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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&amp;gt;C, \u03b2\u2009=\u2009\u22120.74, standard error (SE)\u2009=\u20090.13, P\u2009=\u20099.7 \u00d7 10\u22129].<\/jats:p>\n                  <jats:p>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\u2009=\u20095.5 \u00d7 10\u22126, false discovery rate\u2009=\u20090.04). 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\u2013364; \u03b2\u2009=\u20090.79, SE\u2009=\u20090.14, P\u2009=\u20099.4 \u00d7 10\u22128). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by \u223c11\u2009years in carriers of a rare protease domain variant.<\/jats:p>\n                  <jats:p>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 (\u03b2\u2009=\u20090.26, SE\u2009=\u20090.02, P\u2009=\u20092.9 \u00d7 10\u221259) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (\u03b2\u2009=\u20090.44, SE\u2009=\u20090.14, P\u2009=\u20090.002). 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\u2009=\u20091.5 \u00d7 10\u22124, false discovery rate\u2009=\u20090.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries.<\/jats:p>\n                  <jats:p>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\u2009=\u200912.24, 95%CI: 2.54\u201335.25; P\u2009=\u20098.3 \u00d7 10\u22125]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population.<\/jats:p>","DOI":"10.1093\/brain\/awab253","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T08:16:49Z","timestamp":1625559409000},"page":"2670-2682","source":"Crossref","is-referenced-by-count":47,"title":["Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-2520","authenticated-orcid":false,"given":"Rainer","family":"Malik","sequence":"first","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Beaufort","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Frerich","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benno","family":"Gesierich","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3507-3659","authenticated-orcid":false,"given":"Marios K","family":"Georgakis","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2384-7568","authenticated-orcid":false,"given":"Kristiina","family":"Rannikm\u00e4e","sequence":"additional","affiliation":[{"name":"Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh EH16 4TL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy C","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh EH16 4TL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9823-3528","authenticated-orcid":false,"given":"Christof","family":"Haffner","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6624-8621","authenticated-orcid":false,"given":"Matthew","family":"Traylor","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK"},{"name":"The Barts Heart Centre and NIHR Barts Biomedical Research Centre - Barts Health NHS Trust, The William Harvey Research Institute, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ehrmann","sequence":"additional","affiliation":[{"name":"Center of Medical Biotechnology, Faculty of Biology, University Duisburg-Essen, Essen 45141, Germany"},{"name":"School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7725-7520","authenticated-orcid":false,"given":"Cathie L 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