Jaeyoon Chung

PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation

Much of the genetic basis for Alzheimer disease (AD) is unexplained. We sought to identify novel AD loci using a unique family‐based approach that can detect robust associations with infrequent variants (minor allele frequency < 0.10).

Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Genetic loci for Alzheimers disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages

Genetic associations for endophenotypes of Alzheimers disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated.

Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

RARE CODING MUTATIONS ASSOCIATED WITH ALZHEIMER DISEASE AND OTHER DEMENTIAS

Amit Kawalia, Alfredo Ramirez, Wiesje M. Van der Flier, Philip Scheltens, Marcel JT. Reinders, Isabel Hernandez, Alberto Lle o, Juan Fortea, Najada Stringa, Agust ın Ruiz Ruiz, Ignacio Ill an-Gala, Estrella Morenas-Rodr ıguez, Jordi Clarimon, Carmen Lage, Erik van den Akker, Eloy Rodr ıguez Rodr ıguez, Pascual S anchez-Juan, Yolande A. L. Pijnenburg, Natasja van Schoor, Javier Simon-Sanchez, Afina W. Lemstra, Peter Heutink, Sonja Scholz, Martijn Huisman, Eline Slagboom, Henne Holstege and Alzheimer Disease European DNA Biobank, International Frontotemporal Dementia Genomics Consortium, International Parkinson Disease Genomics Consortium, and the Risk and Modifying Factors in FrontoTemporal Dementia Investigators, VU University Medical Center, Amsterdam, Netherlands; VU Medical Center, Amsterdam, Netherlands; Johns Hopkins University School of Medicine, Baltimore, MD, USA; National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; Amsterdam Neuroscience, Amsterdam, Netherlands; Fundacion Insituto Leloir, Instituto de Investigeciones Bioquimicas de Buenos Aires, National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; VU University Medical Center, Alzheimer Center, Amsterdam Neuroscience, Amsterdam, Netherlands; Delft University of Technology, Delft, Netherlands; Barcelona Alzheimer Treatment and Research Center (Fundacio ACE), Barcelona, Spain; Sant PauMemoryUnit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Aut onoma de Barcelona, Barcelona, Spain; VU University Medical Centre, Amsterdam, Netherlands; Neuroscience Center, Barcelona Alzheimer Treatment and Research Center (Fundacio ACE), Institut Catal a de Neuroci encies Aplicades, Barcelona, Spain; Sant Pau Institute of Biomedical Research, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Centre of Biomedical Investigation Network for Neurodegenerative Diseases, Madrid, Spain; University Hospital Marques de Valdecilla, Santander, Spain; Leiden University Medical Center, Leiden, Netherlands; Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; German Center for Neurodegenerative Diseases, T€ubingen, Germany. Contact e-mail: s.j. vanderlee@vumc.nl

IDENTIFICATION OF MITOCHONDRIAL VARIANTS ASSOCIATED WITH LATE-ONSET ALZHEIMER’S DISEASE

(measured by [F] Florbetapir PET) (p1⁄40.027) (Fig. 3). In addition, cis-eQTL mapping analysis revealed that rs10744645 is associated with FGF23 gene expression in the temporal cortex in healthy individuals (p1⁄40.013; BRAINEAC). Conclusions: This study shows that genetic variation in anti-aging gene FGF23 may be associated with less brain atrophy and better memory performance, and may promotes a resilient brain in AD.

Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer's disease

BackgroundSimultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study.MethodsWe conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data.ResultsGenome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10−8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10−8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10−6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10−3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10−3) and visual (P = 5.6 × 10−4) cortices.ConclusionsOur findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.

NOVEL GENETIC VARIANTS ASSOCIATED WITH FAMILIAL LATE-ONSET ALZHEIMER DISEASE IN THE ALZHEIMER’S DISEASE SEQUENCING PROJECT

Background:The Alzheimer’s Disease Sequencing Project (ADSP) is an initiative to identify rare genetic variation influencing Late Onset Alzheimer’s Disease (LOAD) risk. As part of the ADSP, we performed whole-genome sequencing (WGS) in 67 Caribbean Hispanic (CH) and 44 non-Hispanic white (NHW) extended families multiply affected by LOAD, followed by extensive quality control, variant filtering, and gene-based association tests.Methods: WGS datawere generated for 351 subjects from 67 CH families and 197 subjects from 44 NHW families, including both AD and cognitively intact relatives. Alignment was performed using the Burrows-Wheeler algorithm, followed by genotype calling using a consensus calling pipeline that used both GATK genotype calls and ATLAS genotype calls. Variants were annotated for allele frequency and predicted functional impact, categorized into damaging (e.g., loss of function, high CADD scores, etc) and likely damaging (e.g., non-synonymous, moderate CADD, etc). We performed gene-based association testing, accounting for family structure using the FSKAT software. Association was performed using rare variants (MAF<0.01) and two models (damaging set only; damaging and likely damaging), with CH and NHW sets analyzed separately. Results:Examination of the 30 known LOAD genes (largely identified by GWAS-based meta-analyses) confirmed the role of rare functional variation in a number of genes, including CR1 (p 1⁄40.040 in NHW, p1⁄40.049 in CH; damaging variants only) and SLC24A4 (p1⁄40.002 in NHW, p1⁄40.040 in CH). Other candidate genes showed nominal association in one but not both datasets (AKAP9, FERMT2, GRN, HLA-DRB5, MEF2C in NHW dataset; BIN1, PTK2B in CH). Additional genes showed strong association in the CH dataset, with nominal association in the NHW. These include ATG2A (p1⁄40.0003 in CH, p1⁄40.02 in NHW), a gene involved in both autophagy and lipid droplet formation, and CD69 (p1⁄40.00054 in CH, p1⁄40.02 in NHW), a gene involved in cell proliferation.Conclusions:These results suggest rare, functional variation may influence LOAD risk in multiplex families, even among genes identified through common variation. We also show association with novel genes, ATG2A and CD69, with support from both CH and NHW families. Variants are currently being validated using other technologies, and follow-up and replication analyses are ongoing.

Transethnic genome-wide meta-analysis for Alzheimer disease

was associated with AD (p1⁄49E-4). We then examined overlapping SNPs in adults with DS, and found rs2378991 to be associated with AD as well as age at onset (p1⁄40.04). Lastly, hippocampal neuron survival assay showed that knocking down CUGBP2 protects neurons from Ab toxicity. Conclusions: Our multi-stage study showed that genetic factors in CUGBP2 are likely to be involved in AD, and may work through the amyloid pathway.

BIVARIATE GENOME-WIDE ASSOCIATION STUDY OF ALZHEIMER DISEASE ENDOPHENOTYPES IDENTIFIES NOVEL LOCI

Jager, Brigham and Women’s Hospital, Boston, Massachusetts, United States; Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States; Rush University Medical Center, Chicago, Illinois, United States; Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States; Rush University Medical Center, Rush Alzheimer’s Disease Center, Chicago, Illinois, United States. Contact e-mail: jmr@broadinstitute.org