Jiang Li1, Vida Abedi1,2, Ramin Zand3, Christoph J Griessenauer4,5. 1. Department of Molecular and Functional Genomics, Geisinger, Danville, PA (J.L., V.A.). 2. Biocomplexity Institute, Virginia Tech, Blacksburg (V.A.). 3. Department of Neurology (R.Z.), Neuroscience Institute, Geisinger, Danville, PA. 4. Department of Neurosurgery (C.J.G.), Neuroscience Institute, Geisinger, Danville, PA. 5. Research Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria (C.J.G.).
Abstract
BACKGROUND AND PURPOSE: The purpose of this study was to replicate the top loci associated with white matter hyperintensity (WMH) phenotypes identified by large genome-wide association studies and the loci identified from the previous candidate gene studies. METHODS: A total of 946 Geisinger MyCode patients with acute ischemic stroke with validated European ancestry and magnetic resonance imaging data were included in this study. Log-transformed WMH volume, as a quantitative trait, was calculated by a fully automated quantification process. The genome-wide association studies was carried out by a linear mixed regression model (GEMMA). A candidate-single nucleotide polymorphism analysis by including known single nucleotide polymorphisms, reported from a meta-analysis and several large GWAS for WMH, was conducted in all cases and binary converted extreme cases. RESULTS: No genome-wide significantly associated variants were identified. In a candidate-single nucleotide polymorphism study, rs9515201 (COL4A2) and rs3744028 (TRIM65), 2 known genetic loci, showed nominal or trend of association with the WMH volume (β=0.13 and P=0.001 for rs9515201; β=0.094 and P=0.094 for rs3744028), and replicated in a subset of extreme cases versus controls (odds ratio=1.78, P=7.74×10-4 for rs9515201; odds ratio=1.53, P=0.047 for rs3744028, respectively). MTHFR677 cytosine/thymine (rs1801133) also showed an association with the binary WMH with odds ratio=1.47 for T allele (P=0.019). CONCLUSIONS: Replication of COL4A1/2 associated with WMH reassures that the genetic risk factors for monogenic and polygenic ischemic stroke are shared at gene level.
BACKGROUND AND PURPOSE: The purpose of this study was to replicate the top loci associated with white matter hyperintensity (WMH) phenotypes identified by large genome-wide association studies and the loci identified from the previous candidate gene studies. METHODS: A total of 946 Geisinger MyCode patients with acute ischemic stroke with validated European ancestry and magnetic resonance imaging data were included in this study. Log-transformed WMH volume, as a quantitative trait, was calculated by a fully automated quantification process. The genome-wide association studies was carried out by a linear mixed regression model (GEMMA). A candidate-single nucleotide polymorphism analysis by including known single nucleotide polymorphisms, reported from a meta-analysis and several large GWAS for WMH, was conducted in all cases and binary converted extreme cases. RESULTS: No genome-wide significantly associated variants were identified. In a candidate-single nucleotide polymorphism study, rs9515201 (COL4A2) and rs3744028 (TRIM65), 2 known genetic loci, showed nominal or trend of association with the WMH volume (β=0.13 and P=0.001 for rs9515201; β=0.094 and P=0.094 for rs3744028), and replicated in a subset of extreme cases versus controls (odds ratio=1.78, P=7.74×10-4 for rs9515201; odds ratio=1.53, P=0.047 for rs3744028, respectively). MTHFR677cytosine/thymine (rs1801133) also showed an association with the binary WMH with odds ratio=1.47 for T allele (P=0.019). CONCLUSIONS: Replication of COL4A1/2 associated with WMH reassures that the genetic risk factors for monogenic and polygenic ischemic stroke are shared at gene level.
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