It took more than a million samples, but researchers have managed to extract seven fresh AD risk loci from a genome-wide association study. Published September 7 in Nature Genetics, this GWAS included 90,338 samples from people who were either diagnosed with AD or had a family history of the disease, as well as from 1,036,225 controls. It pegged 38 AD risk loci, 31 of which had been netted in previous GWAS. Seven new ones included two that had been previously tied to frontotemporal dementia, and five relative newcomers to neurodegeneration. In all, the findings build further support for the role of microglia, immune function, and protein homeostasis in AD.
- From more than 90,000 cases and a million controls, a GWAS pulled 38 AD risk loci.
- Among seven new ones, TMEM106B and GRN were previously tied to frontotemporal dementia.
- Variants implicate immunity and protein catabolism in Alzheimer's disease.
Despite eclipsing the million-person milestone, this latest GWAS, led by Danielle Posthuma of VU Amsterdam, The Netherlands, identified fewer risk loci than a recently posted study led by Jean-Charles Lambert at the Institut Pasteur de Lille in France, which identified 75 loci, including 42 new ones, from 111,326 cases and 677,663 controls (Feb 2021 news). First author Douglas Wightman attributed the bigger haul of Lambert’s GWAS both to the larger number of cases included in that study and to the authors’ generation of novel genotyping data.
For their study, Wightman and colleagues drew genotyping data from 13 cohorts, including the International Genomics of Alzheimer's Project (IGAP), deCODE, UK Biobank, 23andMe, BioVU, the Trøndelag Health Study, DemGene, TwinGene, STSA, GR@CE, Gothenburg, ANMerge, and Finngen. The 90,338 cases included 43,725 AD and 46,613 proxy cases, i.e., people with a family history of AD. Of the 1,036,225 controls, 318,246 were considered proxy controls, having no family history of AD. The study more than doubles the sample size of a previous GWAS led by many of the same authors, adding more than 18,000 cases and 650,000 controls (Mar 2019 news on Jansen et al., 2019).
Growing AD Skyline. Manhattan plot of genome-wide significant AD risk loci. Newcomers are displayed in green. [Courtesy of Wightman et al., Nature Genetics, 2021.]
From this genotypic trove, the researchers identified 3,915 genome-wide significant variants across 38 independent loci. Of the seven new ones, five—AGRN, TNIP1, AVCR2, NTN5, LILRB2—had never been linked to a neurodegenerative disease in GWAS. Two—TMEM106B and GRN—are important in frontotemporal dementia.
The researchers used the genomic position of each variant, as well as co-localization with expression quantitative trait loci (eQTL) and previously published data, to estimate which gene might account for each of the 38 loci. These genes were involved in amyloid and tau aggregation, catabolism of plaques, immune cell recruitment, and glial cell function. Combing through single-cell RNA sequencing data, the scientists found the risk genes to likely be expressed in microglia.
“This study is a great example of what genetics can do,” said Carlos Cruchaga of Washington University in St. Louis. He was referring to the integration of tissue and cell type-specific expression data to narrow down the list of potential causal genes in each loci, adding that “These tools are helping us understand the biological context behind associations.”
What do scientists know about the newbies? TNIP1 previously popped up in an autoimmune GWAS; it is thought to fuel hyperinflammation (Shamilov and Aneskievich, 2018). TNIP1cropped up in a transcription module in inflamed, aging mouse microglia; there, it was regulated by Bcl3, a gene that ramps up in AD brain and has come up in AD biomarker studies (e.g., Cho et al., 2019; Marques-Coelho et al., 2021).
LILRB2 belongs to the leukocyte immunoglobulin-like receptor family. These transmembrane glycoproteins are MHC class 1 receptors, i.e., they influence immune activation (Zhang et al., 2017). A small literature going back eight years has shown LILRB2 is expressed in brain and tied it to AD by way of Aβ oligomer binding (Sep 2013 news; Oct 2018 news). Carla Shatz of Stanford University, who led this line of research, said she was gratified to see LilrB2 emerge as a potential risk gene in AD. “Their GWAS results show how important it is to take high-quality basic science studies seriously, and fund basic research even in the absence of support from GWAS results,” she wrote.
While the study's sheer size helped unearth more AD risk loci, it also came at the price of lower specificity, Cruchaga said. He noted that especially with the use of proxy cases, it is difficult to determine whether the genetic associations relate to AD specifically or perhaps other types of dementia.
John Hardy of University College London made a similar point. “We know the diagnostic accuracy even in the highly cited clinic-based GWAS is only about 80 percent, and so is undoubtedly less in these GWAS, which use reported (parental) cases,” he wrote. “As FTD genes start to show up, perhaps we should note this concern,” he added (full comment below).
Even with more than a million samples, the study only scratches the surface of genetic heritability underpinning AD, the authors noted. Anders Dale, University of California, San Diego, and colleagues estimate that 2.2 million samples would be required to detect 80 percent of genetic variance on chromosome 19, which houses the ApoE gene, while a whopping 7.8 million samples would be needed to detect 80 percent of the variance from the rest of the genome (Holland et al., 2021). Wightman estimated that their current GWAS was powered to explain about 6 percent of the variance outside of chromosome 19, and 59 percent of the variance within it. Besides continually growing GWAS samples, other approaches, including chasing rare and private variants, will be needed to dig up the remaining AD risk influencers.—Jessica Shugart
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No Available Further Reading
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