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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,
Environmental Risk for Alzheimer’s disease (GERAD1) Consortium,
Kevin Morgan,
Steven G. Younkin
PLoS ONE 01/2013; · 4.09 Impact Factor
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Sarah Lincoln,
Mariet Allen,
Claire L Cox,
Louise P Walker,
Kimberly Malphrus,
Yushi Qiu,
Thuy Nguyen,
Christopher Rowley,
Naomi Kouri,
Julia Crook, [......],
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
[show abstract]
[hide abstract]
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.
PLoS ONE 01/2013; 8(6):e64164. · 4.09 Impact Factor
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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, [......],
Jonathan L Haines,
Richard Mayeux,
Margaret A Pericak-Vance,
Lindsay A Farrer,
Gerard D Schellenberg,
Ronald C Petersen,
Neill R Graff-Radford,
Dennis W Dickson,
Steven G Younkin,
Nilüfer Ertekin-Taner
[show abstract]
[hide abstract]
ABSTRACT: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.
We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.
CLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).
CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.
Neurology 06/2012; 79(3):221-8. · 8.31 Impact Factor
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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, [......],
Jonathan L Haines,
Richard Mayeux,
Margaret A Pericak-Vance,
Lindsay A Farrer,
Gerard D Schellenberg,
Ronald C Petersen,
Neill R Graff-Radford,
Dennis W Dickson,
Steven G Younkin,
Nilüfer Ertekin-Taner
[show abstract]
[hide abstract]
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.
PLoS Genetics 06/2012; 8(6):e1002707. · 8.69 Impact Factor
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Olivia Belbin,
Minerva M. Carrasquillo,
Michael Crump,
Oliver J. Culley,
Talisha A. Hunter,
Li Ma,
Gina Bisceglio, Fanggeng Zou,
Mariet Allen,
Dennis W. Dickson,
Neill R. Graff-Radford,
Ronald C. Petersen,
Kevin Morgan,
Steven G. Younkin
[show abstract]
[hide abstract]
ABSTRACT: The 12 genome-wide association studies (GWAS) published to-date for late-onset Alzheimer’s disease (LOAD) have identified
over 40 candidate LOAD risk modifiers, in addition to apolipoprotein (APOE) ε4. A few of these novel LOAD candidate genes, namely BIN1, CLU, CR1, EXOC3L2 and PICALM, have shown consistent replication, and are thus credible LOAD susceptibility genes. To evaluate other promising LOAD candidate
genes, we have added data from our large, case–control series (n=5,043) to meta-analyses of all published follow-up case–control association studies for six LOAD candidate genes that have
shown significant association across multiple studies (TNK1, GAB2, LOC651924, GWA_14q32.13, PGBD1 and GALP) and for an additional nine previously suggested candidate genes. Meta-analyses remained significant at three loci after
addition of our data: GAB2 (OR=0.78, p=0.007), LOC651924 (OR=0.91, p=0.01) and TNK1 (OR=0.92, p=0.02). Breslow–Day tests revealed significant heterogeneity between studies for GAB2 (p<0.0001) and GWA_14q32.13 (p=0.006). We have also provided suggestive evidence that PGBD1 (p=0.04) and EBF3 (p=0.03) are associated with age-at-onset of LOAD. Finally, we tested for interactions between these 15 genes, APOE ε4 and the five novel LOAD genes BIN1, CLU, CR1, EXOC3L2 and PICALM but none were significant after correction for multiple testing. Overall, this large, independent follow-up study for 15
of the top LOAD candidate genes provides support for GAB2 and LOC651924 (6q24.1) as risk modifiers of LOAD and novel associations between PGBD1 and EBF3 with age-at-onset.
Human Genetics 04/2012; 129(3):273-282. · 5.07 Impact Factor
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Mariet Allen, Fanggeng Zou,
High Seng Chai,
Curtis S Younkin,
Richard Miles,
Asha A Nair,
Julia E Crook,
V Shane Pankratz,
Minerva M Carrasquillo,
Christopher N Rowley, [......],
Jan O Aasly,
Maria Barcikowska,
Ryan J Uitti,
Zbigniew K Wszolek,
Owen A Ross,
Ronald C Petersen,
Neill R Graff-Radford,
Dennis W Dickson,
Steven G Younkin,
Nilüfer Ertekin-Taner
[show abstract]
[hide abstract]
ABSTRACT: Glutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative stress and may underlie the pathophysiology of both diseases. GSTO polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, GSTO1 rs4925 and GSTO2 rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects).
