|Title||Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Armstrong NJ, Mather KA, Sargurupremraj M, Knol MJ, Malik R, Satizabal CL, Yanek LR, Wen W, Gudnason VG, Dueker ND, Elliott LT, Hofer E, Bis J, Jahanshad N, Li S, Logue MA, Luciano M, Scholz M, Smith AV, Trompet S, Vojinovic D, Xia R, Alfaro-Almagro F, Ames D, Amin N, Amouyel P, Beiser AS, Brodaty H, Deary IJ, Fennema-Notestine C, Gampawar PG, Gottesman R, Griffanti L, Jack CR, Jenkinson M, Jiang J, Kral BG, Kwok JB, Lampe L, Liewald DCM, Maillard P, Marchini J, Bastin ME, Mazoyer B, Pirpamer L, Romero JRafael, Roshchupkin GV, Schofield PR, Schroeter ML, Stott DJ, Thalamuthu A, Trollor J, Tzourio C, van der Grond J, Vernooij MW, Witte VA, Wright MJ, Yang Q, Morris Z, Siggurdsson S, Psaty B, Villringer A, Schmidt H, Håberg AK, van Duijn CM, J Jukema W, Dichgans M, Sacco RL, Wright CB, Kremen WS, Becker LC, Thompson PM, Mosley TH, Wardlaw JM, M Ikram A, Adams HHH, Seshadri S, Sachdev PS, Smith SM, Launer L, Longstreth W, DeCarli C, Schmidt R, Fornage M, Debette S, Nyquist PA|
|Date Published||2020 07|
|Keywords||Aged, Brain, Cerebral Small Vessel Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, White Matter|
BACKGROUND AND PURPOSE: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.
METHODS: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.
RESULTS: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (), 10q23.1 (), and 10q24.33 ( In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 () and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: (2q32.1), (3q27.1), (5q27.1), and (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.
CONCLUSIONS: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
|PubMed Central ID||PMC7365038|
|Grant List||P41 EB015922 / EB / NIBIB NIH HHS / United States |
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
MR/R024065/1 / MRC_ / Medical Research Council / United Kingdom
MR/N027558/1 / MRC_ / Medical Research Council / United Kingdom
U54 EB020403 / EB / NIBIB NIH HHS / United States
G0701120 / MRC_ / Medical Research Council / United Kingdom
MR/L023784/2 / MRC_ / Medical Research Council / United Kingdom
R01 NS062059 / NS / NINDS NIH HHS / United States
MR/M013111/1 / MRC_ / Medical Research Council / United Kingdom
G1001245 / MRC_ / Medical Research Council / United Kingdom
J-0901 / PUK_ / Parkinson's UK / United Kingdom
R56 AG058854 / AG / NIA NIH HHS / United States
G0700704 / MRC_ / Medical Research Council / United Kingdom
/ WT_ / Wellcome Trust / United Kingdom
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
R01 AG022381 / AG / NIA NIH HHS / United States
R01 AG050595 / AG / NIA NIH HHS / United States
R01 AG059874 / AG / NIA NIH HHS / United States