Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities

Abstract

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.

An incomplete Circle of Willis is not a risk factor for white matter hyperintensities: The Tromsø Study

“…As expected, some of the WMH risk factors were associated with increased DWMH and PWMH. Interestingly, diabetes was only associated with increased PWMH, lending support to the notion that DWMH and PWMH have differing aetiology [2,43]. Also, vascular risk factors, age and gender explained 45.8% of the variance in PWMH, while only 16.7% of the variance of DWMH, suggesting that PWMH is more closely associated with cerebrovascular disease than DWMH.…”

“…Despite diverging results from prior studies, there is evidence suggesting that an incomplete CoW may be a risk factor for WMH possibly via impaired autoregulation of cerebral blood flow [19] which has been shown to be associated with WMH [33]. Furthermore, PWMH is more strongly associated with cerebral blood flow [43], blood pressure [17] and vasculature in general [2] than DWMH. Therefore, PWMH may be more sensitive to variations in the CoW than DWMH, and this may in part explain possible diverging findings relating to WMH and anatomical variants of the CoW.…”

An incomplete Circle of Willis is not a risk factor for white matter hyperintensities: The Tromsø Study

“…As expected, some of the WMH risk factors were associated with increased DWMH and PWMH. Interestingly, diabetes was only associated with increased PWMH, lending support to the notion that DWMH and PWMH have differing aetiology (Armstrong et al, 2020;ten Dam et al, 2007). Also, vascular risk factors, age and gender explained 45.8% of the variance All rights reserved.…”

Association between polygenic risk for Alzheimer’s disease, brain structure and cognitive abilities in UK Biobank.

“…This could be due to vascular risk factors and diseases which tend to be associated with development of WMH, and comorbid with dementias, rather than WMH being linked to dementia directly and in isolation 19 . Armstrong et al 20 conducted a GWAS for periventricular WMH and deep WMH and found that candidate WMH loci were implicated in stroke, vascular and neuronal functions, but not dementia in isolation. This raises the concern of differentiating LOAD markers from non-LOAD markers such as vascular dementias, which is difficult as AD refers to an aggregate of neuropathological changes assessed postmortem .…”