We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10-11-1.9 × 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003).
These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.
Molecular Neurodegeneration 04/2012; 7:13. · 4.28 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: ABSTRACT:
Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNP)s that are essentially unequivocally associated with peripheral cholesterol. Since the alleles of the APOE gene, which modulate peripheral cholesterol metabolism, and midlife plasma cholesterol are both associated with Alzheimer's disease (AD) risk, we have evaluated the hypothesis that SNPs associated with plasma cholesterol are also associated with AD.
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.
Molecular Neurodegeneration 08/2011; 6:62. · 4.28 Impact Factor
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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,
Maria Barcikowska,
Zbigniew K Wszolek,
Dennis W Dickson,
Neill R Graff-Radford,
Ronald C Petersen,
Kevin Morgan,
Steven G Younkin
[show abstract]
[hide abstract]
ABSTRACT: The most recent late-onset Alzheimer's disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 × 10-11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 × 10-9). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR = 1.17, p = 1.1 × 10-4) comparable to that previously reported (OR = 1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p = 0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p = 3.8 × 10-20). We also tested for epistatic interaction between these variants and APOE ε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1: rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further.
Journal of Alzheimer's disease: JAD 02/2011; 24(4):751-8. · 3.74 Impact Factor
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Christiane Reitz,
Rong Cheng,
Ekaterina Rogaeva,
Joseph H Lee,
Shinya Tokuhiro, Fanggeng Zou,
Karolien Bettens,
Kristel Sleegers,
Eng King Tan,
Ryo Kimura, [......],
Benedetta Nacmias,
Masatoshi Takeda,
Margaret A Pericak-Vance,
Jonathan L Haines,
Steven Younkin,
Julie Williams,
Christine van Broeckhoven,
Lindsay A Farrer,
Peter H St George-Hyslop,
Richard Mayeux
[show abstract]
[hide abstract]
ABSTRACT: To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD).
Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies.
Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy.
All published white and Asian case-control data sets, which included a total of 12,464 cases and 17,929 controls.
Alzheimer disease according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association).
In the white data sets, several markers were associated with AD after correction for multiple testing, including previously reported SNPs 8, 9, and 10 (P < .001). In addition, the C-G-C haplotype at SNPs 8 through 10 was associated with AD risk (P < .001). In the combined Asian data sets, SNPs 19 and 23 through 25 were associated with AD risk (P < .001). The disease-associated alleles at SNPs 8, 9, and 10 (120,873,131-120,886,175 base pairs [bp]; C-G-C alleles), at SNP 19 (120,953,300 bp; G allele), and at SNPs 24 through 25 (120,988,611 bp; T and C alleles) were the same previously reported alleles. The SNPs 4 through 5, 8 through 10, 12, and 19 through 25 belong to distinct linkage disequilibrium blocks. The same alleles at SNPs 8 through 10 (C-G-C), 19 (G), and 24 and 25 (T and C) have also been associated with AD endophenotypes, including white matter hyperintensities and hippocampal atrophy on magnetic resonance imaging, cerebrospinal fluid measures of amyloid β-peptide 42, and full-length SORL1 expression in the human brain.
This comprehensive meta-analysis provides confirmatory evidence that multiple SORL1 variants in distinct linkage disequilibrium blocks are associated with AD.
Archives of neurology 01/2011; 68(1):99-106. · 6.31 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Rheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis.
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.
Molecular Neurodegeneration 01/2011; 6:33. · 4.28 Impact Factor
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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,
Maria Barcikowska,
Zbigniew K Wszolek,
Dennis W Dickson,
Neill R Graff-Radford,
Ronald C Petersen,
Peter Passmore,
Kevin Morgan,
Steven G Younkin
[show abstract]
[hide abstract]
ABSTRACT: A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 dosage.
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).
