Greenfest‐Allen, Emily;
Stoeckert, Christian J.;
Wang, Li‐San;
Schellenberg, Gerard D.;
Naj, Adam C.
Pleiotropy analyses using TADs identify genomic regions affecting risk of AD and stroke : Genetics/genetic factors of Alzheimer's disease
: Genetics/genetic factors of Alzheimer's disease
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Media type:
E-Article
Title:
Pleiotropy analyses using TADs identify genomic regions affecting risk of AD and stroke : Genetics/genetic factors of Alzheimer's disease
:
Genetics/genetic factors of Alzheimer's disease
Contributor:
Greenfest‐Allen, Emily;
Stoeckert, Christian J.;
Wang, Li‐San;
Schellenberg, Gerard D.;
Naj, Adam C.
Description:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Although stroke is an established risk factor for Alzheimer’s disease (AD), the role vascular factors play in driving AD remains uncertain. Here we leverage GWAS summary statistics to assess the genetic correlation (pleiotropy) between stroke and AD and introduce a novel fine‐mapping approach to pinpoint shared causal variants in the context of higher‐order genome organization.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>32 stroke‐risk associated variants identified by the MEGASTROKE consortium (Malik et al. Nat Genet 2018) were mapped to topologically associating domains (TADs) identified in H1‐hESCs (Dixon et al. Nature 2015). <jats:italic>Coloc</jats:italic> was used to compare GWAS summary statistics for stroke and AD (Kunkle et. al Nat Genet 2019) within the TADs containing each stroke variant. As genes located within the same TAD tend to be coregulated and contacts between enhancers and gene promoters are mainly restricted within TADs, predicted shared causal variants can be functionally linked to genes and their downstream interactants within the same domain. STRING pathway analysis was run on the resultant gene sets to tie putative target genes to processes affecting disease progression.</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p>The strongest evidence for shared genetic risk between AD and stroke is in the promoter region of <jats:italic>CDK6</jats:italic> (posterior probability [PP] of common causal variants in the TAD>70%; Figure 1, Tables 1/2), which encodes a serine/threonine‐protein kinase involved in the negative regulation of cell cycle and the promotion of G1/S transition. Levels of <jats:italic>CDK6</jats:italic> have been found to be higher in AD patients and affect pathways tied to neuronal cell death in stroke. Genetic correlations supporting pleiotropy due to distinct causal variants were found in TADs containing known interactants of <jats:italic>CDK6</jats:italic>, including <jats:italic>FBXO31</jats:italic> (PP<jats:sub>D</jats:sub> = 19.1%) and <jats:italic>CDKN2A/B</jats:italic> (PP<jats:sub>D</jats:sub> = 66.6%; Table 2). <jats:italic>CDKN2A/B</jats:italic> is part of a known chromosome 9p21.3 susceptibility locus for both AD and vascular dementia.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>We identified several candidate loci affecting AD/stroke pleiotropy, most of which contain no documented variants with genome‐wide significance for AD risk. Pathway analysis of genes contained within TADs reveals a link between the shared risk between AD and stroke and the disruption of neuronal cell cycle at the onset of the G1/S phase.</jats:p></jats:sec>