Genome-wide meta-analysis, fine-mapping, and integrative prioritization identify new Alzheimer’s disease risk genes

Schwartzentruber, Jeremy; Cooper, Sarah; Liu, Jimmy Z; Barrio-Hernandez, Iñigo; Bello, Erica; Kumasaka, Natsuhiko; Johnson, Toby; Estrada, Karol; Gaffney, Daniel J.; Beltrão, Pedro; Bassett, Andrew

doi:10.1101/2020.01.22.20018424

Cited by 20 publications

(33 citation statements)

References 111 publications

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“…After validation by conditional analyses (see Supplementary Information and Supplementary Tables 3 and 4), this approach led us to confirm 38 signals in 34 loci already known to be associated with the risk of developing AD in the main previous AD GWASs 6,[10][11][12][13][14][15] (Table 1) and to propose 31 new loci (Table 2 and Supplementary Figures 2-24). Five of these loci (APP, CCDC6, NCK2, TSPAN14 and Sharpin) were already reported in two preprints using GWAS data included in our study 16,17 . Besides, the NDUFAF6 and IGH loci were previously reported in a gene-wide analysis 18 .…”

Section: Gwas Analysismentioning

confidence: 75%

New insights on the genetic etiology of Alzheimer’s and related dementia

Bellenguez¹,

Küçükali²,

Jansen³

et al. 2020

Preprint

127

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Deciphering the genetic landscape of Alzheimer disease (AD) is essential to define the pathophysiological pathways involved and to successfully translate genomics to potential tailored medical care. To generate the most complete knowledge of the AD genetics, we developed through the European Alzheimer Disease BioBank (EADB) consortium a discovery meta-analysis of genome-wide association studies (GWAS) based on a new large case-control study and previous GWAS (in total 39,106 clinically diagnosed cases, 46,828 proxy-AD cases and 401,577 controls) with the most promising signals followed-up in independent samples (18,063 cases and 23,207 controls). In addition to 34 known AD loci, we report here the genome-wide significant association of 31 new loci with the risk of AD. Pathway-enrichment analyses strongly indicated the involvement of gene sets related to amyloid and Tau, but also highlighted microglia, in which increased gene expression corresponds to more significant AD risk. In addition, we successfully prioritized candidate genes in the majority of our new loci, with nine being primarily expressed in microglia. Finally, we observed that a polygenic risk score generated from this new genetic landscape was strongly associated with the risk of progression from mild cognitive impairment (MCI) to dementia (4,609 MCI cases of whom 1,532 converted to dementia), independently of age and the APOE e4 allele.

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Section: Gwas Analysismentioning

confidence: 75%

New insights on the genetic etiology of Alzheimer’s and related dementia

Bellenguez¹,

Küçükali²,

Jansen³

et al. 2020

Preprint

127

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“…We next applied GenIE to screen 11 variants at the clusterin ( CLU ) locus that form the 99% confidence set of credibly causal variants identified by fine mapping of an AD GWAS ( 19 ). The CLU gene has been implicated in AD progression, likely due to an effect on amyloid beta aggregation or clearance ( 24 ), and CLU knockout is neuroprotective in rodents ( 25–27 ) and in hiPSC neurons ( 28 ).…”

Section: Resultsmentioning

confidence: 99%

“…SNPs in CLU associated with Alzheimer's disease were identified previously, as described in Schwartzentruber et al. ( 19 ). The locus likely contains two causal variants, one in PTK2B and one in CLU .…”

Section: Methodsmentioning

confidence: 99%

Screening for functional transcriptional and splicing regulatory variants with GenIE

Cooper

Schwartzentruber

Bello

et al. 2020

Nucleic Acids Research

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Genome-wide association studies (GWAS) have identified numerous genetic loci underlying human diseases, but a fundamental challenge remains to accurately identify the underlying causal genes and variants. Here, we describe an arrayed CRISPR screening method, Genome engineering-based Interrogation of Enhancers (GenIE), which assesses the effects of defined alleles on transcription or splicing when introduced in their endogenous genomic locations. We use this sensitive assay to validate the activity of transcriptional enhancers and splice regulatory elements in human induced pluripotent stem cells (hiPSCs), and develop a software package (rgenie) to analyse the data. We screen the 99% credible set of Alzheimer's disease (AD) GWAS variants identified at the clusterin (CLU) locus to identify a subset of likely causal variants, and employ GenIE to understand the impact of specific mutations on splicing efficiency. We thus establish GenIE as an efficient tool to rapidly screen for the role of transcribed variants on gene expression.

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“…We also analyzed the UKBB data alone as a GWAS of parental history of AD/dementia to compare patterns of association between AD and AD proxy phenotypes. GWS common variant associations ( Supplementary Tables 3 and 4 ) included signals in or around known susceptibility loci such as APOE , BIN1 , NYAP1 / PILRB , and HLA-DRB1 , as well as an association near VKORC1 / BCKDK ( P =3.82×10 −8 ), which was observed in the Schwarzentruber AD family history analysis 41 and reported as KAT8 in the Jansen et al study 13 which also included UKBB AD/dementia family history data. Discovery-level associations ( P <10 −5 ) were observed for several known AD susceptibility loci, including ABCA7 , PICALM , MS4A Region, ADAM10 / MINDY2 , EPHA1 , and CR1 .…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

Naj

Leonenko

Jian

et al. 2021

Preprint

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Risk for late-onset Alzheimer's disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)>0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimer's Project (IGAP). Existing genotype data were imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P<10-5 were meta-analyzed with the European Alzheimer's Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF≥0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 (P=2.33×10-12), SHARPIN (P=1.56×10-9), and ATF5/SIGLEC11 (P=1.03[mult]10-8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80×10-8), APH1B (P=2.10×10-13), and CLNK (P=2.24×10-10). Rare variant (MAF<0.01) associations with genome-wide significance in stage 2 included multiple variants in APOE and TREM2, and a novel association of a rare variant (rs143080277; MAF=0.0054; P=2.69×10-9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17×10-13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.

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Genome-wide meta-analysis, fine-mapping, and integrative prioritization identify new Alzheimer’s disease risk genes

Cited by 20 publications

References 111 publications

New insights on the genetic etiology of Alzheimer’s and related dementia

New insights on the genetic etiology of Alzheimer’s and related dementia

Screening for functional transcriptional and splicing regulatory variants with GenIE

Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

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