Molecular Neurodegeneration 01/2011; 6(1):54. · 4.28 Impact Factor
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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,
Julia Crook,
V Shane Pankratz,
Dennis W Dickson,
Ronald C Petersen,
Steven G Younkin,
Nilüfer Ertekin-Taner
[show abstract]
[hide abstract]
ABSTRACT: KIBRA single nucleotide polymorphism (SNP) rs17070145 was identified in a genome-wide association study (GWAS) of memory performance, with some but not all follow-up studies confirming association of its T allele with enhanced memory. This allele was associated with reduced Alzheimer's disease (AD) risk in 1 study, which also found overexpression of KIBRA in memory-related brain regions of AD. We genotyped rs17070145 and 14 additional SNPs in 2571 late onset Alzheimer's disease (LOAD) patients vs. 2842 controls, including African-Americans. We found significantly reduced risk for rs17070145 T allele in the older African-American subjects (p = 0.007) and a suggestive effect in the older Caucasian series. Meta-analysis of this allele in > 8000 subjects from our and published series showed a suggestive protective effect (p = 0.07). Analysis of episodic memory in control subjects did not identify associations with rs17070145, though other SNPs showed significant associations in 1 series. KIBRA showed evidence of overexpression in the AD temporal cortex (p = 0.06) but not cerebellum. These results suggest a modest role for KIBRA as a cognition and AD risk gene, and also highlight the multifactorial complexity of its genetic associations.
Neurobiology of aging 12/2010; 32(3):557.e1-9. · 5.94 Impact Factor
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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,
Ronald C Petersen,
Kevin Morgan,
Steven G Younkin
[show abstract]
[hide abstract]
ABSTRACT: To test for replication of the association between variants in the CLU, CR1, and PICALM genes with Alzheimer disease.
Follow-up case-control association study.
The Mayo Clinics at Jacksonville, Florida, and Rochester, Minnesota.
Community-based patients of European descent with late-onset Alzheimer disease (LOAD) and controls without dementia who were seen at the Mayo clinics, and autopsy-confirmed cases and controls whose pathology was evaluated at the Mayo Clinic in Jacksonville. Additional samples were obtained from the National Cell Repository for Alzheimer Disease (NCRAD). A total of 1829 LOAD cases and 2576 controls were analyzed.
The most significant single-nucleotide polymorphisms in CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179) were tested for allelic association with LOAD. Main Outcome Measure Clinical or pathology-confirmed diagnosis of LOAD.
Odds ratios for CLU, CR1, and PICALM were 0.82, 1.15, and 0.80, respectively, comparable in direction and magnitude with those originally reported. P values were 8.6 x 10(-5), .014, and 1.3 x 10(-5), respectively; they remain significant even after Bonferroni correction for the 3 single-nucleotide polymorphisms tested.
These results show near-perfect replication and provide the first additional evidence that CLU, CR1, and PICALM are associated with the risk of LOAD.
Archives of neurology 08/2010; 67(8):961-4. · 6.31 Impact Factor
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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, [......],
Reinhard Heun,
Heike Kölsch,
Noor Kalsheker,
V Shane Pankratz,
Dennis W Dickson,
Neill R Graff-Radford,
Ronald C Petersen,
Alan F Wright,
Steven G Younkin,
Kevin Morgan
[show abstract]
[hide abstract]
ABSTRACT: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).
We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10(-8), fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Abeta40 levels (ss = -0.124, p = 0.011) and total measured plasma Abeta levels (b = -0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association.
Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.
PLoS ONE 01/2010; 5(1):e8764. · 4.09 Impact Factor
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Fanggeng Zou,
Mariet Allen,
Olivia Belbin,
Talisha Hunter,
Li Ma,
Gina Bisceglio,
Minerva Carrasquillo,
Curtis Younkin,
Ronald Petersen,
Neill Graff-Radford,
Dennis Dickson,
Ferenc Deak
Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2010; 6(4).
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Ryan Palusak, Fanggeng Zou,
Richard Miles,
Minerva Carrasquillo,
Li Ma, Thuy Nguyen,
Dennis Dickson,
Ronald C. Petersen,
Neil R. Graff-Radford,
Steven G. Younkin,
Nilufer Ertekin-Taner
Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2010; 6(4).
