Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects

Aniket Mishra; Ganesh Chauhan; Marie Helene Violleau; Dina Vojinovic; Xueqiu Jian; Joshua C. Bis; Shuo Li; Yasaman Saba; Benjamin Grenier-Boley; Qiong Yang; Traci M. Bartz; Edith Hofer; Aïcha Soumaré; Fen Peng; Marie Gabrielle Duperron; Mario Foglio; Thomas H. Mosley; Reinhold Schmidt; Bruce M. Psaty; Lenore J. Launer; Eric Boerwinkle; Yicheng Zhu; Bernard Mazoyer; Mark Lathrop; Celine Bellenguez; Cornelia M. Van Duijn; M. Arfan Ikram; Helena Schmidt; W. T. Longstreth; Myriam Fornage; Sudha Seshadri; Anne Joutel; Christophe Tzourio; Stephanie Debette

doi:10.1093/brain/awz024

Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects

Aniket Mishra, Ganesh Chauhan, Marie Helene Violleau, Dina Vojinovic, Xueqiu Jian, Joshua C. Bis, Shuo Li, Yasaman Saba, Benjamin Grenier-Boley, Qiong Yang, Traci M. Bartz, Edith Hofer, Aïcha Soumaré, Fen Peng, Marie Gabrielle Duperron, Mario Foglio, Thomas H. Mosley, Reinhold Schmidt, Bruce M. Psaty, Lenore J. LaunerEric Boerwinkle, Yicheng Zhu, Bernard Mazoyer, Mark Lathrop, Celine Bellenguez, Cornelia M. Van Duijn, M. Arfan Ikram, Helena Schmidt, W. T. Longstreth, Myriam Fornage, Sudha Seshadri, Anne Joutel, Christophe Tzourio, Stephanie Debette

Research output: Contribution to journal › Article › peer-review

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Abstract

We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 10^-5, Preplication = 5.25 10^-3, Pcombined = 4.72 10^-5) and of NOTCH3 using genebased tests (Pdiscovery = 1.61 10^-2, Preplication = 3.99 10^-2, Pcombined = 5.31 10^-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

Original language	English (US)
Pages (from-to)	1009-1023
Number of pages	15
Journal	Brain
Volume	142
Issue number	4
DOIs	https://doi.org/10.1093/brain/awz024
State	Published - Apr 1 2019

Keywords

Cerebral small vessel disease
Exome sequencing study
Extreme phenotype
Lacunes of presumed vascular origin
White matter hyperintensity

ASJC Scopus subject areas

Clinical Neurology

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10.1093/brain/awz024

Cite this

Mishra, A., Chauhan, G., Violleau, M. H., Vojinovic, D., Jian, X., Bis, J. C., Li, S., Saba, Y., Grenier-Boley, B., Yang, Q., Bartz, T. M., Hofer, E., Soumaré, A., Peng, F., Duperron, M. G., Foglio, M., Mosley, T. H., Schmidt, R., Psaty, B. M., ... Debette, S. (2019). Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. Brain, 142(4), 1009-1023. https://doi.org/10.1093/brain/awz024

Mishra, A, Chauhan, G, Violleau, MH, Vojinovic, D, Jian, X, Bis, JC, Li, S, Saba, Y, Grenier-Boley, B, Yang, Q, Bartz, TM, Hofer, E, Soumaré, A, Peng, F, Duperron, MG, Foglio, M, Mosley, TH, Schmidt, R, Psaty, BM, Launer, LJ, Boerwinkle, E, Zhu, Y, Mazoyer, B, Lathrop, M, Bellenguez, C, Van Duijn, CM, Arfan Ikram, M, Schmidt, H, Longstreth, WT, Fornage, M, Seshadri, S, Joutel, A, Tzourio, C & Debette, S 2019, 'Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects', Brain, vol. 142, no. 4, pp. 1009-1023. https://doi.org/10.1093/brain/awz024

