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 WMH volume, the contribution of rare variants to WMH burden in the general population remains largely unexplored.
We conducted a comprehensive analysis of WMH burden in the UK Biobank using publicly available whole-exome sequencing data (N=16,511)
Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 to associate with increased WMH volume (p=5.5E-6). Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (p=9.4E-8). The frequency of such variants in the UK Biobank population was 1 in 450. WMH volume was brought forward by approximately 11 years in carriers of a rare protease domain variant. A comparison with established risk factors revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than being in the upper 99.8% percentile of a polygenic risk score based on common genetic variants. In biochemical experiments, most (6/9) of the identified protease domain variants resulted in reduced protease activity. We further found EGFL8 to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries.
Collectively, these findings highlight an important role of rare genetic variation and of the HTRA1 protease in determining WMH burden in the general population.