Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities

Abstract

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, β = −0.74, standard error (SE) = 0.13, P = 9.7 × 10−9]. Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10−6, false discovery rate = 0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204–364; β = 0.79, SE = 0.14, P = 9.4 × 10−8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by ∼11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (β = 0.26, SE = 0.02, P = 2.9 × 10−59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (β = 0.44, SE = 0.14, P = 0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (P = 1.5 × 10−4, false discovery rate = 0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (odds ratio = 12.24, 95%CI: 2.54–35.25; P = 8.3 × 10−5]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population.

Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates

“…Still, the precise mechanisms linking HTRA1 to vascular degeneration in CAA type 1 remain unknown. Notably, a recent large-scale sequencing study in the general population has uncovered an association of rare loss-of-function HTRA1 variants with white matter lesion volume, a quantitative marker of cerebral SVD, indicating a potential role of HTRA1 also in sporadic SVD forms [ 37 ].…”

Clinically reversible ustekinumab-induced encephalopathy: case report and review of the literature

“… 8 , 27 It is important to note that rare variants in HTRA1 have been associated with increased white matter hyperintensity burden on MRI but with a pattern typical of small vessel disease. 28 Nevertheless, we cannot rule out whether the genetic variant of our patient on a gene associated with cerebral small vessel and white matter disease could have provided an increased susceptibility to ustekinumab-induced clinical manifestations.…”

Stroke Genetics: Discovery, Insight Into Mechanisms, and Clinical Perspectives

“…Autosomal dominant HTRA1 is rarer than CADASIL but typical mutations have been reported in as many as 1 in 275 individuals in UK Biobank. 34 Therefore, it appears as if monogenic cSVD mutations are much more common than previously appreciated and may play a role in the burden of apparently sporadic SVD.…”