Meta-Analysis

. 2019 Mar;51(3):404-413.

doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.

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

Iris E Jansen^#^{1

2}, Jeanne E Savage^#¹, Kyoko Watanabe¹, Julien Bryois³, Dylan M Williams³, Stacy Steinberg⁴, Julia Sealock⁵, Ida K Karlsson^{3

6}, Sara Hägg³, Lavinia Athanasiu^{7

8}, Nicola Voyle⁹, Petroula Proitsi⁹, Aree Witoelar^{7

10}, Sven Stringer¹, Dag Aarsland^{9

11}, Ina S Almdahl^{12

13

14}, Fred Andersen¹⁵, Sverre Bergh^{16

17}, Francesco Bettella^{7

10}, Sigurbjorn Bjornsson¹⁸, Anne Brækhus^{16

19}, Geir Bråthen^{20

21}, Christiaan de Leeuw¹, Rahul S Desikan²², Srdjan Djurovic^{7

23}, Logan Dumitrescu^{24

25}, Tormod Fladby^{12

13}, Timothy J Hohman^{24

25}, Palmi V Jonsson^{18

26}, Steven J Kiddle²⁷, Arvid Rongve^{28

29}, Ingvild Saltvedt^{20

30}, Sigrid B Sando^{20

21}, Geir Selbæk^{16

31}, Maryam Shoai³², Nathan G Skene^{33

34}, Jon Snaedal¹⁸, Eystein Stordal^{35

36}, Ingun D Ulstein³⁷, Yunpeng Wang^{7

10}, Linda R White^{20

21}, John Hardy³², Jens Hjerling-Leffler³³, Patrick F Sullivan^{3

38

39}, Wiesje M van der Flier², Richard Dobson^{9

40

41

42}, Lea K Davis^{25

43}, Hreinn Stefansson⁴, Kari Stefansson⁴, Nancy L Pedersen³, Stephan Ripke^#^{44

45

46}, Ole A Andreassen^#^{7

10}, Danielle Posthuma^#^{47

48}

Affiliations

¹ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands.
² Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴ deCODE Genetics/Amgen, Reykjavik, Iceland.
⁵ Interdisciplinary Graduate Program, Vanderbilt University, Nashville, TN, USA.
⁶ Institute of Gerontology and Aging Research Network-Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Jönköping, Sweden.
⁷ NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁸ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁹ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁰ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹¹ Center for Age-Related Diseases, Stavanger University Hospital, Stavanger, Norway.
¹² Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
¹³ AHUS Campus, University of Oslo, Oslo, Norway.
¹⁴ Department of Psychiatry of Old Age, Oslo University Hospital, Oslo, Norway.
¹⁵ Department of Community Medicine, University of Tromsø, Tromsø, Norway.
¹⁶ Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
¹⁷ Centre for Old Age Psychiatry Research, Innlandet Hospital Trust, Ottestad, Norway.
¹⁸ Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland.
¹⁹ Geriatric Department, Oslo University Hospital, Oslo, Norway.
²⁰ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
²¹ Department of Neurology, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
²² Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
²³ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
²⁴ Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁵ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁶ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
²⁷ MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK.
²⁸ Department of Research and Innovation, Helse Fonna, Haugesund, Norway.
²⁹ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
³⁰ Department of Geriatrics, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
³¹ Institute of Health and Society, University of Oslo, Oslo, Norway.
³² Department of Neurodegenerative Disorders, Institute of Neurology, UCL, London, UK.
³³ Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
³⁴ Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
³⁵ Department of Psychiatry, Namsos Hospital, Namsos, Norway.
³⁶ Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
³⁷ Memory Clinic, Geriatric Department, Oslo University Hospital, Oslo, Norway.
³⁸ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
³⁹ Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
⁴⁰ NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
⁴¹ Institute of Health Informatics Research, University College London, London, UK.
⁴² Health Data Research UK London, University College London, London, UK.
⁴³ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁴⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴⁶ Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
⁴⁷ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands. d.posthuma@vu.nl.
⁴⁸ Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands. d.posthuma@vu.nl.

^# Contributed equally.

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

Meta-Analysis

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

Iris E Jansen et al. Nat Genet. 2019 Mar.

. 2019 Mar;51(3):404-413.

doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.

Authors

Affiliations

¹ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands.
² Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴ deCODE Genetics/Amgen, Reykjavik, Iceland.
⁵ Interdisciplinary Graduate Program, Vanderbilt University, Nashville, TN, USA.
⁶ Institute of Gerontology and Aging Research Network-Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Jönköping, Sweden.
⁷ NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁸ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁹ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹⁰ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹¹ Center for Age-Related Diseases, Stavanger University Hospital, Stavanger, Norway.
¹² Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
¹³ AHUS Campus, University of Oslo, Oslo, Norway.
¹⁴ Department of Psychiatry of Old Age, Oslo University Hospital, Oslo, Norway.
¹⁵ Department of Community Medicine, University of Tromsø, Tromsø, Norway.
¹⁶ Norwegian National Advisory Unit on Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway.
¹⁷ Centre for Old Age Psychiatry Research, Innlandet Hospital Trust, Ottestad, Norway.
¹⁸ Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland.
¹⁹ Geriatric Department, Oslo University Hospital, Oslo, Norway.
²⁰ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
²¹ Department of Neurology, St Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
²² Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
²³ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
²⁴ Vanderbilt Memory & Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁵ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁶ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
²⁷ MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK.
²⁸ Department of Research and Innovation, Helse Fonna, Haugesund, Norway.
²⁹ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
³⁰ Department of Geriatrics, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.
³¹ Institute of Health and Society, University of Oslo, Oslo, Norway.
³² Department of Neurodegenerative Disorders, Institute of Neurology, UCL, London, UK.
³³ Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
³⁴ Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
³⁵ Department of Psychiatry, Namsos Hospital, Namsos, Norway.
³⁶ Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
³⁷ Memory Clinic, Geriatric Department, Oslo University Hospital, Oslo, Norway.
³⁸ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
³⁹ Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
⁴⁰ NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK.
⁴¹ Institute of Health Informatics Research, University College London, London, UK.
⁴² Health Data Research UK London, University College London, London, UK.
⁴³ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
⁴⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴⁶ Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
⁴⁷ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands. d.posthuma@vu.nl.
⁴⁸ Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands. d.posthuma@vu.nl.

