| Literature DB >> 30002152 |
Xueqiu Jian1, Claudia L Satizabal2, Albert V Smith3, Katharina Wittfeld4, Joshua C Bis5, Jennifer A Smith6, Fang-Chi Hsu7, Kwangsik Nho8, Edith Hofer9, Saskia P Hagenaars10, Paul A Nyquist11, Aniket Mishra12, Hieab H H Adams13, Shuo Li14, Alexander Teumer15, Wei Zhao6, Barry I Freedman16, Yasaman Saba17, Lisa R Yanek18, Ganesh Chauhan12, Mark A van Buchem19, Mary Cushman20, Natalie A Royle10, R Nick Bryan21, Wiro J Niessen22,23, Beverly G Windham, Anita L DeStefano14, Mohamad Habes24, Susan R Heckbert5, Nicholette D Palmer25, Cora E Lewis26, Gudny Eiriksdottir3, Pauline Maillard27, Rasika A Mathias18, Georg Homuth28, Maria Del C Valdés-Hernández10, Jasmin Divers7, Alexa S Beiser14, Sönke Langner29, Kenneth M Rice30, Mark E Bastin10, Qiong Yang14, Joseph A Maldjian31, John M Starr10, Stephen Sidney32, Shannon L Risacher8, André G Uitterlinden33, Vilmundur G Gudnason3, Matthias Nauck34, Jerome I Rotter35, Pamela J Schreiner36, Eric Boerwinkle37, Cornelia M van Duijn13, Bernard Mazoyer38, Bettina von Sarnowski39, Rebecca F Gottesman11, Daniel Levy40, Sigurdur Sigurdsson3, Meike W Vernooij41, Stephen T Turner42, Reinhold Schmidt9, Joanna M Wardlaw10, Bruce M Psaty5, Thomas H Mosley, Charles S DeCarli27, Andrew J Saykin, Donald W Bowden25, Diane M Becker18, Ian J Deary10, Helena Schmidt17, Sharon L R Kardia6, M Arfan Ikram43, Stéphanie Debette12, Hans J Grabe44, W T Longstreth45, Sudha Seshadri2, Lenore J Launer46, Myriam Fornage1.
Abstract
Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, 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 and 2929 of African ancestry. 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 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal ( PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8×10-8). Conclusions- 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.Entities:
Keywords: cerebral small vessel disease; exome; magnetic resonance imaging; meta-analysis; white matter
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Year: 2018 PMID： 30002152 PMCID： PMC6202149 DOI： 10.1161/STROKEAHA.118.020689
Source DB: PubMed Journal: Stroke ISSN： 0039-2499 Impact factor: 7.914