes of the AB processing pathway. Our specific aims are to (1) perform whole genome scans to identify novel quantitative trait loci (QTLs) linked to plasma AB levels, (2) identify novel LOAD susceptibility alleles by using multiple, large case control series to analyze the variants in conserved regions of major genes in the AB processing pathway (SORL1, APP, IDE, MME, ECE1, PLAU, BACE1, PSEN1, PSEN2, and VR22), and (3) evaluate the functional effects of the susceptibility alleles identified in specific aim 2. Depending on the specific location of each susceptibility allele identified, function will be analyzed by evaluating the effect of the variant on (i) plasma AB and/or (ii) brain mRNA. Our recent results suggest that many susceptibility alleles may act by altering gene expression or splicing. There is strong evidence that reducing the AB42 peptide in normal elderly subjects could prevent Alzheimer's disease (AD), a disorder that inflicts enormous suffering and financial loss on our society. To perform affordable prevention trials and administer drugs to normal elderly people with an acceptable risk/benefit ratio, methods must be developed for identifying those elderly individuals who are at increased risk for AD. In this application, we propose experimentation to identify many genes with variants that alter AB42 thereby influencing risk for AD;we do so because each new AD gene identified opens new therapeutic possibilities and improves our ability to identify the at risk population.
26 Resulting Publications
Rita Guerreiro; Aleksandra Wojtas; Jose Bras; Minerva Carrasquillo; Ekaterina Rogaeva; Elisa Majounie; Carlos Cruchaga; Celeste Sassi; John S K Kauwe; Steven Younkin; et al.The New England journal of medicine 2013;368(2):117-27.
M I Kamboh; M M Barmada; F Y Demirci; R L Minster; M M Carrasquillo; V S Pankratz; S G Younkin; A J Saykin; ; R A Sweet; et al.Molecular psychiatry 2012;17(12):1340-6.
Gillian Hamilton; Richard Killick; ; ; Jean-Charles Lambert; Philippe Amouyel; ; Minerva M Carrasquillo; V Shane Pankratz; Neill R Graff-Radford; et al.Neurobiology of aging 2012;33(8):1848.e1-13.
Mariet Allen; Fanggeng Zou; High Seng Chai; Curtis S Younkin; Julia Crook; V Shane Pankratz; Minerva M Carrasquillo; Christopher N Rowley; Asha A Nair; Sumit Middha; et al.Neurology 2012;79(3):221-8.
Mariet Allen; Claire Cox; Olivia Belbin; Li Ma; Gina D Bisceglio; Samantha L Wilcox; Chanley C Howell; Talisha A Hunter; Oliver Culley; Louise P Walker; et al.Neurobiology of aging 2012;33(1):203.e25-33.
Fanggeng Zou; High Seng Chai; Curtis S Younkin; Mariet Allen; Julia Crook; V Shane Pankratz; Minerva M Carrasquillo; Christopher N Rowley; Asha A Nair; Sumit Middha; et al.PLoS genetics 2012;8(6):e1002707.
M I Kamboh; F Y Demirci; X Wang; R L Minster; M M Carrasquillo; V S Pankratz; S G Younkin; A J Saykin; ; G Jun; et al.Translational psychiatry 2012;2():e117.
Aleksandra Wojtas; Kristin A Heggeli; Nicole Finch; Matt Baker; Mariely Dejesus-Hernandez; Steven G Younkin; Dennis W Dickson; Neill R Graff-Radford; Rosa RademakersAmerican journal of neurodegenerative disease 2012;1(1):107-18.
Owen A Ross; Nicola J Rutherford; Matt Baker; Alexandra I Soto-Ortolaza; Minerva M Carrasquillo; Mariely DeJesus-Hernandez; Jennifer Adamson; Ma Li; Kathryn Volkening; Elizabeth Finger; et al.Human molecular genetics 2011;20(16):3207-12.
Olivia Belbin; Minerva M Carrasquillo; Michael Crump; Oliver J Culley; Talisha A Hunter; Li Ma; Gina Bisceglio; Fanggeng Zou; Mariet Allen; Dennis W Dickson; et al.Human genetics 2011;129(3):273-82.
Jeremy D Burgess; Otto Pedraza; Neill R Graff-Radford; Meron Hirpa; Fanggeng Zou; Richard Miles; Thuy Nguyen; Ma Li; John A Lucas; Robert J Ivnik; et al.Neurobiology of aging 2011;32(3):557.e1-9.