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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,
Nilufer Ertekin-Taner,
Julia E Crook,
Dennis W Dickson,
Ronald C Petersen,
Neill R Graff-Radford,
Steven G Younkin
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ABSTRACT: By analyzing late-onset Alzheimer's disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases and 1,255 controls) and evaluating the 25 SNPs with the most significant allelic association in four additional series (1,547 cases and 1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in individuals of European descent from the United States. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.7 x 10(-5) in stage 1, 4.8 x 10(-6) in stage 2 and 3.9 x 10(-12) in the combined data. Odds ratios were 1.75 (95% CI = 1.42-2.16) for female homozygotes (P = 2.0 x 10(-7)) and 1.26 (95% CI = 1.05-1.51) for female heterozygotes (P = 0.01) compared to female noncarriers. For male hemizygotes (P = 0.07) compared to male noncarriers, the odds ratio was 1.18 (95% CI = 0.99-1.41).
Nature Genetics 02/2009; 41(2):192-8. · 35.53 Impact Factor
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Jungsu Kim,
Victor M Miller,
Yona Levites,
Karen Jansen West,
Craig W Zwizinski,
Brenda D Moore,
Fredrick J Troendle,
Maralyssa Bann,
Christophe Verbeeck,
Robert W Price,
Lisa Smithson,
Leilani Sonoda,
Kayleigh Wagg,
Vijayaraghavan Rangachari, Fanggeng Zou,
Steven G Younkin,
Neill Graff-Radford,
Dennis Dickson,
Terrone Rosenberry,
Todd E Golde
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ABSTRACT: Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid beta precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer's disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-Abeta1-40 transgenes in APP mouse models. Expression of BRI2-Abeta1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral Abeta deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits Abeta aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Abeta deposition in vivo.
Journal of Neuroscience 06/2008; 28(23):6030-6. · 7.11 Impact Factor
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Fanggeng Zou,
Rangaraj K Gopalraj,
Johann Lok,
Haiyan Zhu,
I-Fang Ling,
James F Simpson,
H Michael Tucker,
Jeremiah F Kelly,
Samuel G Younkin,
Dennis W Dickson,
Ronald C Petersen,
Neill R Graff-Radford,
David A Bennett,
Julia E Crook,
Steven G Younkin,
Steven Estus
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ABSTRACT: Since apoE allele status is the predominant Alzheimer's disease (AD) genetic risk factor, functional single nucleotide polymorphisms (SNPs) in brain apoE receptors represent excellent candidates for association with AD. Recently, we identified a SNP, rs688, as modulating the splicing efficiency of low-density lipoprotein receptor (LDLR) exon 12 in female human liver and in minigene-transfected HepG2 cells. Moreover, the rs688T minor allele was associated with significantly higher LDL and total cholesterol in women within the Framingham Offspring Study cohort. Since LDLR is a major apoE receptor in the brain, we hypothesized that rs688 modulates LDLR splicing in neural tissues and associates with AD. To evaluate this hypothesis, we first transfected LDLR minigenes into SH-SY5Y neuroblastoma cells and found that the rs688T allele reduces exon 12 inclusion in this neural model. We then evaluated the association of rs688 allele with exon 12 splicing efficiency in vivo by quantifying LDLR splicing in human anterior cingulate tissue obtained at autopsy; the rs688T allele is associated with decreased LDLR exon 12 splicing efficiency in aged males, but not females. Lastly, we evaluated whether rs688 associates with AD by genotyping DNA from 1457 men and 2055 women drawn from three case-control series. The rs688T/T genotype was associated with increased AD odds in males [recessive model, odds ratio (OR) of 1.49, 95% confidence interval (CI) of 1.13-1.97, uncorrected P = 0.005], but not in females. In summary, these studies identify a functional apoE receptor SNP that is associated with AD in a sex-dependent fashion.
Human Molecular Genetics 05/2008; 17(7):929-35. · 7.64 Impact Factor
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Ekaterina Rogaeva, Joseph H. Lee,
Yan Meng,
Yosuke Wakutani, Fanggeng Zou,
Danielle Moreno, Rong Cheng,
Sandro Sorbi,
Amalia Bruni,
Ranjan Duara, Neill Graff-Radford,
Ronald C. Petersen
Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2008; 4(4).
