Citations 2
Abstract 154: Sex-specific Genome Wide Association Study Of Early-onset Ischemic Stroke
Leeuw, Frank‐Erik de , Cadenas, Israel Fernández, Słowik, Agnieszka, Conde, Jordi Jiménez, Schmidt, Reinhold, Sharma, Pankaj , Rothwell, Peter M. , Sudlow, Catherine, Debette, Stéphanie , Markus, Hugh S. , Saleheen, Danish , Danesh, John , Zand, Ramin , Worrall, Bradford B. , Woo, Daniel , Lee, Jin-moo, Irvin, Marguerite R. , Rosand, Jonathan, Kamatani, Yoichiro, Xu, Huichun , Kittner, Steven J. , Debette, Stephanie , Zand, Ramin , Tomppo, Liisa , Rannikmäe, Kristiina , Stanne, Tara M. , Putaala, Jukka , Strbian, Daniel , Jern, Christina , Boncoraglio, Giorgio B. , Lindgren, Arne G. , Lemmens, Robin , Melander, Olle , Levi, Christopher , Sudlow, Catherine, Metso, Tiina M. , Paré, Guillaume , Meschia, James F. , Rundek, Tatjana , Lee, Jin‐Moo , McDonough, Caitrin W. , Rexrode, Kathryn M. , Wassertheil-Smoller, Sylvia W , Rosand, Jonathan M. , Gieger, Christian , Müller‐Nurasyid, Martina , Salomaa, Veikko , Kamatani, Yoichiro, Walters, Robin G. , Chen, Zhengming , Dichgans, Martin , Malik, Rainer , Gaynor, Brady J. , Cole, John W. , Mitchell, Braxton D.
Stroke | February 3, 2022 | Volume: 53 | Issue: Suppl_1 | Pages: No page available
Introduction: Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets generalizable also to later-onset disease. Few studies have investigated the sex-specific genetic associations with early-onset ischemic stroke even though several features of ischemic stroke differ between males and females. We hypothesized that stratifying the GWAS by sex would reveal novel stroke loci. Methods: We performed a transethnic ischemic stroke GWAS of 3,056 female cases and 4,462 male cases < 60 years-old and 16,192 and 16,048 sex-matched controls, respectively, from the Early Onset Stroke Genetics Consortium. Results: We identified a significant association in women with a locus in close proximity to TMX1 , a transmembrane platelet protein that inhibits platelet function. Additionally, we identified 2 other suggestive (P < 5 x 10 -6 ) loci in females (see Table), i.e., at APOH , which encodes beta2-glycoprotein I, an established GWAS locus for lipoprotein(a), and LRFN2 which has been previously reported to associate with obesity-related measures and type II diabetes. We observed suggestive evidence for association in males with MMP3/MMP12 , a known stroke susceptibility locus. Conclusions: Despite a very modest sample size, sex-specific analyses identified suggestive associations at biologically important novel loci in females and a known stroke locus in males. Further studies of sex-specific associations in both early- and later-onset ischemic stroke are needed.
Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage
Falcone, Guido J. , Kirsch, Elayna , Noche, Rommell B. , Leasure, Audrey C. , Marini, Sandro , Chung, Jaeyoon , Meschia, James F. , Brown, Devin L. , Worrall, Bradford B. , Tirschwell, David , Jagiełła, Jeremiasz , Schmidt, Helena , Jiménez-Conde, Jordi , Lindgren, Arne, Słowik, Agnieszka , Gill, Dipender , Petersen, Nils , Matouk, Charles N., Bennett, Derrick , Sun, Luan L., Clarke, Robert , Biffi, Alessandro , Kathiresan, Sekar , Langefeld, Carl D. , Woo, Daniel , Anderson, Christopher D. , James, Michael L. , Leasure, Audrey , Meschia, James F , Biffi, Alessandro , Acosta, Julián , Selim, Magdy H. , Fernández‐Cadenas, Israel , Lindgren, Arne, Holmes, Michael Vaclav , Phuah, Chia‐Ling , Matouk, Charles , Günel, Murat , Sansing, Lauren H , Chen, Zhengming , Walters, Robin G. , Gill, Thomas M. , Rosand, Jonathan M. , Sheth, Kevin N.
Annals of Neurology | April 11, 2020 | Volume: 88 | Issue: 1 | Pages: 56-66
ObjectiveObservational studies point to an inverse correlation between low‐density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH.MethodsWe constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high‐density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses.ResultsWe identified 410, 339, 393, and 317 lipid‐related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10‐100). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85–0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81–0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively.InterpretationGenetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56–66