Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk

AbstractLate onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of 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 randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

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Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk

Translational Psychiatry ◽

10.1038/s41398-021-01272-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daichi Shigemizu ◽

Risa Mitsumori ◽

Shintaro Akiyama ◽

Akinori Miyashita ◽

Takashi Morizono ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Japanese Population ◽

Disease Risk ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

AbstractAlzheimer’s disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including APOE and SORL1, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case–control cohort. The novel locus FAM47E reached genome-wide significance in a meta-analysis of association results. This is the first report associating the FAM47E locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer’s Project identified an additional novel susceptibility locus in OR2B2. Our data highlight the importance of performing GWAS in non-European populations.

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Author Correction: Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes

Nature Genetics ◽

10.1038/s41588-021-00822-1 ◽

2021 ◽

Author(s):

Jeremy Schwartzentruber ◽

Sarah Cooper ◽

Jimmy Z. Liu ◽

Inigo Barrio-Hernandez ◽

Erica Bello ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fine Mapping ◽

Disease Risk ◽

Meta Analysis ◽

Risk Genes ◽

Genome Wide

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Genome-wide meta-analysis, fine-mapping, and integrative prioritization identify new Alzheimer’s disease risk genes

10.1101/2020.01.22.20018424 ◽

2020 ◽

Cited By ~ 4

Author(s):

Jeremy Schwartzentruber ◽

Sarah Cooper ◽

Jimmy Z Liu ◽

Inigo Barrio-Hernandez ◽

Erica Bello ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fine Mapping ◽

Disease Risk ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association Studies ◽

Specific Expression ◽

Genome Wide ◽

Causal Genes

AbstractGenome-wide association studies (GWAS) have discovered numerous genomic loci associated with Alzheimer’s disease (AD), yet the causal genes and variants remain incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including novel associations near genes CCDC6, TSPAN14, NCK2, and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with greater than 50% probability each of being causally involved in AD risk, and others strongly suggested by functional annotation. We followed this with colocalisation analyses across 109 gene expression quantitative trait loci (eQTL) datasets, and prioritization of genes using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we find that evidence converges on likely causal genes, including the above four genes, and those at previously discovered AD loci including BIN1, APH1B, PTK2B, PILRA, and CASS4.

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