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

dc.rights.licenseopenen_US
dc.contributor.authorJIAN, X.
dc.contributor.authorSATIZABAL, C. L.
dc.contributor.authorSMITH, A. V.
dc.contributor.authorWITTFELD, K.
dc.contributor.authorBIS, J. C.
dc.contributor.authorSMITH, J. A.
dc.contributor.authorHSU, F. C.
dc.contributor.authorNHO, K.
dc.contributor.authorHOFER, E.
dc.contributor.authorHAGENAARS, S. P.
dc.contributor.authorNYQUIST, P. A.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorMISHRA, Aniket
dc.contributor.authorADAMS, H. H. H.
dc.contributor.authorLI, S.
dc.contributor.authorTEUMER, A.
dc.contributor.authorZHAO, W.
dc.contributor.authorFREEDMAN, B. I.
dc.contributor.authorSABA, Y.
dc.contributor.authorYANEK, L. R.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorCHAUHAN, Ganesh
dc.contributor.authorVAN BUCHEM, M. A.
dc.contributor.authorCUSHMAN, M.
dc.contributor.authorROYLE, N. A.
dc.contributor.authorBRYAN, R. N.
dc.contributor.authorNIESSEN, W. J.
dc.contributor.authorWINDHAM, B. G.
dc.contributor.authorDESTEFANO, A. L.
dc.contributor.authorHABES, M.
dc.contributor.authorHECKBERT, S. R.
dc.contributor.authorPALMER, N. D.
dc.contributor.authorLEWIS, C. E.
dc.contributor.authorEIRIKSDOTTIR, G.
dc.contributor.authorMAILLARD, P.
dc.contributor.authorMATHIAS, R. A.
dc.contributor.authorHOMUTH, G.
dc.contributor.authorVALDES-HERNANDEZ, M. D. C.
dc.contributor.authorDIVERS, J.
dc.contributor.authorBEISER, A. S.
dc.contributor.authorLANGNER, S.
dc.contributor.authorRICE, K. M.
dc.contributor.authorBASTIN, M. E.
dc.contributor.authorYANG, Q.
dc.contributor.authorMALDJIAN, J. A.
dc.contributor.authorSTARR, J. M.
dc.contributor.authorSIDNEY, S.
dc.contributor.authorRISACHER, S. L.
dc.contributor.authorUITTERLINDEN, A. G.
dc.contributor.authorGUDNASON, V. G.
dc.contributor.authorNAUCK, M.
dc.contributor.authorROTTER, J. I.
dc.contributor.authorSCHREINER, P. J.
dc.contributor.authorBOERWINKLE, E.
dc.contributor.authorVAN DUIJN, C. M.
dc.contributor.authorMAZOYER, Bernard
dc.contributor.authorVON SARNOWSKI, B.
dc.contributor.authorGOTTESMAN, R. F.
dc.contributor.authorLEVY, D.
dc.contributor.authorSIGURDSSON, S.
dc.contributor.authorVERNOOIJ, M. W.
dc.contributor.authorTURNER, S. T.
dc.contributor.authorSCHMIDT, R.
dc.contributor.authorWARDLAW, J. M.
dc.contributor.authorPSATY, B. M.
dc.contributor.authorMOSLEY, T. H.
dc.contributor.authorDECARLI, C. S.
dc.contributor.authorSAYKIN, A. J.
dc.contributor.authorBOWDEN, D. W.
dc.contributor.authorBECKER, D. M.
dc.contributor.authorDEARY, I. J.
dc.contributor.authorSCHMIDT, H.
dc.contributor.authorKARDIA, S. L. R.
dc.contributor.authorIKRAM, M. A.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDEBETTE, Stephanie
dc.contributor.authorGRABE, H. J.
dc.contributor.authorLONGSTRETH, W. T., Jr.
dc.contributor.authorSESHADRI, Sudha
dc.contributor.authorLAUNER, L. J.
dc.contributor.authorFORNAGE, M.
dc.date.accessioned2020-11-23T08:54:24Z
dc.date.available2020-11-23T08:54:24Z
dc.date.issued2018-08
dc.identifier.issn1524-4628 (Electronic) 0039-2499 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/15561
dc.description.abstractEnBACKGROUND 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 approximately 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<6x10(-7)). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5x10(-8)) partially independent of known common signal (PEA(conditional)=1.4x10(-3)). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9x10(-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=2.8x10(-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.
dc.language.isoENen_US
dc.subject.enVINTAGE
dc.title.enExome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging
dc.title.alternativeStrokeen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1161/strokeaha.118.020689en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed30002152en_US
bordeaux.journalStrokeen_US
bordeaux.page1812-1819en_US
bordeaux.volume49en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - U1219en_US
bordeaux.issue8en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.teamVINTAGEen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.exportfalse
bordeaux.COinSctx_ver=Z39.88-2004&amp;rft_val_fmt=info:ofi/fmt:kev:mtx:journal&amp;rft.jtitle=Stroke&amp;rft.date=2018-08&amp;rft.volume=49&amp;rft.issue=8&amp;rft.spage=1812-1819&amp;rft.epage=1812-1819&amp;rft.eissn=1524-4628%20(Electronic)%200039-2499%20(Linking)&amp;rft.issn=1524-4628%20(Electronic)%200039-2499%20(Linking)&amp;rft.au=JIAN,%20X.&amp;SATIZABAL,%20C.%20L.&amp;SMITH,%20A.%20V.&amp;WITTFELD,%20K.&amp;BIS,%20J.%20C.&amp;rft.genre=article


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