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

Bis, Joshua C.; Jian, Xueqiu; Kunkle, Brian W.; Chen, Yuning; Hamilton‐Nelson, Kara L.; Bush, William S.; Salerno, William; Lancour, Daniel; Ma, Yiyi; Renton, Alan E.; Marcora, Edoardo; Farrell, John; Zhao, Yi; Qu, Liming; Ahmad, Shahzad; Amin, Najaf; Amouyel, Philippe; Beecham, Gary W.; Below, Jennifer E.; Campion, Dominique; Cantwell, Laura B.; Charbonnier, Camille; Chung, Jaeyoon; Crane, Paul K.; Cruchaga, Carlos; Cupples, L. Adrienne; Dartigues, Jean‐François; Debette, Stéphanie; Deleuze, Jean‐François; Fulton, Lucinda A.; Gabriel, Stacey; Génin, Emmanuelle; Gibbs, Richard A.; Goate, Alison M.; Grenier‐Boley, Benjamin; Gupta, Namrata; Haines, Jonathan L.; Havulinna, Aki S.; Helisalmi, Seppo; Hiltunen, Mikko; Howrigan, Daniel P.; Ikram, M. Arfan; Kaprio, Jaakko; Konrad, Jan; Kuzma, Amanda B.; Lander, Eric S.; Lathrop, Mark; Lehtimäki, Terho; Lin, Honghuang; Mattila, Kari M.; Mayeux, Richard; Nasser, Waleed; Neale, Benjamin M.; Nho, Kwangsik; Nicolas, Gaël; Patel, Devanshi; Pericak‐Vance, Margaret A.; Perola, Markus; Psaty, Bruce M.; Quenez, Olivier; Rajabli, Farid; Redon, Richard; Reitz, Christiane; Remes, Anne M.; Salomaa, Veikko; Sarnowski, Chloé; Schmidt, Helena; Schmidt, Michael A.; Schmidt, Reinhold; Thornton, Timothy A.; Tosto, Giuseppe; Tzourio, Christophe; Lee, Sven J. van der; Duijn, Cornelia M. van; Valladares, Otto; Vardarajan, Badri N.; Wang, Li-San; Wang, Weixin; Wijsman, Ellen M.; Wilson, Richard K.; Witten, Daniela; Worley, Kim C.; Bellenguez, Céline; Lambert, Jean‐Charles; Kurki, Mitja; Palotie, Aarno; Daly, Mark J.; Boerwinkle, Eric; Lunetta, Kathryn L.; DeStefano, Anita L.; Dupuis, Josée; Martin, Eden R.; Schellenberg, Gerard D.; Seshadri, Sudha; Naj, Adam C; Fornage, Myriam; Farrer, Lindsay A.

doi:10.1038/s41380-019-0529-7

Cited by 10 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many attempts have been made to identify additional genetic risk factors. The development of high-throughput genotyping and massively parallel next-generation sequencing has enabled genome-wide association studies (GWAS), which have successfully identified several genetic risk factors that affect the development of AD 5 , 6 , 11 , 12 . These findings are expected not only to explain some of the heritability of AD, but also to contribute to the understanding of the underlying etiologic, biologic, and pathologic mechanisms of AD.…”

Section: Introductionmentioning

confidence: 99%

Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk

et al. 2021

View full text Add to dashboard Cite

Alzheimer’s disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including APOE and SORL1, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case–control cohort. The novel locus FAM47E reached genome-wide significance in a meta-analysis of association results. This is the first report associating the FAM47E locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer’s Project identified an additional novel susceptibility locus in OR2B2. Our data highlight the importance of performing GWAS in non-European populations.

show abstract

Section: Introductionmentioning

confidence: 99%

Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Finally, although this investigation was conducted using tissue obtained from participants enrolled in studies of AD, the direct testing of the relevance of findings from the set-based tests of rare variants to AD status was not feasible, because the sample size was insufficient to have representation of the sentinel variants in both the case and control groups. This limitation is analogous to the difficulty encountered in the replication of the aggregated rare variant test findings in AD genetic association studies [ 7 , 8 ]. Thus, further studies of some genes are needed to establish their role in AD.…”

