Adams, Hieab H H

Bastin, Mark

Becker, Diane M

Beiser, Alexa S

Bis, J. C.

Boerwinkle, Eric

Bowden, Donald W

Bryan, R Nick

Chauhan, Ganesh

Cushman, Mary

Deary, Ian

Debette, Stephanie

DeCarli, Charles

DeStefano, Anita L.

Divers, Jasmin

Eiriksdottir, Gudny

Fornage, Myriam

Freedman, Barry I

Gottesman, Rebecca F

Grabe, Hans J

Gudnason, Vilmundur

Habes, Mohamad

Hagenaars, Saskia

Heckbert, Susan R.

Hofer, Edith

Homuth, Georg

Hsu, Fang-Chi

Ikram, M Arfan

Jian, Xueqiu

Kardia, Sharon L R

Langner, Sönke

Launer, Lenore J.

Levy, Daniel

Lewis, Cora E

Li, Shuo

Longstreth, W T

Maillard, Pauline

Maldjan, Joseph A.

Mathias, Rasika A

Mazoyer, Bernard

Mishra, Aniket

Mosley, Thomas H

Nauck, Matthias

Nho, Kwangsik

Niessen, Wiro J.

Nyquist, Paul A

Palmer, Nicholette D

Psaty, Bruce M.

Rice, Kenneth M.

Risacher, Shannon L

Rotter, Jerome I.

Royle, Natalie

Saba, Yasaman

Satizabal, Claudia L

Saykin, Andrew J

Schmidt, Helena

Schmidt, Reinhold

Schreiner, Pamela J.

Seshadri, Sudha

Sidney, Stephen S

Sigurdsson, Sigurdur

Smith, Albert V

Smith, Jennifer

Starr, John

Teumer, Alexander

Turner, Stephen T

Uitterlinden, André G

Valdes Hernandez, Maria

Van Buchem, Mark A

van Duijn, Cornelia

Vernooij, Meike W

von Sarnowski, Bettina

Wardlaw, Joanna

Windham, Beverly G

Wittfield, Katharina

Yanek, Lisa R

Yang, Qiong

Zhao, Wei

English

Satizabal, Claudia

Smith, Albert

Wittfeld, Katharina

Bis, Joshua

Nyquist, Paul

Adams, Hieab H.H.

Teumer, Alexa

Freedman, Barry

Yanek, Lisa

van Buchem, Mark

Bryan, R. Nick

Niessen, Wiro, J.

Windham, Beverly

Destefano, Anita

Heckbert, Susan

Palmer, Nicholette

Lewis, Cora

Mathias, Rasika

Valdés-Hernández, Maria del C.

Beiser, Alexa

Rice, Kenneth

Maldjian, Joseph

Sidney, Stephen

Risacher, Shannon

Uitterlinden, Andre

Rotter, Jerome

Schreiner, Pamela

Gottesman, Rebecca

Lévy, Daniel

Vernooij, Meike

Turner, Stephen

Psaty, Bruce

Mosley, Thomas

Decarli, Charles

Saykin, Andrew

Bowden, Donald

Becker, Diane

Deary, Ian, J

Kardia, Sharon L.R.

Ikram, M. Arfan, Arfan

Debette, Stéphanie

Grabe, Hans, J

Longstreth, W.T.

Launer, Lenore

Portail HAL EHESS (École des hautes études en sciences sociales)

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging

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&lt;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

Edinburgh Research Explorer

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

HAL-Paris1

Hal - Université Grenoble Alpes

Crossref

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38

Niessen, Wiro,

DeStefano, Anita

Van Duijn, Cornelia

Deary, Ian,

Ikram, M. Arfan,

Grabe, Hans,

HAL Descartes

HAL-Ecole des Ponts ParisTech

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&lt;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

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

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