Exome chip analysis identifies low-frequency and rare variants in MRPL38 for white matter hyperintensities on brain MRI

Autor: Jian, Xueqiu, Satizabal, Claudia L, Smith, Albert V, Wittfield, Katharina, Bis, J. C., Smith, Jennifer, Hsu, Fang-Chi, Nho, Kwangsik, Hofer, Edith, Hagenaars, Saskia, Nyquist, Paul A, Mishra, Aniket, Adams, Hieab H H, Li, Shuo, Teumer, Alexander, Zhao, Wei, Freedman, Barry I, Saba, Yasaman, Yanek, Lisa R, Chauhan, Ganesh, Van Buchem, Mark A, Cushman, Mary, Royle, Natalie, Bryan, R Nick, Niessen, Wiro J., Windham, Beverly G, DeStefano, Anita L., Habes, Mohamad, Heckbert, Susan R., Palmer, Nicholette D, Lewis, Cora E, Eiriksdottir, Gudny, Maillard, Pauline, Mathias, Rasika A, Homuth, Georg, Valdes Hernandez, Maria, Divers, Jasmin, Beiser, Alexa S, Langner, Sönke, Rice, Kenneth M., Bastin, Mark, Yang, Qiong, Maldjan, Joseph A., Starr, John, Sidney, Stephen S, Risacher, Shannon L, Uitterlinden, André G, Gudnason, Vilmundur, Nauck, Matthias, Rotter, Jerome I., Schreiner, Pamela J., Boerwinkle, Eric, van Duijn, Cornelia, Mazoyer, Bernard, von Sarnowski, Bettina, Gottesman, Rebecca F, Levy, Daniel, Sigurdsson, Sigurdur, Vernooij, Meike W, Turner, Stephen T, Schmidt, Reinhold, Wardlaw, Joanna, Psaty, Bruce M., Mosley, Thomas H, DeCarli, Charles, Saykin, Andrew J, Bowden, Donald W, Becker, Diane M, Deary, Ian, Schmidt, Helena, Kardia, Sharon L R, Ikram, M Arfan, Debette, Stephanie, Grabe, Hans J, Longstreth, W T, Seshadri, Sudha, Launer, Lenore J., Fornage, Myriam
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Jian, X, Satizabal, C L, Smith, A V, Wittfield, K, Bis, J C, Smith, J, Hsu, F-C, Nho, K, Hofer, E, Hagenaars, S, Nyquist, P A, Mishra, A, Adams, H H H, Li, S, Teumer, A, Zhao, W, Freedman, B I, Saba, Y, Yanek, L R, Chauhan, G, Van Buchem, M A, Cushman, M, Royle, N, Bryan, R N, Niessen, W J, Windham, B G, DeStefano, A L, Habes, M, Heckbert, S R, Palmer, N D, Lewis, C E, Eiriksdottir, G, Maillard, P, Mathias, R A, Homuth, G, Valdes Hernandez, M, Divers, J, Beiser, A S, Langner, S, Rice, K M, Bastin, M, Yang, Q, Maldjan, J A, Starr, J, Sidney, S S, Risacher, S L, Uitterlinden, A G, Gudnason, V, Nauck, M, Rotter, J I, Schreiner, P J, Boerwinkle, E, van Duijn, C, Mazoyer, B, von Sarnowski, B, Gottesman, R F, Levy, D, Sigurdsson, S, Vernooij, M W, Turner, S T, Schmidt, R, Wardlaw, J, Psaty, B M, Mosley, T H, DeCarli, C, Saykin, A J, Bowden, D W, Becker, D M, Deary, I, Schmidt, H, Kardia, S L R, Ikram, M A, Debette, S, Grabe, H J, Longstreth, W T, Seshadri, S, Launer, L J & Fornage, M 2018, ' Exome chip analysis identifies low-frequency and rare variants in MRPL38 for white matter hyperintensities on brain MRI ', Stroke, vol. 49, no. 8, pp. 1812-1819 . https://doi.org/10.1161/STROKEAHA.118.020689
Popis: Background and PurposeWhite matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various pre-clinical, age-related neurological disorders such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.Methods In the discovery sample we recruited 20,719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17,790 were of European ancestry (EA) and 2,929 of African ancestry (AA). We genotyped these participants at ~250,000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1,192 adults (EA) with whole exome/genome sequencing data from two independent studies.ResultsAt 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 (pConclusions Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
Databáze: OpenAIRE
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