Section: Discussionmentioning

confidence: 99%

“…Highly penetrant rare variants may account for some of the missing heritability [3]. Whole-exome sequencing studies have identified robust AD associations with rare missense variants in TREM2, AKAP9, UNC5C, ZNF655, IGHG3, CASP7 and NOTCH3 [4][5][6][7][8][9], and it is expected that more AD-related rare variants will be identified by whole-genome sequencing (WGS) studies, because some rare variants, including those in non-coding regions, likely contribute Genes 2021, 12, 419 2 of 16 to AD risk. However, identification of genes that are impacted by these rare variants, and thus likely have a functional role in AD, remains challenging.…”

Section: Introductionmentioning

confidence: 99%

Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants

Patel

Farrell

Lunetta

et al. 2021

Genes

Self Cite

View full text Add to dashboard Cite

Because studies of rare variant effects on gene expression have limited power, we investigated set-based methods to identify rare expression quantitative trait loci (eQTL) related to Alzheimer disease (AD). Gene-level and pathway-level cis rare-eQTL mapping was performed genome-wide using gene expression data derived from blood donated by 713 Alzheimer’s Disease Neuroimaging Initiative participants and from brain tissues donated by 475 Religious Orders Study/Memory and Aging Project participants. The association of gene or pathway expression with a set of all cis potentially regulatory low-frequency and rare variants within 1 Mb of genes was evaluated using SKAT-O. A total of 65 genes expressed in the brain were significant targets for rare expression single nucleotide polymorphisms (eSNPs) among which 17% (11/65) included established AD genes HLA-DRB1 and HLA-DRB5. In the blood, 307 genes were significant targets for rare eSNPs. In the blood and the brain, GNMT, LDHC, RBPMS2, DUS2, and HP were targets for significant eSNPs. Pathway enrichment analysis revealed significant pathways in the brain (n = 9) and blood (n = 16). Pathways for apoptosis signaling, cholecystokinin receptor (CCKR) signaling, and inflammation mediated by chemokine and cytokine signaling were common to both tissues. Significant rare eQTLs in inflammation pathways included five genes in the blood (ALOX5AP, CXCR2, FPR2, GRB2, IFNAR1) that were previously linked to AD. This study identified several significant gene- and pathway-level rare eQTLs, which further confirmed the importance of the immune system and inflammation in AD and highlighted the advantages of using a set-based eQTL approach for evaluating the effect of low-frequency and rare variants on gene expression.

show abstract

“…Genetic Considerations in Selecting Biological Domains. In genetics, we focused on key genome wide association studies (GWAS), the newer genome wide association study by proxy (GWAX) [15][16][17][18][19][74][75][76][77][78][79][80] using the parental disease status, and whole exome sequencing studies [81][82][83][84][85][86][87][88][89][90][91][92][93][94][95] that have transpired over the last decade. The identification of potential genetic risk associated with individual genes is represented in the genetics score (detailed below), and the goal here is not to recapitulate the scoring methodology, but to assess the potential biological contexts of the imputed genes' biological function.…”

Section: Alzheimer's Disease Biological Domains and Enrichment Analysismentioning

confidence: 99%

Genetic and Multi-omic Risk Assessment of Alzheimer’s Disease Implicates Core Associated Biological Domains

Cary

Wiley

Gockley

et al. 2022

Preprint

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly-funded consortia driving large-scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome. Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi-omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify systems level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genome-wide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive gene ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease-associated biology. This rank and organize approach, performed genome-wide, allows the characterization of aggregations of AD risk across biological domains. The top AD-risk associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains. This provides an objective methodology to localize risk within specific biological endophenotypes, and drill down into the most significantly associated sets of GO-terms and annotated genes for potential therapeutic targets.

show abstract

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

Abstract: A correction to this paper has been published and can be accessed via a link at the top of the paper.

Cited by 10 publications

References 0 publications

Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk

Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk

Set-Based Rare Variant Expression Quantitative Trait Loci in Blood and Brain from Alzheimer Disease Study Participants

Genetic and Multi-omic Risk Assessment of Alzheimer’s Disease Implicates Core Associated Biological Domains

Contact Info

Product

Resources

About