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. 2022 May 19;12(1):8404.
doi: 10.1038/s41598-022-12391-2.

Genome-wide association of polygenic risk extremes for Alzheimer's disease in the UK Biobank

Catarina Gouveia  1 , Elizabeth Gibbons  1 , Nadia Dehghani  1 , James Eapen  1 , Rita Guerreiro  1   2 , Jose Bras  3   4
Affiliations

Genome-wide association of polygenic risk extremes for Alzheimer's disease in the UK Biobank

Catarina Gouveia et al. Sci Rep. .

Abstract

In just over a decade, advances in genome-wide association studies (GWAS) have offered an approach to stratify individuals based on genetic risk for disease. Using recent Alzheimer's disease (AD) GWAS results as the base data, we determined each individual's polygenic risk score (PRS) in the UK Biobank dataset. Using individuals within the extreme risk distribution, we performed a GWAS that is agnostic of AD phenotype and is instead based on known genetic risk for disease. To interpret the functions of the new risk factors, we conducted phenotype analyses, including a phenome-wide association study. We identified 246 loci surpassing the significance threshold of which 229 were not reported in the base AD GWAS. These include loci that showed suggestive levels of association in the base GWAS and loci not previously suspected to be associated with AD. Among these, there are loci, such as IL34 and KANSL1, that have since been shown to be associated with AD in recent studies. We also show highly significant genetic correlations with multiple health-related outcomes that provide insights into prodromal symptoms and comorbidities. This is the first study to utilize PRS as a phenotype-agnostic group classification in AD genetic studies. We identify potential new loci for AD and detail phenotypic analysis of these PRS extremes.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Density plot with the distribution of PRS when applied to samples from the UKBB. Solid grey vertical lines depict the 5% extremes of the PRS distribution. PRS were rescaled between zero and one.
Figure 2
Figure 2
Manhattan plot of the GWAS performed in AD PRS extremes. We compared results with those from Refs.,. Genomic loci are labeled with the gene name that is nearest to that position. Black labels indicate novel signals; grey labels show previously replicated loci. The bottom panel shows the location of the significant variants depicted in the Manhattan plot that reached significance in the studies considered. Signals were annotated with FUMA and LocusZoom.
Figure 3
Figure 3
Regional association plots for significant loci in the GWAS performed in AD PRS extremes that had previously been implicated in AD in studies other than typical GWAS, but were not significant from the base AD GWAS.
Figure 4
Figure 4
Phenotype-based gene set enrichment from GWAS Catalog. The top 10 most significant traits are shown in (A). The top 10 most significant traits where the overlapping genes include genes located in the APOE locus (chr19q13) are shown in (B) and the top 10 most significant traits where the overlapping genes do not include genes located in this locus are shown in (C).
Figure 5
Figure 5
Genetic correlation of most significant MRC IEU traits. Most significant (p < 0.05) correlations from ldsc analysis of OpenGWAS ieu-a traits. Results are shown for the full sumstats (no loci excluded) (A) and in the absence of the APOE locus (B). Color of points denotes p value. Asterisk indicates p value below 1e−5.
Figure 6
Figure 6
Phenome Scan results. The analysis was made with individuals in each extreme of the PRS distribution (including and excluding the APOE locus) using PHESANT. Each color represents a group of traits/diseases, according to the UKBB hierarchical tree. Downward triangles represent results from individuals in the extremes of the PRS calculated when excluding APOE (no APOE). The size of triangles represents the beta value for the association. Vertical dashed lines connect results for the same trait in the APOE and no APOE analyses. Y-axis is the logarithmic scale for the p value, multiplied by the beta value, to depict whether the trait is negatively or positively associated. Red dashed lines represent the adjusted Bonferroni p value threshold. *Note: "Illnesses of father/mother: Alzheimer's Disease/Dementia" had a software output p value of 0, to represent these we attributed a p value of 1 × 10–150.
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