Genes from a translational analysis support a multifactorial nature of white matter hyperintensities

Lorna M Lopez; W David Hill; Sarah E Harris; Maria Valdes Hernandez; Susana Munoz Maniega; Mark E Bastin; Emma Bailey; Colin Smith; Martin McBride; John McClure; Delyth Graham; Anna Dominiczak; Qiong Yang; Myriam Fornage; M Arfan Ikram; Stephanie Debette; Lenore Launer; Joshua C Bis; Reinhold Schmidt; Sudha Seshadri; David J Porteous; John Starr; Ian J Deary; Joanna M Wardlaw

doi:10.1161/STROKEAHA.114.007649

Genes from a translational analysis support a multifactorial nature of white matter hyperintensities

Stroke. 2015 Feb;46(2):341-7. doi: 10.1161/STROKEAHA.114.007649. Epub 2015 Jan 13.

Authors

Lorna M Lopez¹, W David Hill¹, Sarah E Harris¹, Maria Valdes Hernandez¹, Susana Munoz Maniega¹, Mark E Bastin¹, Emma Bailey¹, Colin Smith¹, Martin McBride¹, John McClure¹, Delyth Graham¹, Anna Dominiczak¹, Qiong Yang¹, Myriam Fornage¹, M Arfan Ikram¹, Stephanie Debette¹, Lenore Launer¹, Joshua C Bis¹, Reinhold Schmidt¹, Sudha Seshadri¹, David J Porteous¹, John Starr¹, Ian J Deary¹, Joanna M Wardlaw¹

Affiliation

¹ From the Centre for Cognitive Ageing and Cognitive Epidemiology (L.M.L., M.V.H., S.M.M., M.E.B., J.S., I.J.D., J.M.W.), Division of Neuroimaging Sciences, Brain Research Imaging Centre, (M.V.H., S.M.M., M.E.B., J.M.W.) and Academic Neuropathology (C.S.), Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (W.D.H., S.E.H., D.J.P.); Department of Bioengineering, Imperial College London, London, United Kingdom (E.B.); BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (M.M., J.M., D.G., A.D.); Department of Biostatistics, Boston University School of Public Health, MA (Q.Y.); The Framingham Heart Study, Boston, MA (Q.Y., S.S.); The Human Genetics Center and Institute of Molecular Medicine, The University of Texas Health Science Center, Houston (M.F.); Departments of Epidemiology, Radiology and Neurology, Erasmus Medical Center, Rotterdam, The Netherlands (M.A.I.); Netherlands Consortium for Healthy Aging, Leiden, The Netherlands (M.A.I.); 12 INSERM U740 (Paris 7 University) and U708 (Bordeaux University), Bordeaux, France (S.D.); Department of Neurology, Lariboisière Hospital, 7 University, DHU Neurovasc Paris Sorbonne, Paris, France (S.D.); University of Versailles Saint-Quentin-en-Yvelines, Versailles, France (S.D.); Department of Neurology, Boston University School of Medicine, MA (S.D., S.S.); Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD (L.L.); Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle (J.C.B.); and Clinical Division of Neurogeri

Abstract

Background and purpose: White matter hyperintensities (WMH) of presumed vascular origin increase the risk of stroke and dementia. Despite strong WMH heritability, few gene associations have been identified. Relevant experimental models may be informative.

Methods: We tested the associations between genes that were differentially expressed in brains of young spontaneously hypertensive stroke-prone rats and human WMH (using volume and visual score) in 621 subjects from the Lothian Birth Cohort 1936 (LBC1936). We then attempted replication in 9361 subjects from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE). We also tested the subjects from LBC1936 for previous genome-wide WMH associations found in subjects from CHARGE.

Results: Of 126 spontaneously hypertensive stroke-prone rat genes, 10 were nominally associated with WMH volume or score in subjects from LBC1936, of which 5 (AFP, ALB, GNAI1, RBM8a, and MRPL18) were associated with both WMH volume and score (P<0.05); 2 of the 10 (XPNPEP1, P=6.7×10(-5); FARP1, P=0.024) plus another spontaneously hypertensive stroke-prone rat gene (USMG5, P=0.00014), on chromosomes 10, 13, and 10 respectively, were associated with WMH in subjects from CHARGE. Gene set enrichment showed significant associations for downregulated spontaneously hypertensive stroke-prone rat genes with WMH in humans. In subjects from LBC1936, we replicated CHARGE's genome-wide WMH associations on chromosomes 17 (TRIM65 and TRIM47) and, for the first time, 1 (PMF1).

Conclusions: Despite not passing multiple testing thresholds individually, these genes collectively are relevant to known WMH associations, proposed WMH mechanisms, or dementia: associations with Alzheimer's disease, late-life depression, ATP production, osmotic regulation, neurodevelopmental abnormalities, and cognitive impairment. If replicated further, they suggest a multifactorial nature for WMH and argue for more consideration of vascular contributions to dementia.

Keywords: genetics; humans; leukoencephalopathies; magnetic resonance imaging.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / diagnosis
Alzheimer Disease / epidemiology
Alzheimer Disease / genetics
Animals
Brain / pathology
Causality
Dementia / diagnosis
Dementia / epidemiology
Dementia / genetics
Female
Genome-Wide Association Study / methods*
Humans
Leukoencephalopathies / diagnosis*
Leukoencephalopathies / epidemiology
Leukoencephalopathies / genetics*
Male
Polymorphism, Single Nucleotide / genetics*
Rats
Rats, Inbred SHR
Rats, Wistar
Risk Factors
Translational Research, Biomedical / methods*
White Matter / pathology*

Abstract

Publication types

MeSH terms

Grants and funding