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; 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

doi:10.1038/s41588-018-0311-9

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 BjornssonAnne 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^*

^*Corresponding author for this work

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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 (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.

Original language	English
Pages (from-to)	404-413
Number of pages	10
Journal	Nature Genetics
Volume	51
Issue number	3
Early online date	7 Jan 2019
DOIs	https://doi.org/10.1038/s41588-018-0311-9
Publication status	Published - 1 Mar 2019

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Jansen, I. E., Savage, J. E., Watanabe, K., Bryois, J., Williams, D. M., Steinberg, S., Sealock, J., Karlsson, I. K., Hägg, S., Athanasiu, L., Voyle, N., Proitsi, P., Witoelar, A., Stringer, S., Aarsland, D., Almdahl, I. S., Andersen, F., Bergh, S., Bettella, F., ... Posthuma, D. (2019). Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nature Genetics, 51(3), 404-413. https://doi.org/10.1038/s41588-018-0311-9

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title = "Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer{\textquoteright}s disease risk",

abstract = "Alzheimer{\textquoteright}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.",

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

year = "2019",

month = mar,

day = "1",

doi = "10.1038/s41588-018-0311-9",

language = "English",

volume = "51",

pages = "404--413",

journal = "Nature Genetics",

issn = "1061-4036",

number = "3",

}

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

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 - 2019/3/1

Y1 - 2019/3/1

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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U2 - 10.1038/s41588-018-0311-9

DO - 10.1038/s41588-018-0311-9

M3 - Article

AN - SCOPUS:85059641255

SN - 1061-4036

VL - 51

SP - 404

EP - 413

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

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