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 | |
| State | Published - Apr 1 2019 |
| Externally published | Yes |
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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Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. / Mishra, Aniket; Chauhan, Ganesh; Violleau, Marie Helene; Vojinovic, Dina; Jian, Xueqiu; Bis, Joshua C.; Li, Shuo; Saba, Yasaman; Grenier-Boley, Benjamin; Yang, Qiong; Bartz, Traci M.; Hofer, Edith; Soumaré, Aïcha; Peng, Fen; Duperron, Marie Gabrielle; Foglio, Mario; Mosley, Thomas H.; Schmidt, Reinhold; Psaty, Bruce M.; Launer, Lenore J.; Boerwinkle, Eric; Zhu, Yicheng; Mazoyer, Bernard; Lathrop, Mark; Bellenguez, Celine; Van Duijn, Cornelia M.; Arfan Ikram, M.; Schmidt, Helena; Longstreth, W. T.; Fornage, Myriam; Seshadri, Sudha; Joutel, Anne; Tzourio, Christophe; Debette, Stephanie.
In: Brain, Vol. 142, No. 4, 01.04.2019, p. 1009-1023.Research output: Contribution to journal › Article › peer-review
}
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
N1 - Funding Information: The Austrian Stroke Prevention Study (ASPS): The research reported in this article was funded by the Austrian Science Fund (FWF) grant number P20545-P05, P13180 and P20545-B05, by the Austrian National Bank Anniversary Fund, P15435, and the Austrian Ministry of Science under the aegis of the EU Joint Programme - Neurodegenerative Disease Research (JPND) www.jpnd.eu received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643417. Funding Information: Funding support for ‘Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium’ was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Data for ‘Building on GWAS for NHLBI-diseases: the U.S. CHARGE Consortium’ were provided by Eric Boerwinkle on behalf of the Atherosclerosis Risk in Communities (ARIC) Study, L. Adrienne Cupples, principal investigator for the Framingham Heart Study, and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was carried out at the Baylor Genome Center (U54 HG003273). Funding Information: The Rotterdam Study: The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911–03–012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014– 93–015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050–060–810. The Exome Sequencing dataset was funded by the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) sponsored Netherlands Consortium for Healthy Aging (NCHA; project nr. 050–060–810), by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the and by a Complementation Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl; project number CP2010–41). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Funding Information: The Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contracts No. N01-HC-25195 and No. HHSN268201500001I), and its contract with Affymetrix, Inc. for genotyping services (Contract No. N02-HL-6–4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study was also supported by grants from the National Institute of Aging (R01s AG033040, AG033193, AG054076, AG049607, AG008122, and U01-AG049505) and the National Institute of Neurological Disorders and Stroke (R01-NS017950, UH2 NS100605). Funding Information: The Three City Study: The Three City (3C) Study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Bordeaux, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Programme ‘Cohortes et collections de données biologiques.’ C.T. and S.D. have received investigator-initiated research funding from the French National Research Agency (OPE-2016-0500) and from the Fondation Leducq (12CVD01). This work was supported by the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille, the Centre National de Génotypage, the French government’s LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer’s disease), and the GENMED labex. Funding Information: This project is supported by the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of SVD of the Brain) and is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND www.jpnd.eu: Australia, National Health and Medical Research Council, Austria, Federal Ministry of Science, Research and Economy; Canada, Canadian Institutes of Health Research; France, French National Research Agency; Germany, Federal Ministry of Education and Research; Netherlands, The Netherlands Organisation for Health Research and Development; United Kingdom, Medical Research Council. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643417. This project has also received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 640643. This project has received funding from European Union’s Horizon 2020 research and innovation programme under grant agreement No 667375. Computations were performed on the Bordeaux Bioinformatics Center (CBiB) computer resources, Université de Bordeaux. Funding support for additional computer resources has been provided to S.D. by the Fondation Claude Pompidou. Funding Information: The Atherosclerosis Risk in Communities study: The Atherosclerosis Risk in Communities study (ARIC) was performed as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HSN268201100006C, HSN26 8201100007C, HHSN268201100008C, HHSN2682011 00009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL70825, R01HL087 641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health (NIH) contract HHSN268200625226C. Infrastructure was partly supported by grant No. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This project was also supported by NIH R01 grant NS087541 to M.F. Funding Information: The Cardiovascular Health Study: The Cardiovascular Health study (CHS) research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN 268201800001C, N01HC55222, N01HC85079, N01HC 85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC15103, and HHSN2682009 60009C and grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL 085251, and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI) with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 and R01AG033193 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at chs-nhlbi.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2019 The Author(s).
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
UR - http://www.scopus.com/inward/record.url?scp=85064239977&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064239977&partnerID=8YFLogxK
U2 - 10.1093/brain/awz024
DO - 10.1093/brain/awz024
M3 - Article
C2 - 30859180
AN - SCOPUS:85064239977
VL - 142
SP - 1009
EP - 1023
JO - Brain
JF - Brain
SN - 0006-8950
IS - 4
ER -