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 Selseth; Andersen, Fred; Bergh, Sverre; Bettella, Francesco; Björnsson, Sigurbjörn; Brækhus, Anne; Bråthen, Geir; de Leeuw, Christiaan A.; Desikan, Rahul S.; Djurovic, Srdjan; Dumitrescu, Logan; Fladby, Tormod; Hohman, Timothy J.; Jónsson, Pálmi V.; Kiddle, Steven J; Rongve, Arvid; Saltvedt, Ingvild; Sando, Sigrid Botne; Selbæk, Geir; Shoai, Maryam; Skene, Nathan G.; Snædal, Jón G.; Stordal, Eystein; Ulstein, Ingun; Wang, Yunpeng; White, Linda Rosemary; Hardy, John; Hjerling-Leffler, Jens; Sullivan, Patrick; van der Flier, Wiesje M.; Dobson, Richard; Davis, Lea K; Stefánsson, Hreinn; Stefánsson, Kári; Pedersen, Nancy L; Ripke, Stephan; Andreassen, Ole Andreas; Posthuma, Danielle
Journal article, Peer reviewed
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Original versionNature Genetics. 2019, 51 (3), 404-413. 10.1038/s41588-018-0311-9
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.