Literature DB >> 30617256

Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.

Iris E Jansen1,2, Jeanne E Savage1, Stephan Ripke3,4,5, Ole A Andreassen6,7, Danielle Posthuma8,9, Kyoko Watanabe1, Julien Bryois10, Dylan M Williams10, Stacy Steinberg11, Julia Sealock12, Ida K Karlsson10,13, Sara Hägg10, Lavinia Athanasiu6,14, Nicola Voyle15, Petroula Proitsi15, Aree Witoelar6,7, Sven Stringer1, Dag Aarsland15,16, Ina S Almdahl17,18,19, Fred Andersen20, Sverre Bergh21,22, Francesco Bettella6,7, Sigurbjorn Bjornsson23, Anne Brækhus21,24, Geir Bråthen25,26, Christiaan de Leeuw1, Rahul S Desikan27, Srdjan Djurovic6,28, Logan Dumitrescu29,30, Tormod Fladby17,18, Timothy J Hohman29,30, Palmi V Jonsson23,31, Steven J Kiddle32, Arvid Rongve33,34, Ingvild Saltvedt25,35, Sigrid B Sando25,26, Geir Selbæk21,36, Maryam Shoai37, Nathan G Skene38,39, Jon Snaedal23, Eystein Stordal40,41, Ingun D Ulstein42, Yunpeng Wang6,7, Linda R White25,26, John Hardy37, Jens Hjerling-Leffler38, Patrick F Sullivan10,43,44, Wiesje M van der Flier2, Richard Dobson15,45,46,47, Lea K Davis30,48, Hreinn Stefansson11, Kari Stefansson11, Nancy L Pedersen10.   

Abstract

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

Entities:  

Mesh：

Year:  2019        PMID： 30617256      PMCID： PMC6836675          DOI： 10.1038/s41588-018-0311-9

Source DB:  PubMed          Journal:  Nat Genet        ISSN： 1061-4036            Impact factor:   38.330


  60 in total

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Journal:  Nat Rev Drug Discov       Date:  2011-08-19       Impact factor: 84.694

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Journal:  Nat Genet       Date:  2015-03-25       Impact factor: 38.330

Review 3.  The global prevalence of dementia: a systematic review and metaanalysis.

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Journal:  Alzheimers Dement       Date:  2013-01       Impact factor: 21.566

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Authors:  Rita Cacace; Kristel Sleegers; Christine Van Broeckhoven
Journal:  Alzheimers Dement       Date:  2016-03-24       Impact factor: 21.566

5.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.

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Journal:  Arch Gen Psychiatry       Date:  2006-02

9.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

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Journal:  Nat Genet       Date:  2013-10-27       Impact factor: 38.330

10.  Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.

Authors:  R Sherrington; E I Rogaev; Y Liang; E A Rogaeva; G Levesque; M Ikeda; H Chi; C Lin; G Li; K Holman; T Tsuda; L Mar; J F Foncin; A C Bruni; M P Montesi; S Sorbi; I Rainero; L Pinessi; L Nee; I Chumakov; D Pollen; A Brookes; P Sanseau; R J Polinsky; W Wasco; H A Da Silva; J L Haines; M A Perkicak-Vance; R E Tanzi; A D Roses; P E Fraser; J M Rommens; P H St George-Hyslop
Journal:  Nature       Date:  1995-06-29       Impact factor: 49.962
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  563 in total

Review 1.  [Neuroinflammation as motor of Alzheimer's disease].

Authors:  Sergio Castro-Gomez; Julius Binder; Michael T Heneka
Journal:  Nervenarzt       Date:  2019-09       Impact factor: 1.214

Review 2.  Interpretation of risk loci from genome-wide association studies of Alzheimer's disease.

Authors:  Shea J Andrews; Brian Fulton-Howard; Alison Goate
Journal:  Lancet Neurol       Date:  2020-01-24       Impact factor: 44.182

Review 3.  Microglial memory of early life stress and inflammation: Susceptibility to neurodegeneration in adulthood.

Authors:  Paula Desplats; Ashley M Gutierrez; Marta C Antonelli; Martin G Frasch
Journal:  Neurosci Biobehav Rev       Date:  2019-11-05       Impact factor: 8.989

4.  Multivariate genome wide association and network analysis of subcortical imaging phenotypes in Alzheimer's disease.

Authors:  Xianglian Meng; Jin Li; Qiushi Zhang; Feng Chen; Chenyuan Bian; Xiaohui Yao; Jingwen Yan; Zhe Xu; Shannon L Risacher; Andrew J Saykin; Hong Liang; Li Shen
Journal:  BMC Genomics       Date:  2020-12-29       Impact factor: 3.969

5.  Fast Algorithms for Conducting Large-Scale GWAS of Age-at-Onset Traits Using Cox Mixed-Effects Models.

Authors:  Liang He; Alexander M Kulminski
Journal:  Genetics       Date:  2020-03-04       Impact factor: 4.562

Review 6.  Evaluation of CD33 as a genetic risk factor for Alzheimer's disease.

Authors:  Steven Estus; Benjamin C Shaw; Nicholas Devanney; Yuriko Katsumata; Eileen E Press; David W Fardo
Journal:  Acta Neuropathol       Date:  2019-04-04       Impact factor: 17.088

Review 7.  The genetics of human ageing.

Authors:  David Melzer; Luke C Pilling; Luigi Ferrucci
Journal:  Nat Rev Genet       Date:  2019-11-05       Impact factor: 53.242

Review 8.  The path to biomarker-based diagnostic criteria for the spectrum of neurodegenerative diseases.

Authors:  Filippo Baldacci; Sonia Mazzucchi; Alessandra Della Vecchia; Linda Giampietri; Nicola Giannini; Maya Koronyo-Hamaoui; Roberto Ceravolo; Gabriele Siciliano; Ubaldo Bonuccelli; Fanny M Elahi; Andrea Vergallo; Simone Lista; Filippo Sean Giorgi; Harald Hampel
Journal:  Expert Rev Mol Diagn       Date:  2020-02-27       Impact factor: 5.225

9.  snpXplorer: a web application to explore human SNP-associations and annotate SNP-sets.

Authors:  Niccolo Tesi; Sven van der Lee; Marc Hulsman; Henne Holstege; Marcel J T Reinders
Journal:  Nucleic Acids Res       Date:  2021-07-02       Impact factor: 16.971

Review 10.  The Role of Sex and Sex Hormones in Neurodegenerative Diseases.

Authors:  Elisabetta Vegeto; Alessandro Villa; Sara Della Torre; Valeria Crippa; Paola Rusmini; Riccardo Cristofani; Mariarita Galbiati; Adriana Maggi; Angelo Poletti
Journal:  Endocr Rev       Date:  2020-04-01       Impact factor: 19.871
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