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2.  Novel late-onset Alzheimer disease loci variants associate with brain gene expression 
Neurology  2012;79(3):221-228.
Objective:
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.
Methods:
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.
Results:
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).
Conclusions:
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.
doi:10.1212/WNL.0b013e3182605801
PMCID: PMC3398432  PMID: 22722634
3.  Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer’s Disease Pathology 
PLoS ONE  2013;8(5):e64802.
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.
doi:10.1371/journal.pone.0064802
PMCID: PMC3665686  PMID: 23724096
4.  Replication of BIN1 association with Alzheimer’s disease and evaluation of genetic interactions 
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, sex 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 APOEε4 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.
doi:10.3233/JAD-2011-101932
PMCID: PMC3489170  PMID: 21321396
Alzheimer Disease; Late Onset; Heterogeneity; Meta-Analysis; Case-Control Studies
5.  Brain Expression Genome-Wide Association Study (eGWAS) Identifies Human Disease-Associated Variants 
PLoS Genetics  2012;8(6):e1002707.
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.
Author Summary
Genetic variants that regulate gene expression levels can also influence human disease risk. Discovery of genomic loci that alter brain gene expression levels (brain expression quantitative trait loci = eQTLs) can be instrumental in the identification of genetic risk underlying both central nervous system (CNS) and non–CNS diseases. To systematically assess the role of brain eQTLs in human disease and to evaluate the influence of brain region and pathology in eQTL mapping, we performed an expression genome-wide association study (eGWAS) in 773 brain samples from the cerebellum and temporal cortex of ∼200 autopsied subjects with Alzheimer's disease (AD) and ∼200 with other brain pathologies (non–AD). We identified ∼3,000 significant associations between cisSNPs near ∼700 genes and their cerebellar transcript levels, which replicate in ADs and non–ADs. More than 2,000 of these associations were reproducible in the temporal cortex. The top cisSNPs are enriched for both CNS and non–CNS disease-associated variants. We identified novel and confirmed previous cisSNP/transcript associations for many disease loci, suggesting gene expression regulation as their mechanism of action. These findings demonstrate the reproducibility of the eQTL approach across different brain regions and pathologies, and advocate the combined use of gene expression and disease GWAS for identification and functional characterization of human disease-associated variants.
doi:10.1371/journal.pgen.1002707
PMCID: PMC3369937  PMID: 22685416
6.  Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications 
Background
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).
Results
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).
Conclusion
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.
doi:10.1186/1750-1326-7-13
PMCID: PMC3393625  PMID: 22494505
GSTO genes; Disease risk; Gene expression; Association
7.  Replication of CLU, CR1 and PICALM associations with Alzheimer’s disease 
Archives of neurology  2010;67(8):961-964.
Background
Harold et al. and Lambert et al. recently published two large genome-wide association studies of late onset Alzheimer’s disease (LOAD) in which CLU, CR1, and PICALM were identified as novel LOAD genes.
Objective
To test for replication of the association between variants in the CLU, CR1 and PICALM genes with Alzheimer’s disease.
Design
Case-control association study
Setting
Community-based ascertainment of patients seen at the Mayo Clinic Jacksonville, FL and Rochester, MN, and autopsy-confirmed cases and controls whose pathology was evaluated at the Mayo Clinic Jacksonville. Additional samples were obtained from the National Cell Repository for Alzheimer’s Disease (NCRAD).
Participants
LOAD case-control series of European descent consisting of 1,829 LOAD cases and 2,576 controls
Main Outcome Measure
Clinical or pathology-confirmed diagnosis of LOAD
Results
In our follow-up study of 1,829 LOAD cases and 2,576 controls, the most significant SNPs in CLU (rs11136000), CR1 (rs3818361), and PICALM (rs3851179) were tested for allelic association and gave ORs of 0.82, 1.15, and 0.80 respectively that were comparable in direction and magnitude to those originally reported with p values of 8.6×10−5, 0.014, and 1.3×10−5 that were significant even after Bonferroni correction for 3 SNPs tested.
Conclusion
These results showing near perfect replication provide the first additional evidence that CLU, CR1, and PICALM are LOAD genes.
doi:10.1001/archneurol.2010.147
PMCID: PMC2919638  PMID: 20554627
8.  Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study 
Background
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.
Results
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).
Conclusions
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).
doi:10.1186/1750-1326-6-54
PMCID: PMC3157442  PMID: 21798052
9.  Multiple Insulin Degrading Enzyme Variants Alter In Vitro Reporter Gene Expression 
PLoS ONE  2011;6(6):e21429.
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.
doi:10.1371/journal.pone.0021429
PMCID: PMC3120874  PMID: 21731745
10.  Investigation of 15 of the top candidate genes for late-onset Alzheimer’s disease 
Human Genetics  2010;129(3):273-282.
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.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-010-0924-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-010-0924-2
PMCID: PMC3036835  PMID: 21132329
11.  Genetic variation in PCDH11X is associated with susceptibility to late onset Alzheimer's disease 
Nature genetics  2009;41(2):192-198.
By analyzing late onset Alzheimer's disease (LOAD) in a genome wide association study (313,504 SNPs, 3 series, 844 cases/1,255 controls) and evaluating the 25 SNPs with most significant allelic association in 4 additional series (1,547 cases/1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in American Caucasians. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.7×10-5 in stage I, 4.8×10-6 in stage II, and 3.9×10-12 in the combined data. Odds ratios were 1.75 (95% CI 1.42-2.16) for female homozygotes (P=2.0×10-7) and 1.26 (95% CI 1.05-1.51) for female heterozygotes (P=0.01) compared to female non-carriers. For male hemizygotes (P=0.07) compared to male non-carriers the odds ratio was 1.18 (95% CI 0.99-1.41).
doi:10.1038/ng.305
PMCID: PMC2873177  PMID: 19136949
12.  Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members 
Brain  2009;132(3):583-591.
Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53–94 ng/ml) and 191 non-GRN mutation carriers (range: 115–386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The ∼75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.
doi:10.1093/brain/awn352
PMCID: PMC2664450  PMID: 19158106
Progranulin; ELISA; frontotemporal lobar degeneration; Alzheimer's disease

Results 1-12 (12)