Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 8, Issue 2, Pages 398-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.114.000858
Keywords
cerebral small vessel diseases; cerebrovascular disorders; genome-wide association study; hypertension; leukoencephalopathies; polymorphisms, single nucleotide
Funding
- National Institutes of Health (NIH) [N01-AG-1-2100]
- National Institute on Aging (NIA) Intramural Research Program
- Althingi (the Icelandic Parliament)
- National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HSN268201100006C, HSN26820 1100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN26820-1100011C, HHSN26820 1100012C, R01HL70825, R01HL087641, R01HL59367, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- NIH [HHSN268200625226C]
- NIH Roadmap for Medical Research
- NIH R01 grants [HL084099, NS087541]
- Austrian Science Fond (FWF) [P20545-P05, P13180]
- NHLBI [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, HHSN26820 0960009C, N01HC15103, HL080295, HL087652, HL105756, HL103612, HL120393]
- NIA [AG023629, AG15928]
- National Center for Advancing Translational Sciences
- CTSI grant [UL1TR000124]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center [DK063491]
- NIH grant [R01-AG-09966, R01-AG-11101, R01-AG-030146]
- University of Alabama at Birmingham [HHSN268201300025C, HHSN268201300026C]
- Northwestern University [HHSN268201300027C]
- University of Minnesota [HHSN268201300028C]
- Kaiser Foundation Research Institute [HHSN268201300029C]
- Johns Hopkins University School of Medicine [HHSN268200900041C]
- Intramural Research Program of the National Institute on Aging (NIA)
- National Institutes of Health R01 grants [HL084099, NS087541]
- National Medical Research Council [0796/2003, IRG07nov013, IRG09nov014, STaR/0003/2008, CG/SERI/2010]
- Biomedical Research Council, Singapore [09/1/35/19/616]
- National Medical Research Council, Singapore [R-184-006-184-511]
- Singapore Ministry of Health's National Medical Research Council [NMRC/CSA/038/2013]
- European Commission FP6 STRP grant [018947, LSHG-CT-2006-01947]
- European Community's Seventh Framework Programme [HEALTH-F4-2007-201413]
- European Commission under the programme Quality of Life and Management of the Living Resources of 5th Framework Programme [QLG2-CT-2002-01254]
- Netherlands Organisation for Scientific Research
- Russian Foundation for Basic Research [NWO-RFBR 047.017.043]
- NHLBI's Framingham Heart Study [N01-HC-25195]
- Affymetrix, Inc [N02-HL-6-4278]
- National Institute of Neurological Disorders and Stroke [R01 NS17950]
- National Institute of Aging [P30 AG10129, R01s AG033193, AG08122, AG16495]
- National Institute of Neurological Disorders and Stroke of the NIH [NS041558]
- European Union's Seventh Framework Programme [259679]
- Innovation-Oriented Research Program on Genomics [SenterNovem IGE05007]
- Centre for Medical Systems Biology
- Netherlands Consortium for Healthy Ageing [050-060-810]
- Netherlands Genomics Initiative
- Netherlands Organization for Scientific Research (NWO)
- UnileverColworth
- BBMRI-NL, a Research Infrastructure - Dutch government (NWO) [184.021.007]
- Age UK's Disconnected Mind programme
- Research Into Ageing [251, 285]
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F019394/1]
- Medical Research Council [G1001401, 8200]
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- Scottish Funding Council through the SINAPSE Collaboration
- NINDS [R37 NS29993, K02 NS 059729]
- Evelyn F. McKnight Brain Institute
- Bristol-Myers Squibb
- European commission [223004]
- Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]
- Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [014-93-015]
- Netherlands Genomics Initiative (NGI)/NWO project [050-060-810]
- Netherlands Heart Foundation [2009B102]
- Veni-grant [916.13.054]
- Erasmus Medical Center
- Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw)
- RIDE
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- German Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]
- Federal Ministry of Education and Research [03ZIK012]
- Siemens Healthcare, Erlangen, Germany
- Federal State of Mecklenburg-West Pomerania
- German Federal Ministry of Education and Research
- German Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- Fondation pour la Recherche Medicale
- Caisse Nationale Maladie des Travailleurs Salaries
- Direction Generale de la Sante
- Mutuelle Generale de l'Education Nationale
- Institut de la Longevite
- Conseils Regionaux of Aquitaine and Bourgogne
- Fondation de France
- Ministry of Research-INSERM Programme Cohortes et collections de donnees biologiques
- Eisai
- National Foundation for Alzheimer Disease and Related Disorders
- Institut Pasteur de Lille
- Centre National de Genotypage
- Washington Heights-Inwood Columbia Aging Project (WHICAP) [P01-AG007232, R01-AG037212, NIH R01-AG034189]
- Hjartavernd (the Icelandic Heart Association)
- Biotechnology and Biological Sciences Research Council [BB/F019394/1] Funding Source: researchfish
- Medical Research Council [G1001401, G0701120, G0700704, G1001245, MR/K026992/1] Funding Source: researchfish
- BBSRC [BB/F019394/1] Funding Source: UKRI
- MRC [G0701120, G1001401, G0700704, G1001245] Funding Source: UKRI
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Background-The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results-We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7x10(-19)) and identified novel loci on chr10q24 (P=1.6x10(-9)) and chr2p21 (P=4.4x10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0x10(-8)) and chr2p16 (P=1.5x10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions-We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.
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