June 27, 2022

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The largest study so far reveals a new genetic locus of Alzheimer’s disease

The largest study so far reveals a new genetic locus of Alzheimer’s disease



Nature Sub-Journal: The largest study so far reveals a new genetic locus of Alzheimer’s disease.

Alzheimer’s disease (AD), commonly known as “Alzheimer’s disease”, is the most common neurodegenerative disease. Patients usually have symptoms such as memory decline, weakened learning ability, and mood regulation disorders. As well as the loss of athletic ability, it greatly affects the development of individuals, families and even society.

Currently, about 50 million people worldwide suffer from Alzheimer’s disease. As the average life expectancy of human beings increases and the aging society intensifies, the prevalence of Alzheimer’s disease is also rising. It is estimated that by 2050, Alzheimer’s patients will increase to more than 150 million.

The pathological feature of Alzheimer’s disease is the presence of β-amyloid (Aβ) and Tau amyloid deposits in the brain. Most patients are diagnosed with Alzheimer’s disease after 65 years of age, called late-onset Alzheimer’s disease (LOAD).

A large part of the individual differences in disease risk are driven by genetics. However, some people believe that due to the huge impact of APOE mutations, LOAD is more of an oligogenic disease than a polygenic disease.

However, only a small part of the genetic variation of Alzheimer’s disease has been identified. Increasing the sample size of genome-wide association studies (GWAS) will improve the ability to identify pathogenic variants and may find other pathogenic mechanisms.

On September 7, 2021, the research team of Vrije Universiteit Amsterdam published a research paper titled: A genome-wide association study with 1,126,563 individuals identifying new risk loci for Alzheimer’s disease in the journal Nature Genetics.

The study investigated the genotyping data of millions of people and found 7 new sites, including 2 sites related to frontotemporal dementia, and five sites related to neurodegeneration. Risk genes were prioritized, emphasizing the role of microglia, immune function, and protein homeostasis in Alzheimer’s disease.

The largest study so far reveals a new genetic locus of Alzheimer's disease

The research team conducted a meta-analysis on the data of 1,126,563 people in 13 cohorts. The 13 cohorts include the International Alzheimer’s Genomics Project (IGAP), deCODE, British Biobank, 23andMe, BioVU, Trøndelag Health Research, DemGene, TwinGene, STSA, GR@CE, Gothenburg, ANMerge, and Finngen. 1,126,563 people included 90,338 people who were diagnosed with Alzheimer’s disease or had a family history of the disease, and 1,036,225 controls.

They found 3915 variants in 38 independent loci. Of these 38 loci, 7 have not been reported by GWAS, and 5 of them have not been reported to be associated with dementia (AGRN, TNIP1, HAVCR2, NTN5, LILRB2).

The largest study so far reveals a new genetic locus of Alzheimer's disease

MAGMA tissue-specific analysis identified the spleen as the only GTEx tissue, and single-cell RNA sequencing data suggested that risk genes may be expressed in microglia. Therefore, microglia and immune tissues are potential experimental models for identifying the contribution of risk-related genes to the pathogenesis of Alzheimer’s disease.

The largest study so far reveals a new genetic locus of Alzheimer's disease

Further analysis of the MAGMA gene set identified 25 gene ontology biological processes, which were significantly enriched in risk-related mutations.

Conditional gene set analysis confirmed that the 4 gene sets in these 25 gene sets are independently related, reflecting the risk-related genes in β-amyloid and tau plaque formation, plaque protein catabolism, immune cell recruitment, and glial cells The role of the further identified important gene sets related to immune cell recruitment and nerve cell types.

As expected, the genomic risk sites identified in this study are enriched with active chromatin and variant annotations related to gene function. Then the research team made functional annotations.

Based on the location and expression quantitative trait loci (eQTL) information from the brain and immune tissues/cells, they mapped the variant functions to genes and identified 989 genes, which were mapped to 38 genomic risk loci.

In order to highlight potentially related genes, the research team used Coloc to co-locate eQTL data from immune tissues, brain and microglia with genomic risk sites.

In addition, susieR was used for statistical fine mapping to narrow the relevant area.

They identified several potential risk genes GPX3, TNIP1, SLC36A1, HAVCR1, TIMD4, and LILRB2. Follow-up animal experiments will help determine the role of these genes in LOAD.

The largest study so far reveals a new genetic locus of Alzheimer's disease


Summary 

In summary, this work:

  • Provides genetic support for the role of immune cells and microglia in Alzheimer’s disease,
  • Identified previously unidentified risk-related areas,
  • Prioritize related disease-causing genes,
  • It also emphasizes the importance of collaboratively identifying the biological processes that mediate the pathology of Alzheimer’s disease.

The study also shows that increasing the sample size can identify more new gene loci that cause Alzheimer’s disease.

Original link:

https://www.nature.com/articles/s41588-021-00921-z

The largest study so far reveals a new genetic locus of Alzheimer’s disease

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