Maria Victoria Fernandez

A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

A genome-wide survival analysis of 14,406 Alzheimers disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

Role of ABCA7 loss-of-function variant in Alzheimer's disease: a replication study in European-Americans

IntroductionA recent study found a significant increase of ABCA7 loss-of-function variants in Alzheimer’s disease (AD) cases compared to controls. Some variants were located on noncoding regions, but it was demonstrated that they affect splicing. Here, we try to replicate the association between AD risk and ABCA7 loss-of-function variants at both the single-variant and gene level in a large and well-characterized European American dataset.MethodsWe genotyped the GWAS common variant and four rare variants previously reported for ABCA7 in 3476 European–Americans.ResultsWe were not able to replicate the association at the single-variant level, likely due to a lower effect size on the European American population which led to limited statistical power. However, we did replicate the association at the gene level; we found a significant enrichment of ABCA7 loss-of-function variants in AD cases compared to controls (P = 0.0388; odds ratio =1.54). We also confirmed that the association of the loss-of-function variants is independent of the previously reported genome-wide association study signal.ConclusionsAlthough the effect size for the association of ABCA7 loss-of-function variants with AD risk is lower in our study (odds ratio = 1.54) compared to the original report (odds ratio = 2.2), the replication of the findings of the original report provides a stronger foundation for future functional applications. The data indicate that different independent signals that modify risk for complex traits may exist on the same locus. Additionally, our results suggest that replication of rare-variant studies should be performed at the gene level rather than focusing on a single variant.

Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits

Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels, and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r, and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects, and complex disease associations in the same locus.

SORL1 variants across Alzheimer's disease European American cohorts.

The accumulation of the toxic Aβ peptide in Alzheimer’s disease (AD) largely relies upon an efficient recycling of amyloid precursor protein (APP). Recent genetic association studies have described rare variants in SORL1 with putative pathogenic consequences in the recycling of APP. In this work, we examine the presence of rare coding variants in SORL1 in three different European American cohorts: early-onset, late-onset AD (LOAD) and familial LOAD.

Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer disease

Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America. Known pathogenic mutations were found in 1.05% of the sporadic cases, in 0.69% of the cognitively normal participants and in 4.22% of the families. A trend towards enrichment, albeit non-significant, was observed for most AD, FTD and PD genes. Only PSEN1 and PINK1 showed consistent association with AD cases when we used ExAC as the control population. These results suggest that current study designs may contain heterogeneity and contamination of the control population, and that current statistical methods for the discovery of novel genes with real pathogenic variants in complex late onset diseases may be inadequate or underpowered to identify genes carrying pathogenic mutations.

Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms

To determine whether the extent of overlap of the genetic architecture among the sporadic late‐onset Alzheimers Disease (sLOAD), familial late‐onset AD (fLOAD), sporadic early‐onset AD (sEOAD), and autosomal dominant early‐onset AD (eADAD).

A COMMON ALLELE IN SPI1 LOWERS RISK AND DELAYS AGE AT ONSET FOR ALZHEIMER'S DISEASE

Kuan-Lin Huang, Sheng Chih Jin, Oscar Harari, Manav Kapoor, Sarah Bertelsen, Jake Czajkowski, jean-Charles Lambert, Vincent Chouraki, C eline Bellenguez, Benjamin Grenier-Boley, Yuetiva Deming, Andrew McKenzie, Alan E. Renton, John Budde, Jorge L. Del-Aguila, Maria Victoria Fernandez, Laura Ibanez, Denise Harold, Paul Hollingworth, Richard Mayeux, Jonathan L. Haines, Lindsay A. Farrer, Margaret A. Pericak-Vance, Sudha Seshadri, Julie Williams, Philippe Amouyel, Gerard D. Schellenberg, Bin Zhang, Ingrid Borecki, John Kauwe, Eduardo Marcora, Carlos Cruchaga, Alison M. Goate, The Alzheimer’s Disease Neuroimaging Initiative, Washington University in St. Louis, Saint Louis, MO, USA; 2 Yale University, New Haven, CT, USA; 3 Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institut Pasteur de Lille, Lille, France; Boston University School of Medicine, Boston, MA, USA; 6 Washington University School of Medicine, Saint Louis, MO, USA; 7 Cardiff University, Cardiff, United Kingdom; 8 Columbia University, New York, NY, USA; Case Western Reserve University, Cleveland, OH, USA; Boston University, Boston, MA, USA; University of Miami, Miller School of Medicine, Miami, FL, USA; 12 MRC Centre for Neuropsychiatric Genetics & Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; 14 Brigham Young University, Provo, UT, USA. Contact e-mail: kuan-lin. huang@wustl.edu

