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Search Results: 1 - 10 of 197991 matches for " Steven G. Younkin "
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Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk
Christopher R Simmons, Fanggeng Zou, Steven G Younkin, Steven Estus
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-62
Abstract: Seventeen non-APOE SNPs reproducibly associated with cholesterol per GWAS were tested for association with AD in ~2,000 AD and ~4,000 non-AD subjects. As a group, these SNPs are associated with AD. Two SNPs in particular, rs3846662 and rs1532085, are associated with AD risk and age-of-onset. Additionally, rs3846662 was associated with HMGCR exon 13 splicing in human liver but not brain, possibly obscured by CNS cell-type heterogeneity. However, rs3846662 was associated with HMGCR exon 13 splicing in liver- and brain-derived cell lines.Cholesterol-associated SNPs outside of APOE confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset. Rs3846662 is associated with HMGCR exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD.Late-onset Alzheimer's disease (AD) is a devastating form of dementia with no clear etiology. As much as 80% of age-adjusted AD risk may be genetic based upon studies of monozygotic twins [1,2]. The primary genetic modulators of AD risk are the alleles of the gene encoding apolipoprotein E (APOE), i.e. APOE-ε2, APOE-ε3 and APOE-ε4. The presence of APOE-ε4 alone accounts for up to 53% of AD risk while the presence of APOE-ε2 is protective against the disease [3-5].Multiple theories have been proposed to account for the mechanism underlying the association of APOE with AD [6,7]. One theory suggests that the alleles of APOE modulate AD risk via their effects on cholesterol homeostasis. This is supported by evidence that the APOE-ε4 and APOE-ε2 alleles are associated with increased and decreased levels of plasma cholesterol, respectively [8]. Furthermore, elevated midlife cholesterol is itself a risk factor for AD, raising the possibility that genetic modulators of cholesterol may also modulate AD risk [9,10]. To this end, prior studies have demonstrated variable associati
Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer's disease
Christopher R Simmons, Fanggeng Zou, Steven G Younkin, Steven Estus
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-33
Abstract: In our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p < 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2, which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively).RA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of BACE2 expression.There is a long-standing, inverse relationship between the prevalence of Alzheimer's disease (AD) and of rheumatoid arthritis (RA). Jenkinson and colleagues first described t
Multiple Insulin Degrading Enzyme Variants Alter In Vitro Reporter Gene Expression
Olivia Belbin, Michael Crump, Gina D. Bisceglio, Minerva M. Carrasquillo, Kevin Morgan, Steven G. Younkin
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021429
Abstract: The insulin degrading enzyme (IDE) variant, v311 (rs6583817), is associated with increased post-mortem cerebellar IDE mRNA, decreased plasma β-amyloid (Aβ), decreased risk for Alzheimer's disease (AD) and increased reporter gene expression, suggesting that it is a functional variant driving increased IDE expression. To identify other functional IDE variants, we have tested v685, rs11187061 (associated with decreased cerebellar IDE mRNA) and variants on H6, the haplotype tagged by v311 (v10; rs4646958, v315; rs7895832, v687; rs17107734 and v154; rs4646957), for altered in vitro reporter gene expression. The reporter gene expression levels associated with the second most common haplotype (H2) successfully replicated the post-mortem findings in hepatocytoma (0.89 fold-change, p = 0.04) but not neuroblastoma cells. Successful in vitro replication was achieved for H6 in neuroblastoma cells when the sequence was cloned 5′ to the promoter (1.18 fold-change, p = 0.006) and 3′ to the reporter gene (1.29 fold change, p = 0.003), an effect contributed to by four variants (v10, v315, v154 and v311). Since IDE mediates Aβ degradation, variants that regulate IDE expression could represent good therapeutic targets for AD.