N Finch; M M Carrasquillo; M Baker; N J Rutherford; G Coppola; M Dejesus-Hernandez; R Crook; T Hunter; R Ghidoni; L Benussi; et al.Neurology 2011;76(5):467-74.
Christiane Reitz; Rong Cheng; Ekaterina Rogaeva; Joseph H Lee; Shinya Tokuhiro; Fanggeng Zou; Karolien Bettens; Kristel Sleegers; Eng King Tan; Ryo Kimura; et al.Archives of neurology 2011;68(1):99-106.
Olivia Belbin; Kristelle Brown; Hui Shi; Christopher Medway; Richard Abraham; Peter Passmore; David Mann; A David Smith; Clive Holmes; Bernadette McGuinness; et al.Journal of Alzheimer's disease : JAD 2011;24(3):587-97.
Minerva M Carrasquillo; Olivia Belbin; Talisha A Hunter; Li Ma; Gina D Bisceglio; Fanggeng Zou; Julia E Crook; V Shane Pankratz; Sigrid B Sando; Jan O Aasly; et al.Journal of Alzheimer's disease : JAD 2011;24(4):751-8.
Olivia Belbin; Michael Crump; Gina D Bisceglio; Minerva M Carrasquillo; Kevin Morgan; Steven G YounkinPloS one 2011;6(6):e21429.
Minerva M Carrasquillo; Alexandra M Nicholson; NiCole Finch; J Raphael Gibbs; Matt Baker; Nicola J Rutherford; Talisha A Hunter; Mariely DeJesus-Hernandez; Gina D Bisceglio; Ian R Mackenzie; et al.American journal of human genetics 2010;87(6):890-7.
Minerva M Carrasquillo; Olivia Belbin; Talisha A Hunter; Li Ma; Gina D Bisceglio; Fanggeng Zou; Julia E Crook; V Shane Pankratz; Dennis W Dickson; Neill R Graff-Radford; et al.Archives of neurology 2010;67(8):961-4.
Sudha Seshadri; Annette L Fitzpatrick; M Arfan Ikram; Anita L DeStefano; Vilmundur Gudnason; Merce Boada; Joshua C Bis; Albert V Smith; Minerva M Carassquillo; Jean Charles Lambert; et al.JAMA : the journal of the American Medical Association 2010;303(18):1832-40.
F Zou; M M Carrasquillo; V S Pankratz; O Belbin; K Morgan; M Allen; S L Wilcox; L Ma; L P Walker; N Kouri; et al.Neurology 2010;74(6):480-6.
Minerva M Carrasquillo; Olivia Belbin; Fanggeng Zou; Mariet Allen; Nilufer Ertekin-Taner; Morad Ansari; Samantha L Wilcox; Mariah R Kashino; Li Ma; Linda H Younkin; et al.PloS one 2010;5(1):e8764.
Minerva M Carrasquillo; Fanggeng Zou; V Shane Pankratz; Samantha L Wilcox; Li Ma; Louise P Walker; Samuel G Younkin; Curtis S Younkin; Linda H Younkin; Gina D Bisceglio; et al.Nature genetics 2009;41(2):192-8.
N Ertekin-Taner; L H Younkin; D M Yager; F Parfitt; M C Baker; S Asthana; M L Hutton; S G Younkin; N R Graff-RadfordNeurology 2008;70(8):596-606.
Nilüfer Ertekin-Taner; James Ronald; Lars Feuk; Jonathan Prince; Michael Tucker; Linda Younkin; Maria Hella; Shushant Jain; Alyssa Hackett; Leah Scanlin; et al.Human molecular genetics 2005;14(3):447-60.
Nilüfer Ertekin-Taner; Mariet Allen; Daniel Fadale; Leah Scanlin; Linda Younkin; Ronald C Petersen; Neill Graff-Radford; Steven G YounkinHuman mutation 2004;23(4):334-42.
Nilüfer Ertekin-Taner; James Ronald; Hideaki Asahara; Linda Younkin; Maria Hella; Shushant Jain; Eugene Gnida; Samuel Younkin; Daniel Fadale; Yasumasa Ohyagi; et al.Human molecular genetics 2003;12(23):3133-43.
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