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title = "Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects",

abstract = "We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 10-5, Preplication = 5.25 10-3, Pcombined = 4.72 10-5) and of NOTCH3 using genebased tests (Pdiscovery = 1.61 10-2, Preplication = 3.99 10-2, Pcombined = 5.31 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.",

keywords = "Cerebral small vessel disease, Exome sequencing study, Extreme phenotype, Lacunes of presumed vascular origin, White matter hyperintensity",

author = "Aniket Mishra and Ganesh Chauhan and Violleau, {Marie Helene} and Dina Vojinovic and Xueqiu Jian and Bis, {Joshua C.} and Shuo Li and Yasaman Saba and Benjamin Grenier-Boley and Qiong Yang and Bartz, {Traci M.} and Edith Hofer and A{\"i}cha Soumar{\'e} and Fen Peng and Duperron, {Marie Gabrielle} and Mario Foglio and Mosley, {Thomas H.} and Reinhold Schmidt and Psaty, {Bruce M.} and Launer, {Lenore J.} and Eric Boerwinkle and Yicheng Zhu and Bernard Mazoyer and Mark Lathrop and Celine Bellenguez and {Van Duijn}, {Cornelia M.} and {Arfan Ikram}, M. and Helena Schmidt and Longstreth, {W. T.} and Myriam Fornage and Sudha Seshadri and Anne Joutel and Christophe Tzourio and Stephanie Debette",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2019",

month = apr,

day = "1",

doi = "10.1093/brain/awz024",

language = "English (US)",

volume = "142",

pages = "1009--1023",

journal = "Brain",

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TY - JOUR

T1 - Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects

AU - Mishra, Aniket

AU - Chauhan, Ganesh

AU - Violleau, Marie Helene

AU - Vojinovic, Dina

AU - Jian, Xueqiu

AU - Bis, Joshua C.

AU - Li, Shuo

AU - Saba, Yasaman

AU - Grenier-Boley, Benjamin

AU - Yang, Qiong

AU - Bartz, Traci M.

AU - Hofer, Edith

AU - Soumaré, Aïcha

AU - Peng, Fen

AU - Duperron, Marie Gabrielle

AU - Foglio, Mario

AU - Mosley, Thomas H.

AU - Schmidt, Reinhold

AU - Psaty, Bruce M.

AU - Launer, Lenore J.

AU - Boerwinkle, Eric

AU - Zhu, Yicheng

AU - Mazoyer, Bernard

AU - Lathrop, Mark

AU - Bellenguez, Celine

AU - Van Duijn, Cornelia M.

AU - Arfan Ikram, M.

AU - Schmidt, Helena

AU - Longstreth, W. T.

AU - Fornage, Myriam

AU - Seshadri, Sudha

AU - Joutel, Anne

AU - Tzourio, Christophe

AU - Debette, Stephanie

PY - 2019/4/1

Y1 - 2019/4/1

N2 - We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 10-5, Preplication = 5.25 10-3, Pcombined = 4.72 10-5) and of NOTCH3 using genebased tests (Pdiscovery = 1.61 10-2, Preplication = 3.99 10-2, Pcombined = 5.31 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

AB - We report a composite extreme phenotype design using distribution of white matter hyperintensities and brain infarcts in a population-based cohort of older persons for gene-mapping of cerebral small vessel disease. We demonstrate its application in the 3C-Dijon whole exome sequencing (WES) study (n = 1924, nWESextremes = 512), with both single variant and gene-based association tests. We used other population-based cohort studies participating in the CHARGE consortium for replication, using whole exome sequencing (nWES = 2,868, nWESextremes = 956) and genome-wide genotypes (nGW = 9924, nGWextremes = 3308). We restricted our study to candidate genes known to harbour mutations for Mendelian small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2 and TREX1. We identified significant associations of a common intronic variant in HTRA1, rs2293871 using single variant association testing (Pdiscovery = 8.21 10-5, Preplication = 5.25 10-3, Pcombined = 4.72 10-5) and of NOTCH3 using genebased tests (Pdiscovery = 1.61 10-2, Preplication = 3.99 10-2, Pcombined = 5.31 10-3). Follow-up analysis identified significant association of rs2293871 with small vessel ischaemic stroke, and two blood expression quantitative trait loci of HTRA1 in linkage disequilibrium. Additionally, we identified two participants in the 3C-Dijon cohort (0.4%) carrying heterozygote genotypes at known pathogenic variants for familial small vessel disease within NOTCH3 and HTRA1. In conclusion, our proof-of-concept study provides strong evidence that using a novel composite MRI-derived phenotype for extremes of small vessel disease can facilitate the identification of genetic variants underlying small vessel disease, both common variants and those with rare and low frequency. The findings demonstrate shared mechanisms and a continuum between genes underlying Mendelian small vessel disease and those contributing to the common, multifactorial form of the disease.

KW - Cerebral small vessel disease

KW - Exome sequencing study

KW - Extreme phenotype

KW - Lacunes of presumed vascular origin

KW - White matter hyperintensity

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Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects

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