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

• Published in: Nature genetics 2019-03, Vol.51 (3), p.404-413
• Main Authors: 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 S., Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S., Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J., Jonsson, Palmi V., Kiddle, Steven J., Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B., Selbæk, Geir, Shoai, Maryam, Skene, Nathan G., Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D., Wang, Yunpeng, White, Linda R., Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F., van der Flier, Wiesje M., Dobson, Richard, Davis, Lea K., Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L., Ripke, Stephan, Andreassen, Ole A., Posthuma, Danielle
• Format: Article
• Language: English
• Subjects: 631/208/205/2138; 692/699/375/365/1283; Adult; Advertising executives; Agriculture; Alzheimer Disease - genetics; Alzheimer's disease; Alzheimers disease; Amyloid; Animal Genetics and Genomics; Basale medisinske, odontologiske og veterinærmedisinske fag: 710; Basic medical, dental and veterinary science disciplines: 710; Biomedical and Life Sciences; Biomedicine; Brain; Cancer Research; Case-Control Studies; Clinical medical disciplines: 750; Cognitive ability; Consortia; Diagnosis; Diseases; Female; Gene expression; Gene Function; Gene loci; Genes; Genetic aspects; Genetic factors; Genetic Predisposition to Disease - genetics; Genetic research; Genetic variance; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genomics; Geriatri: 778; Geriatrics: 778; Health aspects; Health risks; Hepatocytes; Human Genetics; Humans; Identification; Klinisk medisinske fag: 750; Lipids; Liver; Male; Medical disciplines: 700; Medical genetics: 714; Medical research; Medicin och hälsovetenskap; Medisinsk genetikk: 714; Medisinske Fag: 700; Meta-analysis; Microglia; Middle Aged; Nervous system; Neurodegenerative diseases; Neurophysiology; Neurosciences; Novels; Polymorphism, Single Nucleotide - genetics; Proteins; Proxy; Quality control; Quantitative Trait Loci - genetics; Risk; Risk analysis; Risk factors; Spleen; VDP; Young Adult
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 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 ( r g  = 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. Genome-wide meta-analysis of clinically diagnosed Alzheimer’s disease (AD) and AD-by-proxy (71,880 AD cases, 383,378 controls) identifies new loci and functional pathways that contribute to AD risk.