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

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.

Savage, J. E. (author)
Watanabe, K. (author)
Bryois, J.Karolinska Institutet (author)
Williams, D. M.Karolinska Institutet (author)
Steinberg, S.Karolinska Institutet (author)
Sealock, J. (author)
Karlsson, Ida K.Jönköping University,HHJ, Institutet för gerontologi,HHJ. ARN-J (Aging Research Network - Jönköping),Karolinska Institutet, Stockholm, Sweden(Swepub:hj)karida (author)
Hägg, S. (author)
Athanasiu, L. (author)
Voyle, N. (author)
Proitsi, P.Karolinska Institutet (author)
Witoelar, A. (author)
Stringer, S. (author)
Aarsland, D.Karolinska Institutet (author)
Almdahl, I. S. (author)
Andersen, F. (author)
Bergh, S. (author)
Bettella, F. (author)
Bjornsson, S. (author)
Brækhus, A. (author)
Bråthen, G. (author)
de Leeuw, C. (author)
Desikan, R. S. (author)
Djurovic, S. (author)
Dumitrescu, L. (author)
Fladby, T. (author)
Hohman, T. J. (author)
Jonsson, P. V. (author)
Kiddle, S. J. (author)
Rongve, A. (author)
Saltvedt, I. (author)
Sando, S. B. (author)
Selbæk, G. (author)
Shoai, M. (author)
Skene, N. G. (author)
Snaedal, J. (author)
Stordal, E. (author)
Ulstein, I. D. (author)
Wang, Y. (author)
White, L. R. (author)
Hardy, J. (author)
Hjerling-Leffler, J.Karolinska Institutet (author)
Sullivan, P. F. (author)
van der Flier, W. M. (author)
Dobson, R. (author)
Davis, L. K. (author)
Stefansson, H. (author)
Stefansson, K. (author)
Pedersen, N. L.Karolinska Institutet (author)
Ripke, S. (author)
Andreassen, O. A. (author)
Posthuma, D. (author)
Karolinska InstitutetHHJ, Institutet för gerontologi (creator_code:org_t)

By the author/editor: Jansen, I. E.; Savage, J. E.; Watanabe, K.; Bryois, J.; Williams, D. M.; Steinberg, S.; show more...; Sealock, J.; Karlsson, Ida K.; Hägg, S.; Athanasiu, L.; Voyle, N.; Proitsi, P.; Witoelar, A.; Stringer, S.; Aarsland, D.; Almdahl, I. S.; Andersen, F.; Bergh, S.; Bettella, F.; Bjornsson, S.; Brækhus, A.; Bråthen, G.; de Leeuw, C.; Desikan, R. S.; Djurovic, S.; Dumitrescu, L.; Fladby, T.; Hohman, T. J.; Jonsson, P. V.; Kiddle, S. J.; Rongve, A.; Saltvedt, I.; Sando, S. B.; Selbæk, G.; Shoai, M.; Skene, N. G.; Snaedal, J.; Stordal, E.; Ulstein, I. D.; Wang, Y.; White, L. R.; Hardy, J.; Hjerling-Leffler ...; Sullivan, P. F.; van der Flier, W ...; Dobson, R.; Davis, L. K.; Stefansson, H.; Stefansson, K.; Pedersen, N. L.; Ripke, S.; Andreassen, O. A ...; Posthuma, D.; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Neurology

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