Jansen, IE; Savage, JE; Watanabe, K; Bryois, J; Williams, DM; Steinberg, S; Sealock, J; ... Posthuma, D; + view all 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; - view fewer (2019) Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nature Genetics , 51 pp. 404-413. 10.1038/s41588-018-0311-9.

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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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