Interpretation of risk loci from genome-wide association studies of Alzheimer's disease

Summary

Background

Alzheimer'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 developments

Three 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.

Introduction

Alzheimer's disease is a neurological condition characterised by progressive decline in cognition, with concomitant functional decline.¹ The primary pathological hallmark of Alzheimer's disease is the aggregation of amyloid β peptides into extracellular plaques and of hyperphosphorylated tau into intracellular neurofibrillary tangles, accompanied by neuroinflammation, gliosis, and neurodegeneration.²

Genetic factors play an important part in the development of Alzheimer's disease. In autosomal dominant Alzheimer's disease, highly penetrant mutations in APP, PSEN1, or PSEN2 result in monogenic Alzheimer's disease, typically with early onset.³ However, most cases of Alzheimer's disease (99%) involve multiple genetic, environmental, and lifestyle factors, with genetics accounting for up to 53% of total phenotypic variance.⁴ Until 2018, the largest genome-wide association study (GWAS) of Alzheimer's disease had been done in 2013, identifying 19 risk loci.⁵ Beyond locus identification, characterisation of risk loci can implicate functional genetic variants and genes, which can inform mechanistic studies and rational drug development. Compared with drug targets with no evidence of genetic association, drug targets supported by evidence of both genetic association with disease and functional data are twice as likely to progress from phase 1 studies to successful approval.⁶

In 2018 and 2019, three new GWAS in Alzheimer's disease have been published, expanding the number of known genome-wide risk loci to 40.7, 8, 9 In this Rapid Review, we summarise discovered loci, emphasising that the specific functional or causal gene in each locus is often unknown. To ensure genomic risk loci and lead single nucleotide polymorphisms (SNPs) are consistent across studies, we used the default settings of Functional Mapping and Annotation¹⁰ on published GWAS summary statistics, then annotated loci with cytogenetic band using SNPnexus (panel 1).¹¹ Because the lead SNP in each locus varies across studies, we provide a unified list of SNPs associated with Alzheimer's disease across GWAS, highlighting genetic correlations to emphasise when lead SNPs are equivalent or different. Finally, we discuss the strength of GWAS evidence at different loci for Alzheimer's disease, and necessary steps to assign a likely functional gene.