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.
| Original language | English |
|---|---|
| Pages (from-to) | 404-413 |
| Number of pages | 10 |
| Journal | Nature Genetics |
| Volume | 51 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 1 Mar 2019 |
Funding
The authors report the following potentially competing financial interests. P.F.S.: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member), and Roche (grant recipient, speaker reimbursement). J.H.L.: Cartana (Scientific Advisor) and Roche (grant recipient). O.A.A.: Lundbeck (speaker’s honorarium). St.St., H.S., and K.S. are employees of deCODE Genetics/Amgen. J.H. is a cograntee of Cytox from Innovate UK (UK Department of Business). D.A. has received research support and/or honoraria from Astra-Zeneca, Lundbeck, Novartis Pharmaceuticals, and GE Health, and serves as a paid consultant for Lundbeck, Eisai, Heptares, and Axovant. All other authors declare no financial interests or potential conflicts of interest. This work was funded by the Netherlands Organization for Scientific Research (NWO VICI 453-14-005). The analyses were carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO: 480-05-003), by the VU University, Amsterdam, the Netherlands, and by the Dutch Brain Foundation, and is hosted by the Dutch National Computing and Networking Services SurfSARA. The work was also funded by the Research Council of Norway (grant nos. 251134, 248778, 223273, 213837, and 225989), KG Jebsen Stiftelsen, the Norwegian Health Association, European Community’s JPND Program, ApGeM RCN grant no. 237250, and the European Community’s grant no. PIAPP-GA-2011-286213 PsychDPC. This research has been conducted using the UK Biobank resource under application number 16406 and the public ADSP data set, obtained through the Database of Genotypes and Phenotypes under accession number phs000572. Full acknowledgments for the studies that contributed data can be found in the Supplementary Note. We thank the numerous participants, researchers, and staff from many studies who collected and contributed to the data.
| Funders | Funder number |
|---|---|
| Dutch Brain Foundation | |
| Dutch National Computing and Networking Services | |
| Netherlands Organization for Scientific Research | |
| Netherlands Scientific Organization | 480-05-003 |
| National Institute on Aging | K01AG049164 |
| Roche Products | |
| Vrije Universiteit Amsterdam | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | VICI 453-14-005 |
| Norges forskningsråd | 251134, 223273, 213837, 248778, 225989 |
| Nasjonalforeningen for Folkehelsen | PIAPP-GA-2011-286213 PsychDPC, 237250 |