^# Contributed equally.

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

Erratum in

Author Correction: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.
Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, Sealock J, Karlsson IK, Hägg S, Athanasiu L, Voyle N, Proitsi P, Witoelar A, Stringer S, Aarsland D, Almdahl IS, Andersen F, Bergh S, Bettella F, Bjornsson S, Brækhus A, Bråthen G, de Leeuw C, Desikan RS, Djurovic S, Dumitrescu L, Fladby T, Hohman TJ, Jonsson PV, Kiddle SJ, Rongve A, Saltvedt I, Sando SB, Selbæk G, Shoai M, Skene NG, Snaedal J, Stordal E, Ulstein ID, Wang Y, White LR, Hardy J, Hjerling-Leffler J, Sullivan PF, van der Flier WM, Dobson R, Davis LK, Stefansson H, Stefansson K, Pedersen NL, Ripke S, Andreassen OA, Posthuma D. Jansen IE, et al. Nat Genet. 2020 Mar;52(3):354. doi: 10.1038/s41588-019-0573-x. Nat Genet. 2020. PMID: 32029921

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 (r_g = 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.

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Conflict of interest statement

Competing Interests Statement

The authors report the following potentially competing financial interests. P.F.S.: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member), and Roche (grant recipient, speaker reimbursement). J.H.L.: Cartana (Scientific Advisor) and Roche (grant recipient). O.A.A.: Lundbeck (speaker’s honorarium). St.St., H.S., and K.S. are employees of deCODE Genetics/Amgen. J.H. is a cograntee of Cytox from Innovate UK (UK Department of Business). D.A. has received research support and/or honoraria from Astra-Zeneca, Lundbeck, Novartis Pharmaceuticals, and GE Health, and serves as a paid consultant for Lundbeck, Eisai, Heptares, and Axovant. All other authors declare no financial interests or potential conflicts of interest.

Figures

**Figure 1.. Overview of analysis steps.**
The main genetic analysis encompasses the procedures to detect GWAS risk loci for AD. The functional analysis includes the *in silico* functional follow-up procedures with the aim to put the genetic findings in biological context. N=total of individuals within specified dataset.

**Figure 2.. GWAS meta-analysis for AD risk (N=455,258).**
Manhattan plot displays all associations per variant ordered according to their genomic position on the x-axis and showing the strength of the association with the −log10 transformed P-values on the y-axis. The y-axis is limited to enable visualization of non-*APOE* loci. For the Phase 3 meta-analysis, the original −log₁₀ P-value for the *APOE* locus is 276.

**Figure 3.. Functional annotation of GWAS results.**
a) Functional effects of variants in genomic risk loci of the meta-analysis (the colours of the legend are ordered from right to left in the figure) – the second bar shows distribution for exonic variants only; b) Distribution of RegulomeDB score for variants in genomic risk loci, with a low score indicating a higher probability of having a regulatory function (see Methods); c) Distribution of minimum chromatin state across 127 tissue and cell types for variants in genomic risk loci, with lower states indicating higher accessibility (see Methods); d) Heritability enrichment of 28 functional variant annotations calculated with stratified LD score regression (bars represent standard errors). UTR=untranslated region; CTCF=CCCTC-binding factor; DHS=DNaseI Hypersensitive Site; TFBS=transcription factor binding site; DGF=DNAaseI digital genomic footprint; e) Zoomed-in circos plot of chromosome 8; f) Zoomed-in circos plot of chromosome 16. Circos plots show implicated genes by significant loci, where dark blue areas indicate genomic risk loci, green lines indicate eQTL associations and orange lines indicate chromatin interactions. Genes mapped by both eQTL and chromatin interactions are in red. The outer layer shows a Manhattan plot containing the negative log₁₀-transformed P-value of each SNP in the GWAS meta-analysis of AD. Full circos plots of all autosomal chromosomes are provided in Supplementary Figure 4.

**Figure 4.. Functional implications based on gene-set analysis, genetic correlations and functional annotations.**
The gene-set results are displayed per category of biological mechanisms **(a)**, brain cell-types **(b)** and tissue types **(c)**. The red horizontal line indicates the significance threshold corrected for all gene-set tests of all categories, while the blue horizontal lines display the significance threshold corrected only for the number of tests within the three categories (that is, gene-ontology, tissue expression or single cell expression); d) Genetic correlations between AD and other heritable traits (bars represent 95% confidence intervals); e) Venn diagram showing the number of genes mapped by four distinct strategies. ADHD=attention deficit hyperactivity disorder; BMI=body mass index; EBV=Epstein-Barr virus.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical