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 Chauhan; Mark 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

doi:10.1161/STROKEAHA.118.020689

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 journal › Article › peer-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.
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.
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 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).
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 language	English
Pages (from-to)	1812-1819
Journal	Stroke
Volume	49
Issue number	8
Early online date	12 Jul 2018
DOIs	https://doi.org/10.1161/STROKEAHA.118.020689
Publication status	E-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

Access to Document

10.1161/STROKEAHA.118.020689

XueqiuEtalS2018ExomeChipAnalysis
This is the accepted version of the following article: "Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging", Xueqiu Etal, Stroke 49:8, August 2018, 1812-1819 which has been published in final form: https://www.ahajournals.org/doi/10.1161/STROKEAHA.118.020689
Accepted author manuscript, 472 KB

https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.118.020689

The Disconnected Mind Phase 3
Wardlaw, J.
UK-based charities
1/04/16 → 30/09/20
Project: Research
Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III
Wardlaw, J., Bastin, M. & Deary, I.
MRC
1/05/15 → 30/04/19
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research

Cite this

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., ... Fornage, M. (2018). Exome chip analysis identifies low-frequency and rare variants in MRPL38 for white matter hyperintensities on brain MRI. Stroke, 49(8), 1812-1819. https://doi.org/10.1161/STROKEAHA.118.020689

@article{1324b0a6355d40459f399e0f797a238c,

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

abstract = "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 (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).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 = "white matter hyperintensities, brain MRI, cerebral small vessel disease, exome chip, low-frequency/rare coding variant, meta-analysis",

author = "Xueqiu Jian and Satizabal, {Claudia L} and Smith, {Albert V} and Katharina Wittfield and Bis, {J. C.} and Jennifer Smith and Fang-Chi Hsu and Kwangsik Nho and Edith Hofer and Saskia Hagenaars 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 Natalie Royle and Bryan, {R Nick} 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 {Valdes Hernandez}, Maria and Jasmin Divers and Beiser, {Alexa S} and S{\"o}nke Langner and Rice, {Kenneth M.} and Mark Bastin and Qiong Yang and Maldjan, {Joseph A.} and John Starr and Sidney, {Stephen S} and Risacher, {Shannon L} and Uitterlinden, {Andr{\'e} G} and Vilmundur Gudnason and Matthias Nauck and Rotter, {Jerome I.} and Schreiner, {Pamela J.} and Eric Boerwinkle and {van Duijn}, Cornelia and Bernard Mazoyer and {von Sarnowski}, Bettina and Gottesman, {Rebecca F} and Daniel Levy and Sigurdur Sigurdsson and Vernooij, {Meike W} and Turner, {Stephen T} and Reinhold Schmidt and Joanna Wardlaw and Psaty, {Bruce M.} and Mosley, {Thomas H} and Charles DeCarli and Saykin, {Andrew J} and Bowden, {Donald W} and Becker, {Diane M} and Ian Deary and Helena Schmidt and Kardia, {Sharon L R} and Ikram, {M Arfan} and Stephanie Debette and Grabe, {Hans J} and Longstreth, {W T} and Sudha Seshadri and Launer, {Lenore J.} and Myriam Fornage",

year = "2018",

month = jul,

day = "12",

doi = "10.1161/STROKEAHA.118.020689",

language = "English",

volume = "49",

pages = "1812--1819",

journal = "Stroke",

issn = "0039-2499",

publisher = "Lippincott Williams & Wilkins",

number = "8",

}

Jian, X, Satizabal, CL, Smith, AV, Wittfield, K, Bis, JC, Smith, J, Hsu, F-C, Nho, K, Hofer, E, Hagenaars, S, Nyquist, PA, Mishra, A, Adams, HHH, Li, S, Teumer, A, Zhao, W, Freedman, BI, Saba, Y, Yanek, LR, Chauhan, G, Van Buchem, MA, Cushman, M, Royle, N, Bryan, RN, Niessen, WJ, Windham, BG, DeStefano, AL, Habes, M, Heckbert, SR, Palmer, ND, Lewis, CE, Eiriksdottir, G, Maillard, P, Mathias, RA, Homuth, G, Valdes Hernandez, M, Divers, J, Beiser, AS, Langner, S, Rice, KM, Bastin, M, Yang, Q, Maldjan, JA, Starr, J, Sidney, SS, Risacher, SL, Uitterlinden, AG, Gudnason, V, Nauck, M, Rotter, JI, Schreiner, PJ, Boerwinkle, E, van Duijn, C, Mazoyer, B, von Sarnowski, B, Gottesman, RF, Levy, D, Sigurdsson, S, Vernooij, MW, Turner, ST, Schmidt, R, Wardlaw, J, Psaty, BM, Mosley, TH, DeCarli, C, Saykin, AJ, Bowden, DW, Becker, DM, Deary, I, Schmidt, H, Kardia, SLR, Ikram, MA, Debette, S, Grabe, HJ, Longstreth, WT, Seshadri, S, Launer, LJ & 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

TY - JOUR

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

AU - Jian, Xueqiu

AU - Satizabal, Claudia L

AU - Smith, Albert V

AU - Wittfield, Katharina

AU - Bis, J. C.

AU - Smith, Jennifer

AU - Hsu, Fang-Chi

AU - Nho, Kwangsik

AU - Hofer, Edith

AU - Hagenaars, Saskia

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

AU - Bryan, R Nick

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 - Valdes Hernandez, Maria

AU - Divers, Jasmin

AU - Beiser, Alexa S

AU - Langner, Sönke

AU - Rice, Kenneth M.

AU - Bastin, Mark

AU - Yang, Qiong

AU - Maldjan, Joseph A.

AU - Starr, John

AU - Sidney, Stephen S

AU - Risacher, Shannon L

AU - Uitterlinden, André G

AU - Gudnason, Vilmundur

AU - Nauck, Matthias

AU - Rotter, Jerome I.

AU - Schreiner, Pamela J.

AU - Boerwinkle, Eric

AU - van Duijn, Cornelia

AU - Mazoyer, Bernard

AU - von Sarnowski, Bettina

AU - Gottesman, Rebecca F

AU - Levy, Daniel

AU - Sigurdsson, Sigurdur

AU - Vernooij, Meike W

AU - Turner, Stephen T

AU - Schmidt, Reinhold

AU - Wardlaw, Joanna

AU - Psaty, Bruce M.

AU - Mosley, Thomas H

AU - DeCarli, Charles

AU - Saykin, Andrew J

AU - Bowden, Donald W

AU - Becker, Diane M

AU - Deary, Ian

AU - Schmidt, Helena

AU - Kardia, Sharon L R

AU - Ikram, M Arfan

AU - Debette, Stephanie

AU - Grabe, Hans J

AU - Longstreth, W T

AU - Seshadri, Sudha

AU - Launer, Lenore J.

AU - Fornage, Myriam

PY - 2018/7/12

Y1 - 2018/7/12

N2 - 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 (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).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 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 (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).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 - white matter hyperintensities

KW - brain MRI

KW - cerebral small vessel disease

KW - exome chip

KW - low-frequency/rare coding variant

KW - meta-analysis

U2 - 10.1161/STROKEAHA.118.020689

DO - 10.1161/STROKEAHA.118.020689

M3 - Article

SN - 0039-2499

VL - 49

SP - 1812

EP - 1819

JO - Stroke

JF - Stroke

IS - 8

ER -

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

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

The Disconnected Mind Phase 3

Brain imaging and cognitive ageing in the Lothian Birth Cohort 1936: III

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Cite this