Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities
Authors: Armstrong Nicola J. , Mather Karen A. , Sargurupremraj Muralidharan , Knol Maria J. , Malik Rainer , Satizabal Claudia L. , Yanek Lisa R. , Wen Wei , Gudnason Vilmundur G. , Dueker Nicole D. , Elliott Lloyd T. , Hofer Edith , Bis Joshua , Jahanshad Neda , Li Shuo , Logue Mark A. , Luciano Michelle , Scholz Markus , Smith Albert V. , Trompet Stella , Vojinovic Dina , Xia Rui , Alfaro-Almagro Fidel , Ames David , Amin Najaf , Amouyel Philippe , Beiser Alexa S. , Brodaty Henry , Deary Ian J. , Fennema-Notestine Christine , Gampawar Piyush G. , Gottesman Rebecca , Griffanti Ludovica , Jack Clifford R. , Jenkinson Mark , Jiang Jiyang , Kral Brian G. , Kwok John B. , Lampe Leonie , C.M. Liewald David , Maillard Pauline , Marchini Jonathan , Bastin Mark E. , Mazoyer Bernard , Pirpamer Lukas , Rafael Romero José , Roshchupkin Gennady V. , Schofield Peter R. , Schroeter Matthias L. , Stott David J. , Thalamuthu Anbupalam , Trollor Julian , Tzourio Christophe , van der Grond Jeroen , Vernooij Meike W. , Witte Veronica A. , Wright Margaret J. , Yang Qiong , Morris Zoe , Siggurdsson Siggi , Psaty Bruce , Villringer Arno , Schmidt Helena , Haberg Asta K. , van Duijn Cornelia M. , Jukema J. Wouter , Dichgans Martin , Sacco Ralph L. , Wright Clinton B. , Kremen William S. , Becker Lewis C. , Thompson Paul M. , Mosley Thomas H. , Wardlaw Joanna M. , Ikram M. Arfan , Adams Hieab H.H. , Seshadri Sudha , Sachdev Perminder S. , Smith Stephen M. , Launer Lenore , Longstreth William , DeCarli Charles , Schmidt Reinhold , Fornage Myriam , Debette Stephanie , Nyquist Paul A. 
Published: June 2020

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 (
NBEAL
), 10q23.1 (
TSPAN14/FAM231A
), and 10q24.33 (
SH3PXD2A).
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 (
NOS3
) 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:
CALCRL
(2q32.1),
KLHL24
(3q27.1),
VCAN
(5q27.1), and
POLR2F
(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.