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

Xueqiu Jian, Claudia L Satizabal, Albert V Smith, Katharina Wittfield, J. C. Bis, Jennifer Smith, Fang-Chi Hsu, Kwangsik Nho, Edith Hofer, Saskia Hagenaars, Paul A Nyquist, Aniket Mishra, Hieab H H Adams, Shuo Li, Alexander Teumer, Wei Zhao, Barry I Freedman, Yasaman Saba, Lisa R Yanek, Ganesh ChauhanMark A Van Buchem, Mary Cushman, Natalie Royle, R Nick Bryan, Wiro J. Niessen, Beverly G Windham, Anita L. DeStefano, Mohamad Habes, Susan R. Heckbert, Nicholette D Palmer, Cora E Lewis, Gudny Eiriksdottir, Pauline Maillard, Rasika A Mathias, Georg Homuth, Maria Valdes Hernandez, Jasmin Divers, Alexa S Beiser, Sönke Langner, Kenneth M. Rice, Mark Bastin, Qiong Yang, Joseph A. Maldjan, John Starr, Stephen S Sidney, Shannon L Risacher, André G Uitterlinden, Vilmundur Gudnason, Matthias Nauck, Jerome I. Rotter, Pamela J. Schreiner, Eric Boerwinkle, Cornelia van Duijn, Bernard Mazoyer, Bettina von Sarnowski, Rebecca F Gottesman, Daniel Levy, Sigurdur Sigurdsson, Meike W Vernooij, Stephen T Turner, Reinhold Schmidt, Joanna Wardlaw, Bruce M. Psaty, Thomas H Mosley, Charles DeCarli, Andrew J Saykin, Donald W Bowden, Diane M Becker, Ian Deary, Helena Schmidt, Sharon L R Kardia, M Arfan Ikram, Stephanie Debette, Hans J Grabe, W T Longstreth, Sudha Seshadri, Lenore J. Launer, Myriam Fornage

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background and Purpose
White 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.
 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.
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 two low-frequency non-synonymous 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 due to limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the two low-frequency MRPL38 variants (prs34136221=2.8×10−8).
 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.
Original languageEnglish
Pages (from-to)1812-1819
Issue number8
Early online date12 Jul 2018
Publication statusE-pub ahead of print - 12 Jul 2018

Keywords / Materials (for Non-textual outputs)

  • white matter hyperintensities
  • brain MRI
  • cerebral small vessel disease
  • exome chip
  • low-frequency/rare coding variant
  • meta-analysis


Dive into the research topics of 'Exome chip analysis identifies low-frequency and rare variants in MRPL38 for white matter hyperintensities on brain MRI'. Together they form a unique fingerprint.

Cite this