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

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
Early online date2019
DOIs
Publication statusPublished - 1 Mar 2019

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