Persistent Amyloidosis following Suppression of Aβ Production in a Transgenic Model of Alzheimer Disease
Joanna L Jankowsky ,Hilda H Slunt,Victoria Gonzales,Alena V Savonenko,Jason C Wen,Nancy A Jenkins,Neal G Copeland,Linda H Younkin,Henry A Lester,Steven G Younkin,David R Borchelt
PLOS Medicine , 2005, DOI: 10.1371/journal.pmed.0020355
Abstract: Background The proteases (secretases) that cleave amyloid-β (Aβ) peptide from the amyloid precursor protein (APP) have been the focus of considerable investigation in the development of treatments for Alzheimer disease. The prediction has been that reducing Aβ production in the brain, even after the onset of clinical symptoms and the development of associated pathology, will facilitate the repair of damaged tissue and removal of amyloid lesions. However, no long-term studies using animal models of amyloid pathology have yet been performed to test this hypothesis. Methods and Findings We have generated a transgenic mouse model that genetically mimics the arrest of Aβ production expected from treatment with secretase inhibitors. These mice overexpress mutant APP from a vector that can be regulated by doxycycline. Under normal conditions, high-level expression of APP quickly induces fulminant amyloid pathology. We show that doxycycline administration inhibits transgenic APP expression by greater than 95% and reduces Aβ production to levels found in nontransgenic mice. Suppression of transgenic Aβ synthesis in this model abruptly halts the progression of amyloid pathology. However, formation and disaggregation of amyloid deposits appear to be in disequilibrium as the plaques require far longer to disperse than to assemble. Mice in which APP synthesis was suppressed for as long as 6 mo after the formation of Aβ deposits retain a considerable amyloid load, with little sign of active clearance. Conclusion This study demonstrates that amyloid lesions in transgenic mice are highly stable structures in vivo that are slow to disaggregate. Our findings suggest that arresting Aβ production in patients with Alzheimer disease should halt the progression of pathology, but that early treatment may be imperative, as it appears that amyloid deposits, once formed, will require additional intervention to clear.
Expression of SORL1 and a novel SORL1 splice variant in normal and Alzheimers disease brain
Karrie E Grear, I-Fang Ling, James F Simpson, Jennifer L Furman, Christopher R Simmons, Shawn L Peterson, Frederick A Schmitt, William R Markesbery, Qiang Liu, Julia E Crook, Steven G Younkin, Guojun Bu, Steven Estus
Molecular Neurodegeneration , 2009, DOI: 10.1186/1750-1326-4-46
Abstract: To identify SORL1 splice variants, we scanned each of the 46 internal SORL1 exons in human brain RNA samples and readily found SORL1 isoforms that lack exon 2 or exon 19. Quantification in a case-control series of the more abundant isoform lacking exon 2 (delta-2-SORL1), as well as the "full-length" SORL1 (FL-SORL1) isoform containing exon 2 showed that expression of FL-SORL1 was reduced in AD individuals. Moreover, FL-SORL1 was reduced in cognitively intact individuals with significant AD-like neuropathology. In contrast, the expression of the delta-2-SORL1 isoform was similar in AD and non-AD brains. The expression of FL-SORL1 was significantly associated with synaptophysin expression while delta-2-SORL1 was modestly enriched in white matter. Lastly, FL-SORL1 expression was associated with rs661057, a SORL1 intron one SNP that has been associated with AD risk. A linear regression analysis found that rs661057, synaptophysin expression and AD neuropathology were each associated with FL-SORL1 expression.These results confirm that FL-SORL1 expression declines in AD and with AD-associated neuropathology, suggest that FL-SORL1 declines in cognitively-intact individuals with AD-associated neuropathology, identify a novel SORL1 splice variant that is expressed similarly in AD and non-AD individuals, and provide evidence that an AD-associated SNP is associated with SORL1 expression. Overall, these results contribute to our understanding of SORL1 expression in the human brain.SORL1 is a mosaic protein consisting of an amino-terminal portion resembling the vacuolar protein sorting-10 (Vps10) receptor family and a carboxyl-terminal portion having attributes of the low-density lipoprotein receptor (LDLR) family. As such, this type-1 transmembrane protein is capable of binding ligands ranging from receptor-associated protein (RAP) to apolipoprotein E (apoE) [1]. Recently, SORL1 has also been associated with AD at several levels. First, SORL1 interacts with amyloid precursor pro
LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer’s Disease (LOAD)
Sarah Lincoln, Mariet Allen, Claire L. Cox, Louise P. Walker, Kimberly Malphrus, Yushi Qiu, Thuy Nguyen, Christopher Rowley, Naomi Kouri, Julia Crook, V. Shane Pankratz, Samuel Younkin, Linda Younkin, Minerva Carrasquillo, Fanggeng Zou, Samer O. Abdul-Hay, Wolfdieter Springer, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Zbigniew K. Wszolek, Jada M. Lewis, Dennis Dickson, Neill R. Graff-Radford, Ronald C. Petersen, Elizabeth Eckman, Steven G. Younkin, Nilüfer Ertekin-Taner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064164
Abstract: Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer’s disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ~400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5′UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02–0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.
Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, A?, and Alzheimer's Disease
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,Samuel G. Younkin,Curtis S. Younkin,Toros A. Dincman,Melissa E. Howard,Chanley C. Howell,Chloe M. Stanton,Christopher M. Watson,Michael Crump,Veronique Vitart,Caroline Hayward,Nicholas D. Hastie,Igor Rudan,Harry Campbell,Ozren Polasek,Kristelle Brown,Peter Passmore,David Craig,Bernadette McGuinness,Stephen Todd,Patrick G. Kehoe,David M. Mann,A. David Smith,Helen Beaumont,Donald Warden,Clive Holmes,Reinhard Heun,Heike K?lsch,Noor Kalsheker,V. Shane Pankratz,Dennis W. Dickson,Neill R. Graff-Radford,Ronald C. Petersen,Alan F. Wright,Steven G. Younkin,Kevin Morgan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008764
Abstract: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).
Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study
Minerva M Carrasquillo, Olivia Belbin, Talisha A Hunter, Li Ma, Gina D Bisceglio, Fanggeng Zou, Julia E Crook, V Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, Peter Passmore, Kevin Morgan, for the Alzheimer's Research UK (ARUK) consortium, Steven G Younkin
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-54
Abstract: We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10-4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56).Our data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10-15 (EPHA1) and 1.8 × 10-13 (CD33).Following the identification of the APOE ε4 allele as a risk factor for late-onset Alzheimer's disease (LOAD) in 1993 [1], consistent replication of subsequently identified candidates was not achieved until 2009, when two genome-wide association studies (GWAS) [2,3] identified associations of variants in or near CLU, PICALM , and CR1 with LOAD, which were consistently replicated in multiple large, independent case-control studies [4-17]. Subsequently, a variant near BIN1 was reported [4] to achieve genome-wide significant association in a later GWAS published in 2010 that also replicated well in follow-up studies [14-19]. These results demonstrate the utility of the hypothesis-free GWAS approach for identifying loci that associate with LOAD and the necessity of pooling samples and data from multiple centers to obtain resources with sufficient statistical power (GWAS typically > 14,000, follow-up typically total > 28,000) to detect the modest ORs (e.g. 0.8/1.2) associated with these variants in GWAS and follow-up studies.Two recently published companion s
Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer’s Disease Pathology
Fanggeng Zou, Olivia Belbin, Minerva M. Carrasquillo, Oliver J. Culley, Talisha A. Hunter, Li Ma, Gina D. Bisceglio, Mariet Allen, Dennis W. Dickson, Neill R. Graff-Radford, Ronald C. Petersen, the Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium , Kevin Morgan, Steven G. Younkin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064802
Abstract: GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer’s disease (LOAD) with reported odds ratios (ORs) ranging from 0.75–0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61–1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61–0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82–0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5×10?7?9.3×10?6). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = ?0.34, p = 0.0006) and senile plaque counts (r = ?0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = ?0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level.
Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants
Fanggeng Zou equal contributor,High Seng Chai equal contributor,Curtis S. Younkin equal contributor,Mariet Allen equal contributor,Julia Crook,V. Shane Pankratz,Minerva M. Carrasquillo,Christopher N. Rowley,Asha A. Nair,Sumit Middha,Sooraj Maharjan,Thuy Nguyen,Li Ma,Kimberly G. Malphrus,Ryan Palusak,Sarah Lincoln,Gina Bisceglio,Constantin Georgescu,Naomi Kouri,Christopher P. Kolbert,Jin Jen,Jonathan L. Haines,Richard Mayeux,Margaret A. Pericak-Vance,Lindsay A. Farrer,Gerard D. Schellenberg,Alzheimer's Disease Genetics Consortium,Ronald C. Petersen,Neill R. Graff-Radford,Dennis W. Dickson,Steven G. Younkin,Nilüfer Ertekin-Taner
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002707
Abstract: Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n = 197, temporal cortex n = 202) and with other brain pathologies (non–AD, cerebellar n = 177, temporal cortex n = 197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within ±100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non–ADs (q<0.05, p = 7.70×10?5–1.67×10?82). Of these, 2,089 were also significant in the temporal cortex (p = 1.85×10?5–1.70×10?141). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10?6). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9–3.3 fold enrichment (p<10?6) of significant cisSNPs with suggestive AD–risk association (p<10?3) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non–CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.
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