A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Wightman DP
PROVIDER: S-EPMC10243600 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.
Wightman Douglas P DP Jansen Iris E IE Savage Jeanne E JE Shadrin Alexey A AA Bahrami Shahram S Holland Dominic D Rongve Arvid A Børte Sigrid S Winsvold Bendik S BS Drange Ole Kristian OK Martinsen Amy E AE Skogholt Anne Heidi AH Willer Cristen C Bråthen Geir G Bosnes Ingunn I Nielsen Jonas Bille JB Fritsche Lars G LG Thomas Laurent F LF Pedersen Linda M LM Gabrielsen Maiken E ME Johnsen Marianne Bakke MB Meisingset Tore Wergeland TW Zhou Wei W Proitsi Petroula P Hodges Angela A Dobson Richard R Velayudhan Latha L Heilbron Karl K Auton Adam A Sealock Julia M JM Davis Lea K LK Pedersen Nancy L NL Reynolds Chandra A CA Karlsson Ida K IK Magnusson Sigurdur S Stefansson Hreinn H Thordardottir Steinunn S Jonsson Palmi V PV Snaedal Jon J Zettergren Anna A Skoog Ingmar I Kern Silke S Waern Margda M Zetterberg Henrik H Blennow Kaj K Stordal Eystein E Hveem Kristian K Zwart John-Anker JA Athanasiu Lavinia L Selnes Per P Saltvedt Ingvild I Sando Sigrid B SB Ulstein Ingun I Djurovic Srdjan S Fladby Tormod T Aarsland Dag D Selbæk Geir G Ripke Stephan S Stefansson Kari K Andreassen Ole A OA Posthuma Danielle D
Nature genetics 20210907 9
Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identif ...[more]
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Project description:BackgroundAlzheimer's disease is a debilitating and highly heritable neurological condition. As such, genetic studies have sought to understand the genetic architecture of Alzheimer's disease since the 1990s, with successively larger genome-wide association studies (GWAS) and meta-analyses. These studies started with a small sample size of 1086 individuals in 2007, which was able to identify only the APOE locus. In 2013, the International Genomics of Alzheimer's Project (IGAP) did a meta-analysis of all existing GWAS using data from 74 046 individuals, which stood as the largest Alzheimer's disease GWAS until 2018. This meta-analysis discovered 19 susceptibility loci for Alzheimer's disease in populations of European ancestry.Recent developmentsThree new Alzheimer's disease GWAS published in 2018 and 2019, which used larger sample sizes and proxy phenotypes from biobanks, have substantially increased the number of known susceptibility loci in Alzheimer's disease to 40. The first, an updated GWAS from IGAP, included 94 437 individuals and discovered 24 susceptibility loci. Although IGAP sought to increase sample size by recruiting additional clinical cases and controls, the two other studies used parental family history of Alzheimer's disease to define proxy cases and controls in the UK Biobank for a genome-wide association by proxy, which was meta-analysed with data from GWAS of clinical Alzheimer's disease to attain sample sizes of 388 324 and 534 403 individuals. These two studies identified 27 and 29 susceptibility loci, respectively. However, the three studies were not independent because of the large overlap in their participants, and interpretation can be challenging because different variants and genes were highlighted by each study, even in the same locus. Furthermore, neither the variant with the strongest Alzheimer's disease association nor the nearest gene are necessarily causal. This situation presents difficulties for experimental studies, drug development, and other future research. WHERE NEXT?: The ultimate goal of understanding the genetic architecture of Alzheimer's disease is to characterise novel biological pathways that underly Alzheimer's disease pathogenesis and to identify novel drug targets. GWAS have successfully contributed to the characterisation of the genetic architecture of Alzheimer's disease, with the identification of 40 susceptibility loci; however, this does not equate to the discovery of 40 Alzheimer's disease genes. To identify Alzheimer's disease genes, these loci need to be mapped to variants and genes through functional genomics studies that combine annotation of variants, gene expression, and gene-based or pathway-based analyses. Such studies are ongoing and have validated several genes at Alzheimer's disease loci, but greater sample sizes and cell-type specific data are needed to map all GWAS loci.
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