Evaluation of Candidate Genes Related to Neuronal Apoptosis in Late-Onset Alzheimer's Disease

The objective of this study was to identify genetic variation in genes encoding death receptors and signals that modulate their activity. After conducting a meta-analysis with five previous genome-wide association studies and aggregated data, the most significant signals, (TNF locus: rs2395488, rs2534672, and rs9267445; and FASLG locus: rs730278), were replicated in 1,046 cases and 372 controls. The rs2395488 and rs2534672 markers showed a modest protective effect (OR = 0.849, p = 0.49780;OR= 0.687, p = 0.11335), in contrast to rs730278 marker (OR = 1.146, p = 0.17212), which did not follow the previous effect direction; in any case it reached the significance level. Final meta-analysis, adding the replication sample, confirmed these observations. We concluded that FASLG marker is not etiologically linked to Alzheimer’s disease. However, single nucleotide polymorphisms around TNF locus require further analyses in order to explain the association between Alzheimer’s disease and human leukocyte antigen.

NOMINATION OF NOVEL CANDIDATE GENES FOR FAMILIAL LATE ONSET ALZHEIMER DISEASE AFTER EVALUATION OF GENE-BASED FAMILY-BASED METHODS

of this size allowed us to discount or reaffirm the results observed in past experiments.Methods:The data for this study was collected by the Alzheimer’s Disease Genetic Consortium. In total, the experiment included 12,157 cases and 12,729 controls. A logistic regression analysis—with and without the interaction term—was performed on the entire dataset, as well as on each individual series. A Synergy Factor Analysis was also employed in order to analyze the significance of the interaction effect between rs1049296 and rs1800562. Results:Logistic regression analysis revealed no significant association between the main effects of TF and HFE and AD risk (p >1⁄4 0.16). Furthermore, the Synergy Factor Analysis suggests no correlation between the interaction effect and risk for AD (p 1⁄4 .478). Conclusions: Our study finds that risk for Alzheimer’s Disease is not affected by the interaction between rs1049296 and rs1800562. It is important for the scientific community to be aware of the discrepancies between our results and those currently in publication. It is known that complex traits are influenced by epistasis, yet despite this knowledge, gene by gene interactions are understudied in human disease—including that of AD. The results of our study will allow the scientific community to use its time and resources effectively to continue the exploration of these relationships.

THE CONTRIBUTION OF SEX-SPECIFIC ASSOCIATIONS IN GENETIC STUDIES OF ALZHEIMER’S DISEASE PATHOLOGY

Figure 2. X Chromosome variant rs11094635-G demonstrates a protective effect on longitudinal beta-amyloid accumulation. A. Mean annual percent 18 Leigh Christopher, Grace Tam, Valerio Napolioni, Yongha Kim, Michael D. Greicius, Stanford University, Stanford, CA, USA. Contact e-mail: lchris@stanford.edu change in [ F] AV45 in males according to genotype demonstrating reduced beta-amyloid accumulation in the G genotype. B. Mean annual percent change in [F] AV45 in females demonstrating reduced beta-amyloid accumulation with increasing G allele dosage. Background:Brain beta-amyloid accumulation is a hallmark characteristic of Alzheimer’s disease (AD); however, it is unknown whether common genetic variation on the X-Chromosome plays a role. Thus, we performed an X Chromosome-Wide Association Study (XWAS) to discover single nucleotide polymorphisms (SNPs) associated with longitudinal accumulation of beta-amyloid in the brain as a proxy for disease progression. Methods: Participants were part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n1⁄4 621). [F] AV45 PET scans were acquired and pre-processed. [F] AV45 is a radiotracer that binds to beta-amyloid plaques. Genotype data underwent standard quality control and were imputed. XWAS 2.0 was used to run a sex-stratified test (analyzed according to Stouffer’s method) with mean annual percent change in global [F] AV45 (cerebellum normalized) as the quantitative trait. We then tested whether significant variants associated with 1) baseline CSF tau levels 2) longitudinal change in cognitive performance (memory, language and global cognition) using a linear mixed effects model in an independent dataset. Results:A variant upstream of the geneMTM1, rs11094635, was significantly associated with beta-amyloid accumulation (Figure 1, rs11094635 C/G, MAF1⁄4 0.30, Stouffers Z 1⁄4 -4.81, p 1⁄4 1.5 x 10). The minor allele (G) demonstrated a protective effect on beta-amyloid accumulation (Figure 2). Dosage of the minor allele was also associated with lower baseline CSF tau levels (p< 0.05) and a less rapid decline on Boston Naming Task scores in individuals who converted to AD (p1⁄40.012). As a post-hoc analysis, we ran a gene-based test for both beta-amyloid accumulation and AD risk (in a separate case control dataset) to see whether overlapping genes contribute