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

Iris E Jansen, Jeanne E Savage, Kyoko Watanabe, Julien Bryois, Dylan M Williams, Stacy Steinberg, Julia Sealock, Ida K Karlsson, Sara Hägg, Lavinia Athanasiu, Nicola Voyle, Petroula Proitsi, Aree Witoelar, Sven Stringer, Dag Aarsland, Ina S Almdahl, Fred Andersen, Sverre Bergh, Francesco Bettella, Sigurbjorn Bjornsson & 33 others Anne Brækhus, Geir Bråthen, Christiaan de Leeuw, Rahul S Desikan, Srdjan Djurovic, Logan Dumitrescu, Tormod Fladby, Timothy J Hohman, Palmi V Jonsson, Steven J Kiddle, Arvid Rongve, Ingvild Saltvedt, Sigrid B Sando, Geir Selbæk, Maryam Shoai, Nathan G Skene, Jon Snaedal, Eystein Stordal, Ingun D Ulstein, Yunpeng Wang, Linda R White, John Hardy, Jens Hjerling-Leffler, Patrick F Sullivan, Wiesje M van der Flier, Richard Dobson, Lea K Davis, Hreinn Stefansson, Kari Stefansson, Nancy L Pedersen, Stephan Ripke, Ole A Andreassen, Danielle Posthuma

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)404-413
Number of pages10
JournalNature Genetics
Volume51
Issue number3
DOIs
Publication statusPublished - Mar 2019

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Meta-Analysis
Alzheimer Disease
Genome
Proxy
Genes
Aptitude
Neurobiology
Amyloid beta-Protein Precursor
Genome-Wide Association Study
Microglia
Random Allocation
Spleen
Lipids
Liver
Health

Cite this

Jansen, Iris E ; Savage, Jeanne E ; Watanabe, Kyoko ; Bryois, Julien ; Williams, Dylan M ; Steinberg, Stacy ; Sealock, Julia ; Karlsson, Ida K ; Hägg, Sara ; Athanasiu, Lavinia ; Voyle, Nicola ; Proitsi, Petroula ; Witoelar, Aree ; Stringer, Sven ; Aarsland, Dag ; Almdahl, Ina S ; Andersen, Fred ; Bergh, Sverre ; Bettella, Francesco ; Bjornsson, Sigurbjorn ; Brækhus, Anne ; Bråthen, Geir ; de Leeuw, Christiaan ; Desikan, Rahul S ; Djurovic, Srdjan ; Dumitrescu, Logan ; Fladby, Tormod ; Hohman, Timothy J ; Jonsson, Palmi V ; Kiddle, Steven J ; Rongve, Arvid ; Saltvedt, Ingvild ; Sando, Sigrid B ; Selbæk, Geir ; Shoai, Maryam ; Skene, Nathan G ; Snaedal, Jon ; Stordal, Eystein ; Ulstein, Ingun D ; Wang, Yunpeng ; White, Linda R ; Hardy, John ; Hjerling-Leffler, Jens ; Sullivan, Patrick F ; van der Flier, Wiesje M ; Dobson, Richard ; Davis, Lea K ; Stefansson, Hreinn ; Stefansson, Kari ; Pedersen, Nancy L ; Ripke, Stephan ; Andreassen, Ole A ; Posthuma, Danielle. / Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. In: Nature Genetics. 2019 ; Vol. 51, No. 3. pp. 404-413.
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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.",
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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 2019, 'Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk' Nature Genetics, vol. 51, no. 3, pp. 404-413. https://doi.org/10.1038/s41588-018-0311-9

Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. / Jansen, Iris E; Savage, Jeanne E; Watanabe, Kyoko; Bryois, Julien; Williams, Dylan M; Steinberg, Stacy; Sealock, Julia; Karlsson, Ida K; Hägg, Sara; Athanasiu, Lavinia; Voyle, Nicola; Proitsi, Petroula; Witoelar, Aree; Stringer, Sven; Aarsland, Dag; Almdahl, Ina S; Andersen, Fred; Bergh, Sverre; Bettella, Francesco; Bjornsson, Sigurbjorn; Brækhus, Anne; Bråthen, Geir; de Leeuw, Christiaan; Desikan, Rahul S; Djurovic, Srdjan; Dumitrescu, Logan; Fladby, Tormod; Hohman, Timothy J; Jonsson, Palmi V; Kiddle, Steven J; Rongve, Arvid; Saltvedt, Ingvild; Sando, Sigrid B; Selbæk, Geir; Shoai, Maryam; Skene, Nathan G; Snaedal, Jon; Stordal, Eystein; Ulstein, Ingun D; Wang, Yunpeng; White, Linda R; Hardy, John; Hjerling-Leffler, Jens; Sullivan, Patrick F; van der Flier, Wiesje M; Dobson, Richard; Davis, Lea K; Stefansson, Hreinn; Stefansson, Kari; Pedersen, Nancy L; Ripke, Stephan; Andreassen, Ole A; Posthuma, Danielle.

In: Nature Genetics, Vol. 51, No. 3, 03.2019, p. 404-413.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk

AU - Jansen, Iris E

AU - Savage, Jeanne E

AU - Watanabe, Kyoko

AU - Bryois, Julien

AU - Williams, Dylan M

AU - Steinberg, Stacy

AU - Sealock, Julia

AU - Karlsson, Ida K

AU - Hägg, Sara

AU - Athanasiu, Lavinia

AU - Voyle, Nicola

AU - Proitsi, Petroula

AU - Witoelar, Aree

AU - Stringer, Sven

AU - Aarsland, Dag

AU - Almdahl, Ina S

AU - Andersen, Fred

AU - Bergh, Sverre

AU - Bettella, Francesco

AU - Bjornsson, Sigurbjorn

AU - Brækhus, Anne

AU - Bråthen, Geir

AU - de Leeuw, Christiaan

AU - Desikan, Rahul S

AU - Djurovic, Srdjan

AU - Dumitrescu, Logan

AU - Fladby, Tormod

AU - Hohman, Timothy J

AU - Jonsson, Palmi V

AU - Kiddle, Steven J

AU - Rongve, Arvid

AU - Saltvedt, Ingvild

AU - Sando, Sigrid B

AU - Selbæk, Geir

AU - Shoai, Maryam

AU - Skene, Nathan G

AU - Snaedal, Jon

AU - Stordal, Eystein

AU - Ulstein, Ingun D

AU - Wang, Yunpeng

AU - White, Linda R

AU - Hardy, John

AU - Hjerling-Leffler, Jens

AU - Sullivan, Patrick F

AU - van der Flier, Wiesje M

AU - Dobson, Richard

AU - Davis, Lea K

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - Pedersen, Nancy L

AU - Ripke, Stephan

AU - Andreassen, Ole A

AU - Posthuma, Danielle

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

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DO - 10.1038/s41588-018-0311-9

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SP - 404

EP - 413

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

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