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

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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
Issue number3
Publication statusPublished - 1 Mar 2019


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