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

neuroCHARGE Working Group

Research output: Contribution to journalArticle

2 Citations (Scopus)

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; P EA =4.5×10 −8 ) partially independent of known common signal (P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; P all =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 (P rs34136221 =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.

Original languageEnglish (US)
Pages (from-to)1812-1819
Number of pages8
JournalStroke
Volume49
Issue number8
DOIs
StatePublished - Jan 1 2018

Fingerprint

Exome
Magnetic Resonance Imaging
Brain
Meta-Analysis
Cerebral Small Vessel Diseases
Stroke
White Matter
Nervous System Diseases
Dementia
Linear Models
Epidemiology
Cohort Studies
Genome
Research

Keywords

  • Cerebral small vessel disease
  • Exome
  • Magnetic resonance imaging
  • Meta-analysis
  • White matter

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Exome chip analysis identifies low-frequency and rare variants in MRPL38 for white matter hyperintensities on brain magnetic resonance imaging. / neuroCHARGE Working Group.

In: Stroke, Vol. 49, No. 8, 01.01.2018, p. 1812-1819.

Research output: Contribution to journalArticle

@article{2e3153ba0ced47b69718f0754746afdf,
title = "Exome chip analysis identifies low-frequency and rare variants in MRPL38 for white matter hyperintensities on brain magnetic resonance imaging",
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; P EA =4.5×10 −8 ) partially independent of known common signal (P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; P all =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 (P rs34136221 =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.",
keywords = "Cerebral small vessel disease, Exome, Magnetic resonance imaging, Meta-analysis, White matter",
author = "{neuroCHARGE Working Group} and Xueqiu Jian and Satizabal, {Claudia L.} and Smith, {Albert V.} and Katharina Wittfeld and Bis, {Joshua C.} and Smith, {Jennifer A.} and Hsu, {Fang Chi} and Kwangsik Nho and Edith Hofer and Hagenaars, {Saskia P.} and Nyquist, {Paul A.} and Aniket Mishra and Adams, {Hieab H.H.} and Shuo Li and Alexander Teumer and Wei Zhao and Freedman, {Barry I.} and Yasaman Saba and Yanek, {Lisa R.} and Ganesh Chauhan and {Van Buchem}, {Mark A.} and Mary Cushman and Royle, {Natalie A.} and {Nick Bryan}, R. and Niessen, {Wiro J.} and Windham, {Beverly G.} and DeStefano, {Anita L.} and Mohamad Habes and Heckbert, {Susan R.} and Palmer, {Nicholette D.} and Lewis, {Cora E.} and Gudny Eiriksdottir and Pauline Maillard and Mathias, {Rasika A.} and Georg Homuth and Vald{\'e}s-Hern{\'a}ndez, {Maria del C.} and Jasmin Divers and Beiser, {Alexa S.} and S{\"o}nke Langner and Rice, {Kenneth M.} and Bastin, {Mark E.} and Qiong Yang and Maldjian, {Joseph A.} and Starr, {John M.} and Stephen Sidney and Risacher, {Shannon L.} and Uitterlinden, {Andr{\'e} G.} and Gudnason, {Vilmundur G.} and Matthias Nauck and Turner, {Stephen T}",
year = "2018",
month = "1",
day = "1",
doi = "10.1161/STROKEAHA.118.020689",
language = "English (US)",
volume = "49",
pages = "1812--1819",
journal = "Stroke",
issn = "0039-2499",
publisher = "Lippincott Williams and Wilkins",
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TY - JOUR

T1 - Exome chip analysis identifies low-frequency and rare variants in MRPL38 for white matter hyperintensities on brain magnetic resonance imaging

AU - neuroCHARGE Working Group

AU - Jian, Xueqiu

AU - Satizabal, Claudia L.

AU - Smith, Albert V.

AU - Wittfeld, Katharina

AU - Bis, Joshua C.

AU - Smith, Jennifer A.

AU - Hsu, Fang Chi

AU - Nho, Kwangsik

AU - Hofer, Edith

AU - Hagenaars, Saskia P.

AU - Nyquist, Paul A.

AU - Mishra, Aniket

AU - Adams, Hieab H.H.

AU - Li, Shuo

AU - Teumer, Alexander

AU - Zhao, Wei

AU - Freedman, Barry I.

AU - Saba, Yasaman

AU - Yanek, Lisa R.

AU - Chauhan, Ganesh

AU - Van Buchem, Mark A.

AU - Cushman, Mary

AU - Royle, Natalie A.

AU - Nick Bryan, R.

AU - Niessen, Wiro J.

AU - Windham, Beverly G.

AU - DeStefano, Anita L.

AU - Habes, Mohamad

AU - Heckbert, Susan R.

AU - Palmer, Nicholette D.

AU - Lewis, Cora E.

AU - Eiriksdottir, Gudny

AU - Maillard, Pauline

AU - Mathias, Rasika A.

AU - Homuth, Georg

AU - Valdés-Hernández, Maria del C.

AU - Divers, Jasmin

AU - Beiser, Alexa S.

AU - Langner, Sönke

AU - Rice, Kenneth M.

AU - Bastin, Mark E.

AU - Yang, Qiong

AU - Maldjian, Joseph A.

AU - Starr, John M.

AU - Sidney, Stephen

AU - Risacher, Shannon L.

AU - Uitterlinden, André G.

AU - Gudnason, Vilmundur G.

AU - Nauck, Matthias

AU - Turner, Stephen T

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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; P EA =4.5×10 −8 ) partially independent of known common signal (P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; P all =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 (P rs34136221 =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.

AB - 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; P EA =4.5×10 −8 ) partially independent of known common signal (P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; P all =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 (P rs34136221 =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.

KW - Cerebral small vessel disease

KW - Exome

KW - Magnetic resonance imaging

KW - Meta-analysis

KW - White matter

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U2 - 10.1161/STROKEAHA.118.020689

DO - 10.1161/STROKEAHA.118.020689

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SP - 1812

EP - 1819

JO - Stroke

JF - Stroke

SN - 0039-2499

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